nutrients

Review
Plant-Based Nutrition: Exploring Health Benefits for
Atherosclerosis, Chronic Diseases, and Metabolic
Syndrome—A Comprehensive Review
Humberto Peña-Jorquera 1 , Valeska Cid-Jofré 2 , Leslie Landaeta-Díaz 3,4 , Fanny Petermann-Rocha 5,6 ,
Miquel Martorell 7 , Hermann Zbinden-Foncea 8,9 , Gerson Ferrari 10,11 , Carlos Jorquera-Aguilera 12
and Carlos Cristi-Montero 1, *

1 IRyS Group, Physical Education School, Pontificia Universidad Católica de Valparaíso,

Viña del Mar 2530388, Chile; [Link]@[Link]
2 Centro de Investigación Biomédica y Aplicada (CIBAP), Escuela de Medicina, Facultad de Ciencias Médicas,
Universidad de Santiago de Chile (USACH), Santiago 9160019, Chile; [Link]@[Link]
3 Facultad de Salud y Ciencias Sociales, Universidad de las Américas, Santiago 7500975, Chile;
llandaeta@[Link]
4 Núcleo en Ciencias Ambientales y Alimentarias, Universidad de las Américas, Santiago 7500975, Chile
5 Centro de Investigación Biomédica, Facultad de Medicina, Universidad Diego Portales,
Santiago 8370068, Chile; [Link]@[Link]
6 BHF Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health,
University of Glasgow, Glasgow G12 8TA, UK
7 Department of Nutrition and Dietetics, Faculty of Pharmacy, Centre for Healthy Living,
University of Concepción, Concepción 4070386, Chile; mmartorell@[Link]
8 Laboratorio de Fisiología del Ejercicio y Metabolismo, Escuela de Kinesiología, Facultad de Medicina,
Universidad Finis Terrae, Santiago 7500000, Chile; hzbinden@[Link]
9 Facultad de Ciencias de la Salud, Universidad Francisco de Vitoria, 28223 Madrid, Spain
10 Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Av. Pedro de Valdivia 425,
Citation: Peña-Jorquera, H.; Providencia 7500912, Chile; [Link]@[Link]
11 Escuela de Ciencias de la Actividad Física, el Deporte y la Salud, Universidad de Santiago de Chile (USACH),
Cid-Jofré, V.; Landaeta-Díaz, L.;
Petermann-Rocha, F.; Martorell, M.;
Santiago 9170022, Chile
12 Escuela de Nutrición y Dietética, Facultad de Ciencias, Universidad Mayor, Santiago 8580745, Chile;
Zbinden-Foncea, H.; Ferrari, G.;
[Link]@[Link]
Jorquera-Aguilera, C.; Cristi-Montero,
* Correspondence: [Link]@[Link]
C. Plant-Based Nutrition: Exploring
Health Benefits for Atherosclerosis,
Abstract: Atherosclerosis, chronic non-communicable diseases, and metabolic syndrome are highly
Chronic Diseases, and Metabolic
Syndrome—A Comprehensive
interconnected and collectively contribute to global health concerns that reduce life expectancy and
Review. Nutrients 2023, 15, 3244. quality of life. These conditions arise from multiple risk factors, including inflammation, insulin
[Link] resistance, impaired blood lipid profile, endothelial dysfunction, and increased cardiovascular risk.
nu15143244 Adopting a plant-based diet has gained popularity as a viable alternative to promote health and miti-
gate the incidence of, and risk factors associated with, these three health conditions. Understanding
Academic Editor: Isabel Iguacel
the potential benefits of a plant-based diet for human health is crucial, particularly in the face of
Received: 14 June 2023 the rising prevalence of chronic diseases like diabetes, hypertension, dyslipidemia, atherosclerosis,
Revised: 14 July 2023 and cancer. Thus, this review focused on the plausible advantages of consuming a type of food
Accepted: 15 July 2023 pattern for the prevention and/or treatment of chronic diseases, emphasizing the dietary aspects
Published: 21 July 2023
that contribute to these conditions and the evidence supporting the benefits of a plant-based diet for
human health. To facilitate a more in-depth analysis, we present separate evidence for each of these
three concepts, acknowledging their intrinsic connection while providing a specific focus on each
Copyright: © 2023 by the authors. one. This review underscores the potential of a plant-based diet to target the underlying causes of
Licensee MDPI, Basel, Switzerland. these chronic diseases and enhance health outcomes for individuals and populations.
This article is an open access article
distributed under the terms and Keywords: vegetarian diet; plant bioactive compounds; cholesterol; hyperinsulinemia; blood
conditions of the Creative Commons pressure
Attribution (CC BY) license (https://
[Link]/licenses/by/
4.0/).

Nutrients 2023, 15, 3244. [Link] [Link]

Nutrients 2023, 15, 3244 2 of 39

1. Introduction
Many people consider a plant-based diet (PBD), which includes only plant sources
with the absence or occasionally minimal presence of processed food, a novel and even risky
eating choice. This concern is heightened by the potential deficiencies in micronutrients,
such as vitamin B12 and D, calcium, omega 3, or iron, compared to a traditional diet [1,2].
However, over the past decades, a wealth of scientific evidence has accumulated that
provides strong support for the potential health benefits of a PBD. These benefits include
the prevention of various chronic non-communicable diseases, such as type 2 diabetes [3,4],
hypertension [5–7], dyslipidemia [8,9], atherosclerosis, and cancer [10,11]. Studies on
supplementation and natural consumption approaches have demonstrated the practical
advantages of a PBD, which are attributed to the bioactive compounds present in plants,
such as catechins [12,13], anthocyanins [14,15], polyphenols [16], and phytosterols [17,18],
among others.
Metabolic syndrome (MetS) is associated with several adverse effects on human health.
Although there are various definitions, components, and criteria for MetS, they all include
visceral obesity, insulin resistance, hypertension, and dyslipidemia [19]. According to
National Cholesterol Educations Program Adult Treatment Panel ATP III, MetS is consid-
ered present when an individual meets at least three of the following five criteria: waist
circumference over 40 inches (men, or >102 cm) or 35 inches (women, or >88 cm), blood
pressure over 130/85 mmHg, fasting triglyceride level over 150 mg/dL, fasting HDL
cholesterol level less than 40 mg/dL (men) or 50 mg/dL (women), and fasting blood sugar
over 100 mg/dL [20]. Other entities even consider more demanding cut-off points [21].
Individuals with MetS have higher cardiovascular disease and all-cause mortality risk
compared to whose without MetS [22,23].
In this line, a PBD has been found to have numerous positive and protective effects
on metabolic health, significantly reducing the associated risks. For instance, Jovanovic
et al. [24] concluded that a 1-unit increase in daily servings of a healthy plant-based diet,
which excludes added sugars, refined grains, and oils, was associated with a 4% lower
risk prevalence of elevated waist circumference and MetS risk. However, not all evidence
supports these outcomes. Shang et al. [25] found that a vegan diet alone did not decrease the
risk of MetS, but the study only assessed the absence of animal foods (meat, dairy, and eggs),
not the quality of the diet. Previous research suggests that adherence to a healthful plant-
based diet, which includes increased fiber intake, plant bioactive compounds, and lower
consumption of ultra-processed foods, is associated with benefits related to MetS [26,27]. It
is worth noting that there is a vast difference in quality and health outcomes between a
healthy and an unhealthy PBD. Indeed, Li et al. [28] in 2022 established that a healthy PBD
is associated with lower mortality risk than an unhealthy PBD.
A vegan diet is often used as an equivalent to a PBD, although considerable differences
exist between these two concepts, both nutritionally and ethically [29]. While the first is
exclusively related to selecting food for ethical reasons (animal empathy), the second is
related to health and/or environmental protection. Additionally, a vegan diet does not
necessarily prioritize food quality. In contrast, a PBD emphasizes consuming whole foods
and minimally processed products, focusing on legumes, whole grains, fruits, vegetables,
seeds, and nuts [30].
As defined by some authors, plant-based eating patterns include fish, poultry, and
yogurt [31–33]. However, this definition is more accurately described as a pescatarian diet,
including other seafood, or as a lacto-vegetarian diet. Other authors have included a low
frequency of animal sources as a definition of a PBD [34], while other sources explicitly
highlight that a PBD does not necessarily mean being vegetarian or vegan [30]. It is central
to recognize these differences to fully understand the potential benefits and limitations of a
PBD and make informed dietary choices.
This review aimed to highlight the benefits of diverse plant bioactive compounds
and emphasize the significance of including plant-origin macronutrients, vitamins, and
minerals in our diets to prevent and/or treat the pathogenesis of chronic non-communicable
Nutrients 2023, 15, 3244 3 of 39

diseases, metabolic syndrome indicators, and atherosclerosis due to increased prevalence

and incidence globally.

2. Plant-Based Diet and Atherosclerosis

2.1. Brief Summary of the Pathophysiology and Confounding Outcomes
Atherosclerosis (ATE) is considered a principal cause of different coronary heart
diseases.
Nutrients 2023, 15, x FOR PEER REVIEW It is characterized by the accumulation of lipids, fibrous elements, and calcification
4 of 41
within the large arteries, similar to a chronic inflammatory process [35]. This involves
the stimulation of the toll-like receptor (TLR), which activates the transcription factor
(nuclear factor-kappa beta), inducing the activation of proinflammatory components such
artery disease who had low baseline serum LDL cholesterol concentrations had a low risk
as interleukin 1β (IL-1β), IL-6, IL-18, and tumor necrosis factor-alpha (TNF-α) [36] (see
of long-term all-cause mortality.
Figure 1).

Figure 1. A brief description of the atherosclerosis process. MUFA: monounsaturated fatty acids;
Figurepolyunsaturated
PUFA: 1. A brief description of theLDL:
fatty acids; atherosclerosis
low-densityprocess. MUFA:
lipoprotein; monounsaturated
Apo-B: apolipoproteinfatty acids;
B; NF-kB:
PUFA: polyunsaturated fatty acids; LDL: low-density lipoprotein; Apo-B: apolipoprotein B; NF-kB:
nuclear factor-κB; IL: interleukin; TNF-α: tumor necrosis factor alpha.
nuclear factor-κB; IL: interleukin; TNF-α: tumor necrosis factor alpha.
An increase in plasma cholesterol levels can result in changes in arterial endothe-
[Link],
lial Saturated andleading
Unsaturatedto theFatmigration of lipids, particularly low-density lipoprotein
A dietparticles,
cholesterol high in sugar,
into thesalt, cholesterol,
arterial andThis
wall [37]. fat—commonly
process can called a Westernby
be upregulated diet—has
certain
been linked to various
proinflammatory healthsuch
conditions issues, includingglycation
as advanced diabetes mellitus, high (AGEs)
end-products blood pressure, hy-
[38], hyper-
perlipidemia, obesity,
cholesterolemia, and coronary
hypertension [39], or artery
type disease.
1 diabetes These
[40].conditions
The trappedcanlipoproteins
promote athero- are
oxidized, leading to endothelial
genesis, atherosclerosis, dysfunction [36]
and atherothrombotic and forming
coronary arteryfoam cells.
disease LDL
[57]. particlesa
However,
transport different
recent animal study components,
by Huang etincluding apolipoprotein
al. [58] showed B100 (Apo-B100)
that the adverse [41]. Recent
effects of Western diet-
evidence [42,43] suggestscould
induced atherosclerosis that Apo-B contentby
be mitigated is down-regulating
linked to ATE as obesity,
the primary cause of
inflammation,
atherogenic
and chemotaxis pathology.
signaling. These factors are modulated by the microbiota and derived
Previous
short-chain fattystudies
acidshave identified that Apo-B, not LDL cholesterol, is strongly associ-
(SCFAs).
ated with coronary
In contrast, artery
a diet rich calcification
in extra-virgin[44,45]. However,
oil and nuts hasa recent Mendelian
been shown randomized
to have beneficial
analysis
effects. showed
Compared that,toinaindividuals
Western diet, witha equal levelsinofunsaturated
diet high non-HDL cholesterol, the develop-
fats can lead to lower
ment
plasmaof coronary
cholesterol artery
anddisease is not levels,
triglyceride influenced by the
as well number of
as reduced Apo-B particles
inflammation andcarried,
athero-
suggesting that the clinical impact of lipid-lowering therapies is expected
sclerosis in animal models (inhibited foamy monocyte formation, inflammation, adhesion, to be proportional
to thereduced
and reduction in non-HDL in
atherosclerosis cholesterol rather[59].
Ldlr -/- mice) thanPrevious
the reduction
humaninresearch
Apo-B [46]. Thus,
has shown
the
that a high-unsaturated fat diet and a very low-fat diet can lead to a more significantasde-
LDL particle oxidation process is also a critical factor that should be considered, it
has been strongly linked to coronary atherosclerosis, arterial dysfunction,
crease in LDL cholesterol than a high-saturated fat diet [60]. Increasing poly and mono- and mortality,
affecting elasticity
unsaturated fatty and
acids vasodilatory
(PUFAs and endothelial vascular function
MUFAs, respectively) reduce[47,48]. In this line,disease
cardiovascular it has
been suggested that the regulation of oxidative stress could be one of
events mainly due to the degree of cholesterol-lowering. The cardiovascular effects of re-the major strategies to
reduce the trapping of Apo-B in the intima, decreasing atheroma formation,
ducing saturated fat rely on changes in atherosclerosis via serum cholesterol [61], influ- inflammation,
and atherosclerosis
encing pathogenesis
pathways affecting [36].
inflammation, cardiac rhythm homeostasis, apolipoprotein-C
III production, and high-density lipoprotein (HDL) function [62].
Notwithstanding the above, some authors [63] consider that American guidelines
and recommendations may be biased and that saturated fat in certain foods, such as whole
fat dairy or dark chocolate, can benefit health and are not associated with cardiovascular
disease or diabetes. While Gershuni [64] supported this general conclusion, he also indi-
Nutrients 2023, 15, 3244 4 of 39

In parallel, it has been established that people who do not develop atherosclerosis have
an optimal and normal LDL cholesterol range of 50–70 mg/dL [49]. In a Consensus State-
ment from the European Atherosclerosis Society Consensus Panel (EAS), Ference et al. [50]
emphasized the consistent evidence from clinical and genetic studies that unequivocally
establishes the role of LDL in causing atherosclerotic cardiovascular disease (ASCVD).
Despite that, not all the evidence supported this statement [51], which could be explained
by reverse causation [52,53]. While observational studies in middle-aged individuals have
reported a positive association between cardiovascular disease and cholesterol levels, the
role of high cholesterol as a cardiovascular risk factor in individuals above 75 years old is
controversial [54].
Overall, LDL cholesterol levels in plasma may not reflect lifetime LDL cholesterol
levels due to comorbidities [55]. To address this issue, the authors of the study mentioned
above [54] used LDL-GRS (genetic risk score) and found that the genetic predisposition to
high LDL cholesterol levels contributes to mortality throughout life, including in the oldest
individuals. Finally, the coexistence of coronary artery disease and malnutrition may reflect
the intriguing phenomenon known as the “cholesterol paradox.” The last concept refers
to a disparity in some of the results found and what the literature explains. In this line, a
previous study [56] concluded that the worse mortality prognosis observed in patients with
low LDL cholesterol group (<1.8 mmol/L) is mainly mediated by their higher prevalence
of malnutrition. After adjustment for malnutrition, patients with coronary artery disease
who had low baseline serum LDL cholesterol concentrations had a low risk of long-term
all-cause mortality.

2.2. Saturated and Unsaturated Fat

A diet high in sugar, salt, cholesterol, and fat—commonly called a Western diet—has
been linked to various health issues, including diabetes mellitus, high blood pressure,
hyperlipidemia, obesity, and coronary artery disease. These conditions can promote athero-
genesis, atherosclerosis, and atherothrombotic coronary artery disease [57]. However,
a recent animal study by Huang et al. [58] showed that the adverse effects of Western
diet-induced atherosclerosis could be mitigated by down-regulating obesity, inflammation,
and chemotaxis signaling. These factors are modulated by the microbiota and derived
short-chain fatty acids (SCFAs).
In contrast, a diet rich in extra-virgin oil and nuts has been shown to have beneficial
effects. Compared to a Western diet, a diet high in unsaturated fats can lead to lower plasma
cholesterol and triglyceride levels, as well as reduced inflammation and atherosclerosis
in animal models (inhibited foamy monocyte formation, inflammation, adhesion, and
reduced atherosclerosis in Ldlr -/- mice) [59]. Previous human research has shown that a
high-unsaturated fat diet and a very low-fat diet can lead to a more significant decrease in
LDL cholesterol than a high-saturated fat diet [60]. Increasing poly and mono-unsaturated
fatty acids (PUFAs and MUFAs, respectively) reduce cardiovascular disease events mainly
due to the degree of cholesterol-lowering. The cardiovascular effects of reducing saturated
fat rely on changes in atherosclerosis via serum cholesterol [61], influencing pathways
affecting inflammation, cardiac rhythm homeostasis, apolipoprotein-C III production, and
high-density lipoprotein (HDL) function [62].
Notwithstanding the above, some authors [63] consider that American guidelines and
recommendations may be biased and that saturated fat in certain foods, such as whole fat
dairy or dark chocolate, can benefit health and are not associated with cardiovascular dis-
ease or diabetes. While Gershuni [64] supported this general conclusion, he also indicated
that the saturated fatty acid found in meat, eggs, cacao, and nuts is primarily composed
of triglycerides containing palmitic acid and stearic acid, covering 90% of fatty acid in the
standard American diet. However, exogenous palmitic acid can exert a different effect
depending on the source. In both animal and human in vivo and in vitro studies [65,66],
palmitic acid has been associated with promoting atherosclerosis development due to
cholesterol accumulation in LDL particles and macrophages activating the inflammatory
Nutrients 2023, 15, 3244 5 of 39

process [67]. Further, elevated palmitic acid levels enhanced the uptake of oxidized LDL
via the upregulation of lectin-like oxidized LDL receptors in macrophages, mediated by
ROS-p38 pathways rather than TLRs [68].
A vast study involving 76,364 women observed that the consumption of high-fat
foods such as peanuts and tree nuts (two or more times a week) and walnuts (one or
more times a week) was associated with a 13–19% lower risk of total cardiovascular risk
disease and a 15–23% lower risk of coronary heart disease [69,70]. In an animal study [71],
a high-fat diet rich in walnuts was found to cause a 55% reduction in atherosclerotic
plaque development in the aortic arch compared to the control diet. Urpi-Sarda et al. [72]
found that a Mediterranean diet with virgin olive oils and nuts can down-regulate cellular
inflammatory biomarkers associated with atherogenesis [73] and modify the process of
the firm adhesion of circulating monocytes and lymphocytes T to endothelial cells during
inflammation [74]. These findings suggest that adding nuts to a Mediterranean diet or
adopting a whole-food vegan diet can reverse the atherosclerotic process of coronary artery
disease [75].
In this line, a meta-analysis [76] demonstrated that replacing 1% of the dietary car-
bohydrate with MUFAs or PUFAs resulted in increased HDL cholesterol, decreased tria-
cylglycerol concentration, and attenuated increases in LDL and total cholesterol levels. In
contrast, a study on coconut oil found that reducing saturated fat without changing the
polyunsaturated/saturated fatty acid ratio (P/S) did not lower total or LDL cholesterol but
significantly reduced HDL cholesterol. However, a diet high in MUFAs and PUFAs resulted
in a greater reduction in LDL cholesterol, lower LDL/HDL cholesterol, and an improved
Apo-B/Apo-A ratio [77]. This last conclusion is fundamental, considering LDL/HDL ratio
is suggested as a sensitive predictor of coronary atherosclerotic heart disease (CADH) [78].
Overall, although nutritional evidence has not convincingly shown that plant-based fats
alone significantly improve HDL cholesterol, there is evidence that they can lower LDL
cholesterol and maintain unchanged HDL cholesterol, thus improving the LDL/HDL
ratio [79,80].

2.3. Trimethylamine N-Oxide and Gut Microbiota

Trimethylamine N-oxide (TMAO) is a compound that has gained interest due to its
potential mechanistic links to atherosclerosis heart disease [81]. Trimethylamine (TMA)
is generated by gut microbiota in response to nutrients, with eggs and meat being major
dietary sources of the TMA precursor. In the liver, TMA is transformed into TMAO by
flavin-containing monooxygenase 3 [82]. While a considerable body of evidence strongly
supports the detrimental impact of TMAO on health, some results are inconsistent, with
stronger relations observed in patients with preexisting medical conditions compared to
healthy subjects [83]. However, in a previous Mendelian randomization analysis [84],
the authors found that some chronic non-communicable diseases like type 2 diabetes
mellitus and kidney disease increase TMAO levels, and such observational evidence for
cardiovascular disease may be due to confounding or reverse causality. Despite the above,
different non-modifiable factors increase plasma TMAO levels, such as age, sex, and genetic
factors. However, various components found in animal and plant food can also potentially
increase it [83]. Choline, phosphatidylcholine, l-carnitine, betaine, crono-betaine, and
γ-butyrobetaine [85,86] can be used as precursors by gut microbiota to generate TMAO.
Kühn et al. [87] established that TMAO levels could be more affected by intra-
individual variation, which could mediate the result due to physical activity or intestinal
microbiota. Depending on the context, these factors can positively or negatively modify
the type of intestinal bacteria present. For instance, betaine, mainly found in plants, can
potentially affect TMAO levels and be synthesized from dietary choline. Betaine also serves
as an osmoprotectant in the kidney and plays a crucial role in the methionine-homocysteine
cycle, maintaining the s-adenosylmethionine/s-adenosyl-homocysteine ratio in the liver, es-
pecially when folate is insufficient [88]. However, some studies have shown no relationship
between dietary betaine and the incidence of cardiovascular disease, even though TMAO
Nutrients 2023, 15, 3244 6 of 39

increased cardiovascular mortality in some populations [89,90]. A possible explanation lies

in the composition of the gut microbiota.
In a previous study [82], a carnitine challenge test was conducted on omnivorous
and vegetarian/vegan participants using steak and/or veggie caps containing 250 mg of a
stable isotope-labeled d3-L-carnitine to measure TMAO levels. The results showed that
vegetarians/vegans challenged with d3-carnitine had a significantly reduced synthetic
capacity to produce TMAO from oral carnitine compared to omnivorous individuals.
Some authors have suggested that the richness, expressed in the number of species, of
the intestinal microbiota may impact the host’s health, although this is still subject to
debate [91].
However, De Filippo et al. [92] conducted previous research comparing the human
intestinal microbiota among children from Burkina Faso (rural context) with a diet low in
fat and animal protein, rich in starch, fiber, and plant polysaccharides, legumes, sorghum,
and millet grain being predominantly vegetarian, versus children from Italy (urban context)
with a diet high in animal protein, sugar, starch, fat, and low in fiber. The authors found
that diet plays a primary role influencing the composition and diversity of the micro-
biota, suggesting that diet has a dominant influence over other variables such as hygiene,
sanitation, ethnicity, geography, and climate. Gut bacteria can generate SCFA byproduct
formation, named butyrate, propionate, and acetate, which help maintain normal large
bowel function, prevent pathologies through their influence in the gut lumen, the colonic
musculature and vasculature and through their metabolism by colonocytes [93]. At the
same time, increased SCFA from plant-based sources has been associated with reduced
TMAO levels and atherosclerotic risk.
Concerning protein consumption, an early culture-based study on gut microbiota [94]
demonstrated lower counts of Bifidobacterium adolescentis and increased counts of Bac-
teroides and Clostridia in subjects consuming a high beef diet compared to those on a
meatless diet. In a more recent study, Singh et al. [95] analyzed the effect of different
types of protein (animal-based protein and plant-based protein) and found that pea protein
increased intestinal SCFAs levels, which are considered anti-inflammatory and essential
to the maintenance of the mucosal barrier [96]. This increase in SCFAs was associated
with an increased prostaglandin E1/prostaglandin E2 ratio produced by subepithelial
myofibroblasts enhancing mucin-2 (MUC-2) expression in epithelial cells [97]. These posi-
tive effects on the gut barrier, especially in MUC-2, help to reduce bacterial translocation
(endotoxemia), gut permeability, inflammation, and TMAO levels [98–101].
Contrary to what has been stated, recent studies have shown that TMAO levels are
positively correlated with the intake of vegetables and whole-grain cereal, contradicting the
notion that a healthy diet may help reduce TMAO levels [102]. Similarly, Griffin et al. [103]
found that a Mediterranean diet intervention over six months did not significantly mitigate
TMAO concentration in a healthy population. These findings call into question the effec-
tiveness of a high plant-based diet in reducing TMAO levels and, consequently, the risk of
cardiovascular and coronary heart disease.

2.4. Plant-Based Diet, LDL Cholesterol, TMAO, and Atherosclerotic Risk

In a recent randomized cross-over study [104], the authors observed that a PBD that
includes whole eggs might maintain or improve dyslipidemia, oxidative stress, and inflam-
mation biomarkers over vegan or lactovegetarian diets in individuals with MetS. The study
suggested that egg consumption may have theoretical benefits, such as increasing HDL choles-
terol, without causing any adverse effects on LDL cholesterol, triglycerides, or glucose levels.
These findings were consistent with previous research by Zhu et al. [105], who found that two
eggs/day in overweight postmenopausal women significantly increased plasma choline and
betaine levels but did not alter TMAO levels or gut microbiome composition.
In a previous study (2005) related to this topic [106], it was established that individuals
over 60 years old with a healthy lipoprotein profile might consume eggs as part of their
regular diet due to eggs consumption possibly increasing LDL cholesterol, but an increase
Nutrients 2023, 15, 3244 7 of 39

in HDL cholesterol offsets this elevation. However, a meta-analysis [107] conducted earlier
(2001) indicated that the beneficial rise in HDL cholesterol by consuming eggs is insufficient
to offset the negative rise in total LDL cholesterol concentrations, implying that an increase
in dietary cholesterol intake may increase the risk of coronary heart disease. Further,
several decades ago, some studies [108–110] clearly and unequivocally established that
egg consumption leads to an increase in total and LDL cholesterol, although the extent of
the increase depends on baseline cholesterol levels [111]. However, and related to TMAO,
a more recent study [112] concluded that egg consumption did not increase its levels of
plasma. Notwithstanding, in this study, the authors used a 12-h fasting protocol to measure
TMAO levels, and previous evidence has indicated that the kidneys efficiently eliminate
TMAO to maintain a steady state of circulating choline levels in a couple of hours [113,114].

2.5. Endothelial Vascular Function

Endothelial vascular dysfunction is among the risk factors involved in coronary artery
disease [57]. High salt consumption has presented strong evidence of the adverse effect
on endothelial function [115,116] by stiffening human endothelial cells and reducing nitric
oxide (NO) production [115]. NO is a key signaling molecule that regulates blood flow and
tissue oxygenation, and its bioavailability reduction augments atherosclerosis risk [117],
associated with an impairment of endothelium-dependent relaxation. In addition, a single
high-fat (50 g) meal reduces blood flow-mediated vasoactivity in the 2- to 4-h postprandial
period [118]. This previous outcome has also been reported by Keogh et al. [119], who
detailed that a high-saturated fat diet causes deterioration in flow-mediated dilation (FMD)
compared with a high PUFA, MUFA, or even CARB (carbohydrate) diet.
Contrary to what has been previously described, a singular food and/or full PBD has
been recognized as a healthy eating pattern by improving FMD. An 8-week cross-over
feeding trial demonstrated that walnuts consumption as a substitute for 32% of the energy
from MUFAs in a cholesterol-lowering Mediterranean diet improves vascular endothelial
function [120]. A hazelnut-enriched diet for four weeks has also shown a significantly
improved FMD in hypercholesterolemic subjects, besides improving TC (total cholesterol),
TG (triglycerides), LDL, and HDL as well oxidized LDL, CRP (c-reactive protein), and
soluble vascular cell adhesion molecule-1 compared with the control diet [121].
Another study found that daily walnut consumption (56 g) improves endothelial func-
tion in overweight adults with visceral adiposity [122]. Daily consumption of high-flavanol
cocoa drinks has been shown to lead to a sustained reversal of endothelial dysfunction in
approximately five days. Interestedly, the magnitude of this positive effect observed with a
high-flavanol cocoa drink was similar to that observed in a long-term pharmacological ap-
proach with statins [123,124]. Another study using daily inorganic nitrate as beetroot juice
for six weeks in hypercholesterolemic individuals showed a ∼24% improvement in FMD
through the rising in nitrate circulation. This beneficial effect was related to a reduction
in platelet-monocyte aggregate numbers and reduced platelet P-selectin expression [125],
associated with cardiovascular disease progression, which can initiate the release of athero-
genic proinflammatory and adhesive molecules and induce procoagulant microparticle
formation, respectively [126,127].
In this context, nitrate and nitrite have been widely recognized as nitric oxide precur-
sors. In the case of nitrate, certain plant foods can improve vascular function through this
content and enhance NO formation. Spinach, watercress, chervil, chard, arugula, beets,
celery, and lettuce are some plant foods with high nitrate concentrations [128]. In this line,
Bondonno et al. [129], in a study of older women, observed an inverse association between
the intake of vegetable nitrates with CCA-IMT (intima-media thickness of the common
carotid artery) and the risk of an ischemic cerebrovascular event for 15 years. This result
was not observed with non-vegetable nitrates consumption. Although some evidence has
demonstrated an insignificant change in a single and specific indicator, such as systolic
blood pressure, after five weeks of supplementation of leafy green vegetables or pills
Nutrients 2023, 15, 3244 8 of 39

containing the same amount of inorganic nitrate [130], most of the literature corroborates
the benefits of PBD for the improvement of vascular function.
Prolonged consumption of soy nuts as part of a healthy diet improves endothelial
function, LDL cholesterol concentration, and mean arterial pressure [131]. In this recent
study, the enhancement is more related to restoring a condition of nitric oxide impair-
ment rather than enhancing a normal physiological condition [132]. In contrast, previous
evidence has shown that fish, with green tea and a lower consumption of saturated fat
as part of a traditional Chinese diet, also improves endothelial function in older Chinese
people’s arteries [133]. However, in later studies, fish oil supplementation or whole-fish
consumption showed no significant effect on endothelial function [134–136]. Additionally,
in a comparative study between lacto-ovo-vegetarians and omnivores on the measurement
of vascular dilator function, the authors found that the vegetarian diet, by itself, has a direct
beneficial effect on the vascular endothelium and the function of the smooth muscle, and
may help explain the lower incidence of atherosclerosis and cardiovascular mortality [137].

2.6. Short-Chain Fatty Acids, Gut Microbiota, and Atheroma Formation

Gut microbiota, mainly through probiotics, bioactive compounds intake, and SCFA
formation, exerts multiple health benefits, having a significantly positive role in the re-
duction of atherosclerosis. Soybeans, such as tempeh, are rich in bioactive compounds
like genistein and daidzein. These isoflavones are present in different legumes but are
markedly higher in soybean. The growing body of evidence around isoflavones in the
last 15 years suggests their beneficial effects on preventing breast and prostate cancer,
cardiovascular disease, and chronic non-communicable diseases. In animal models, type
2 diabetes has been demonstrated to aggravate colonic damage and inflammation response
and decrease levels of SCFA [4] leading to dysbiosis. Gut dysbiosis can alter different
homeostatic functions increasing the pathophysiology risk of several complications like
diabetes or atherosclerosis, among others [138,139].
Previous evidence has observed different compositions of bacteria between patients
with or without symptomatic atherosclerosis [140]. The production of SCFAs can inhibit
foam cell formation by stimulating the expression of IL-10 and reducing the production of
proinflammatory cytokines by the endothelium, contributing to the recovery of endothelial
dysfunction and reducing atherosclerotic risk [141].
Inflammation can promote alteration in the gut barrier. Increasing gut permeability is
associated with inflammation and reduced expression of specific tight junction proteins,
such as zonula occludens-1, claudin-1, and occluding [142–144]. The reduction of its ex-
pression increases bacteria translocation of LPS (lipopolysaccharides) and proinflammatory
cytokines. Therefore, SCFAs can reduce gut permeability by decreasing nuclear factor-
kappa B (NF-kB) activation and, consequently, reduce proinflammatory cytokines such
as IL-1b, IL-6, IL-8, and TNF-α [145]. Additionally, SCFA has proved to attenuate NF-kB
and peroxisome proliferator-activated receptors’ (PPARγ) activities and, consequently,
suppress adhesion molecules expression like vascular cell adhesion molecule-1 and inter-
cellular adhesion molecule-1 [146]. Accompanying these effects, they showed increased
anti-inflammatory actions. For instance, in macrophages, butyrate had anti-inflammatory
effects by decreasing inducible nitric oxide synthase, TNF-α, monocyte chemo-attractant
protein-1, and IL-6 production through the activation of free fatty acids 3 receptors, which
has been implicated in obesity and metabolic diseases [147]. In a mouse study [148],
genistein has been shown to increase SCFAs concentration and modulate gut microbiota
in mice.
In a regular omnivorous diet, the average daily fiber consumption is lower than
recommended [149]. Additionally, Davies et al. [150] observed that omnivorous, vegetarian,
and vegans reported different fiber intakes, with 23, 37, and 47 g/d, respectively. In both
genders, the highest versus lowest fiber intake was associated with a 22% decrease in
mortality [151] and reduced long-term ASCVD [152]. Nowadays, fiber is known as a
microbiota-accessible carbohydrate (MAC) and represents the primary energy source for
Nutrients 2023, 15, 3244 9 of 39

colonic bacteria. When fiber intake reaches 50–120 g/day, it is associated with a more
diverse gut microbiota than people in Western countries. In the latter, it has been correlated
with highly prevalent diseases [153].
Even so, the connection between MAC and TMAO formation is still debatable. Some
authors propose that a high non-digestible carbohydrate diet may reduce TMAO formation
by modulating the gut microbiota, but conflicting findings have been reported [154]. How-
ever, a previous study to determine the impact of fiber deprivation over four generations on
the gut microbiota in mice colonized with human microbiota from a Westerner diet showed
that the consumption of a regular Western low-fiber diet contributes to the loss of taxa over
generations and may be responsible for the lower diversity of microbiota observed. The
re-introduction of dietary MAC was insufficient to recover taxa [155].
In the context of human health, consuming plant-based foods promotes the develop-
ment of a more diverse gut microbial community and may also impact the distribution
of different species within it [156]. The difference in gut microbiota composition between
omnivorous and vegetarians/vegans has been well documented, and fiber consumption
has shown an inverse relationship with cardiovascular disease, including atherosclero-
sis [152,157]. A soy-based diet has been shown to reduce the risk of atherosclerosis by
inhibiting the formation of foam cells in macrophages. Downregulating scavenger receptors
achieve this effect in a cell culture model using THP-1 macrophages, which is attributed
to the presence of soy pinitol, which could inhibit oxidized LDL formation [158]. Later,
evaluating the consumption of a single high-fat meal, this study found that a high-fat meal
resulted in a transient increase in acLDL (acetyl low-density lipoprotein) endocytosis and
adhesion molecule expression in both classical and nonclassical monocytes, increasing
the susceptibility to foam cell formation [159]. However, this study did not clarify the
specific content of every meal, which varied between subjects. Therefore, it is essential to
differentiate the effects of different diets and fat sources.

2.7. Fermented Plant-Food and Atherosclerosis

Rabbits subjected to a high-cholesterol diet experienced significant health complications.
The progression was retarded by the administration of 3-(4’-hydroxyl-3’,5’-dimethoxyphenyl)
propionic acid (HDMPPA), an active compound of kimchi, which can suppress TC and LDL
cholesterol elevation, reducing the thickness of the aortic arch and antioxidant activity [160].
Yun et al. (2014) [161] also found that HDMPPA had a protective effect on the cell viability of
THP-1-derived macrophages through the inhibition of lipid peroxidation, regulating cluster
of differentiation 36 and ABCA1 expression, both of which at least partially participate in
cholesterol influx and efflux. This context could regulate foam cell formation by attenuating
cholesterol accumulation in macrophages.
Additionally, it is well documented that whole grains can improve health in different
contexts. For instance, a 12-week whole-grain wheat-based diet increases fasting plasma
propionate, a type of SCFA, in individuals with metabolic syndrome [162]. Interestingly,
Lisosan G (LG), a fermented powder obtained from whole grain, has demonstrated an
antioxidant and anti-inflammatory capacity [163]. Moreover, LG protects EPCs exposed
to LPS, reducing intracellular reactive oxygen species (ROS), and is capable of inducing
vascular damage and lowering or normalizing cytokine [164].
A study found that fermented plant beverages, in this case kombucha with pollen, led
to a significant increase in SCFAs, probably depending on a mixture of microorganisms
called the symbiotic culture of bacteria and yeast (SCOBY) [165]. In another beverage
study, fermented Korean tea (chungtaejeon) was proven to scavenge oxidation and inhibit
the cytokine-induced proliferation and migration of human aortic smooth muscle cells.
Vascular smooth muscle cells secrete TNF-α, activating ERK1/2, a crucial mediator of
signals that promote cell growth and motility. This pathway plays a pivotal role in the
development of vascular lesions. Also, the chungtaejeon beverage inhibited the enzymatic
action and protein expression of TNF-α-induce matrix-metalloproteinase (facilitates migra-
Nutrients 2023, 15, 3244 10 of 39

tion of vascular smooth muscle cells via matrix disruption contributing to the pathogenesis
of atherosclerosis) in human aortic smooth muscle cells [166].
Moreover, red yeast rice has been reported to confer multiple health improvements,
including atherosclerosis and lipid profile. Monacolin K is believed to be the key factor
responsible for these positive effects, as recently reported by Rahmani et al. [167]. In
an 8-week intervention study, a daily dose of 200 mg red yeast rice containing 2 mg of
monacolin K significantly reduced LDL cholesterol, blood pressure, and Apo-B levels
compared to the control group [168]. The mechanisms involved in these modifications are
generated through various pathways, including cholesterol biosynthesis, LDL receptor
metabolism, inhibiting acyl-coenzyme A-cholesterol acyltransferase, decreasing the conver-
sion of cholesterol-to-cholesterol esters and the secretion of Apo-B, enhancing endothelial
cell function due to NO activity, reducing ROS, preventing a connection between Lox-1 and
ox-LDL, and reducing proinflammatory cytokines, among others [169].

2.8. Bioactive Compounds

Plant-derived bioactive components have auspicious therapeutic attributes, especially
antioxidative properties [170]. Thus, both independently and in combination with other
bioactive compounds found in plant foods, they have been shown to contribute to reducing
plasma cholesterol. For instance, a pilot study [171] using supplemented pasta with 6%
of β-glucan showed, after 30 days, a significant reduction in LDL cholesterol, IL-6, AGEs
levels, and oxidative stress. In addition, it has been suggested by other researchers [172]
that β-glucan exhibits significant physicochemical properties, including its antioxidant
capability to scavenge reactive oxygen species, its role as a dietary fiber to inhibit cholesterol
absorption, and its ability to promote the production of short-chain fatty acids (SCFAs).
A previous meta-analysis has supported most of these results, indicating that barley β-
glucan can significantly lower LDL and non-HDL cholesterol [173]. In another study, it
was observed that a daily intake of 3 g of oat β-glucan safely reduced total, LDL, and
non-HDL cholesterol in a large cohort of adults with mild hypercholesterolemia and a low
cardiovascular risk profile [174].
In addition, berries as whole fruits, juice, or extract, decrease plasma LDL cholesterol
and triglycerides and/or increase HDL cholesterol in individuals who exhibit elevated
lipid biomarkers [175]. The modulating lipid metabolism primarily involves increasing the
hepatic synthesis of apolipoprotein A-I, downregulating the activity of genes related to fatty
acid synthesis, inducing the regression of aortic lesions, and decreasing inflammation and
oxidative damage in experimental animals [175]. Although previous evidence suggested
no significant change in serum total cholesterol, LDL cholesterol was significantly lower
in the berries-consumed than in the placebo-treated subjects [176]. To complement this,
a meta-analysis and trial sequential analysis of randomized controlled human trials was
evaluated [177]. The authors established the potential role of CRP in cardiovascular disease
since CRP can bind to LDL cholesterol and is present in atherosclerotic plaques. In this line,
berry consumption markedly diminished CRP and TNF-α levels, decreasing inflammation
and preventing the development of cardiovascular disease.
In a recent study [178], the authors established that proanthocyanidins regulate blood
pressure due to antioxidative scavenging of oxidized LDL and LDL cholesterol and the
removal of carotid atherosclerosis plaque. Oxidative stress may be reduced by protecting
the blood–brain barrier during arteriosclerosis by inhibiting oxidized LDL docking to its
receptor LOX-1 to prevent cerebrovascular diseases. Proanthocyanidin extract (0.1–1%)
incorporated into rabbit diets ameliorated cholesterol-induced aortic lesions and atheroscle-
rosis [179] while also decreasing oxidized LDL activation and foam cells via the antioxida-
tive mechanism.
Nutrients 2023, 15, 3244 11 of 39

The benefits and importance of proper daily fruit consumption for health are widely
known. In this line, mulberry has been demonstrated to inhibit the oxidation of LDL and re-
duce the intracellular ROS generation of macrophages. Mulberry leaf extract and mulberry
leaf polyphenolic extract exhibit strong antioxidant properties, effectively neutralizing
free radicals and lipid peroxides. Both improved the expression of antioxidant enzymes
(superoxide dismutase-1, catalase, and glutathione peroxidase), lowered the expression
of scavenger receptors via downregulating the transcription factor PPAR-γ, inhibiting the
oxidized LDL uptake, foam cell formation, and intracellular lipid accumulation [180].
On the other hand, polyphenols can be implicated in a bidirectional relationship with
gut microbiota affecting each other. According to Filosa et al. [181], polyphenols undergo
enzymatic transformation by the microbiota, leading to enhanced bioavailability and im-
proved health. In turn, polyphenols also influence the composition of the microbiota,
preventing the proliferation of pathogens. Specific polyphenols can inhibit/increase the de-
velopment of particular bacteria resulting in modulation of gut microbial composition [182].
Polyphenols can enhance the abundance of beneficial bacteria, such as Bifidobacterium and
Lactobacillus, which contribute to gut barrier protection, Faecalibacterium prausnitzii, which
presents anti-inflammatory action by blocking NF-kB activation, and Roseburia sp., which
are butyrate producers.
In this line, probiotics administered in appropriate doses offer positive effects for the
host [183]. Some bifidobacteria and lactobacilli prevent the adhesion of pathogenic bacteria
by secreting lectin-like bacteriocins. The barrier protective effect involves the release of
metabolic or other molecules, which, in turn, regulates tight junction integrity [184]. Ac-
cording to Gou et al. [185], lactobacillus plantarum MB452 increases the gene and protein
expression of zonula occludens-1, zonula occludens-2, occludin, and cingulin. It also regu-
lates the expression of tight junctions’ protein-degrading genes, stabilizing tight junctions
and improving intestinal barrier function. As well, Bifidobacterium infantis and Lactobacillus
acidophilus normalize the expression of the tight junctions’ proteins, occludin and claudin1,
in an in vitro Caco-2 intestinal epithelial cell model, preventing barrier damage due to IL-1
stimulation. In this line, a six-week wild blueberry powder drink intake can positively
modulate intestinal microbiota composition by increasing bifidobacterium [186].
Another bioactive compound with multiple health benefits is present in coffee. Previ-
ous evidence has investigated the relationship between coffee consumption and oxylipin,
a biomarker related to cardiovascular disease, inflammation, and lipid peroxidation pro-
duced during foam cell formation in atherogenesis. The authors found that, after coffee
consumption, urinary oxylipin was reduced. The phenolic compounds in coffee were
implied to have anti-inflammatory and antioxidant activities. It is interesting to highlight
that the participants received two coffees with different amounts of chlorogenic acid in
this study. Those with a higher chlorogenic acid intake demonstrated higher oxylipin
reduction, suggesting the protection of coffee against cardiovascular disease progression
and development [187]. Finally, Table 1 displays a summary of findings on this matter
and Figure 2 provides a comprehensive overview addressing the overall advantages of
adopting a plant-based diet.
Nutrients 2023, 15, 3244 12 of 39

Table 1. Influence of certain plant components on markers linked to atherosclerosis.

Study Analysis Resume of Main Results Found

Apo-B LDL-c oxLDL HDL-c H/L-cr TG CVD/CHD PROINF SFA UFA FCF
[59] EVOND vs. WD x ↓ ↓ x x ↓ x x x x ↓
[60] HUF vs. HSF x ↓ x = x x x x ↓ ↑ x
Reducing SFA
[61] x ↓ x x x x x x x x x
intake
SFA vs. RO (both
[65] x ↑ x x x ↑ ↑ x ↑ x x
rich fats)
Peanuts and
[69] walnuts x x x x x x ↓ x x x x
consumption
[71] WW vs. WO x ↓ x x x ↓ x x x x x
Changing SFA or
[76] x ↓ x = ↑ ↓ ↓ x x x x
CARB by UFA
LSAFA vs.
[77] = = x ↓ ↓ ↑ x x x x x
HSAFA
HUFA vs. LSAFA
↓ ↓ x ↓ or = ↑ ↓ x x x x x
or HSAFA
[79] Chia vs. Control x = x ↑ x = x x x x x
PBD w/EGGs vs.
[104] x = x ↑ = = x x x x x
wo/EGGs
High SFA diet vs.
[119] ↑ ↑ x ↑ x ↑ x ↑ x x x
PUFA diet
Walnuts replacing
[120] ↓ ↓ x = ↑ = ↓ x x x
MUFAs
Walnuts-enriched
[121] x = x = x = x x x x x
diet vs. Control
Nitrate-rich
[125] x x = x x x ↓ = x x x
beetroot juice
Higher vs. Lower
[152] x x x x x x ↓ x x x x
fiber intake
Whole-grain
[162] x x x x x ↓ x x x x x
cereal vs. Control
Chungtaejeon
[166] x x x x x x ↓ ↓ x x x
(Fermented Tea)
[168] β-glucans intake x ↓ x = x = ↓ ↓ x x x
Berries
[174] = ↓ x ↑ x ↓ ↓ ↓ x x x
consumption
Mulberry leaf
[177] polyphenols x x ↓ x x x x ↓ x x x
effects
Apo-B: apolipoprotein B; LDL-c: low-density lipoprotein cholesterol; oxLDL: oxidized LDL; HDL-c: high-density
lipoprotein cholesterol; H/L-cr: HDL/LDL cholesterol ratio; TG: triglycerides; CVD: cardiovascular disease; CHD:
coronary heart disease; Proinf: proinflammatory cytokines; SFA: saturated fatty acids; UFA: unsaturated fatty
acids; FCF: foam cell formation; EVOND: extra-virgin olive oil and nuts; WD: Western diet; HUF: high-unsaturated
fat diet; HSF: high-saturated fat diet; RO: rapeseed oil; WW: whole walnuts; WO: walnuts oil; CARB: carbohydrate;
LSAFA: low-saturated fatty acid diet; HSAFA: high-saturated fatty acid diet; HUFA: high-unsaturated fatty acids;
PBD: plant-based diet; MUFAs: monounsaturated fatty acids. For more details see the main text. x: not measured
or not informed; Arow down (↓): reduced parameter; Arrow up (↑): increased parameter; Equal sign (=): without
change; Green box: positive change; Red box: negative change. Yellow box: no change.
 Nutrients 2023, 15, x FOR PEER REVIEW 13 of 41
Nutrients 2023, 15, 3244 13 of 39

Figure 2. Benefits of consuming a plant-based diet. TMAO: trimethylamine N-oxide; FMD: flow-
Figure 2. Benefits of consuming a plant-based diet. TMAO: trimethylamine N-oxide; FMD: flow-
mediated dilatation; SFAs: saturated fatty acids; PUFAs: polyunsaturated fatty acids; HDL: high-
mediated dilatation; SFAs: saturated fatty acids; PUFAs: polyunsaturated fatty acids; HDL: high-
density lipoprotein; LDL: low-density lipoprotein; T/HDL cholesterol: total cholesterol and HDL
density lipoprotein;
cholesterol LDL:
ratio; Apo: low-density lipoprotein;
apolipoprotein; SBP: systolicT/HDL cholesterol:
blood pressure; DBP:total cholesterol
diastolic bloodand HDL
pressure;
cholesterol ratio; Apo: apolipoprotein; SBP: systolic blood pressure; DBP: diastolic blood
BMI: body mass index; Glut-4: glucose transporter; SCFAs: short-chain fatty acids; PPAR: peroxi- pressure;
BMI:
some body mass index; Glut-4:receptors;
proliferator-activated glucose transporter; SCFAs: short-chain
AMPK: AMP-activated proteinfatty acids;
kinase; PPAR:
ROS: peroxisome
reactive oxygen
species; HOMA-IR: Homeostasis
proliferator-activated modelAMP-activated
receptors; AMPK: assessment of protein
insulin kinase;
resistance;
ROS:MUC-2: mucin-2.
reactive oxygen species;
HOMA-IR: Homeostasis model assessment of insulin resistance; MUC-2: mucin-2.
Nutrients 2023, 15, 3244 14 of 39

3. A Plant-Based Diet and Chronic Non-Communicable Diseases

3.1. Diabetes
Diabetes is a prevalent common chronic condition affecting the human population.
According to The World Health Organization (WHO), diabetes is projected to rank as the
seventh leading cause of mortality globally by the year 2030 [188]. The macro and mi-
crovascular complications associated with diabetes are more common in older adults than
middle-aged people. According to this, macrovascular complications can lead to an im-
paired platelet function and, thus, an increased risk for thrombus formation, atherosclerosis
progression, and plaque rupture [189]. This has been supported by Huang et al. [190] who
found that some microvascular complications, such as nephropathy and retinopathy, are a
negative consequence but are usually not detected until late in the course of cardiovascular
disease. In a 5-year follow-up observational study that included nearly 3000 participants
adhering to a vegetarian diet while abstaining from smoking and alcohol consumption,
a 35% lower risk of the incidence of diabetes was observed. The transition to a vegetarian
diet also decreased the incidence of diabetes by 53% [191].
In this line, a PBD represents an appropriate option by which to enhance antioxidant
consumption [192]. These outcomes have been supported by a recent meta-analysis [193].
The strength of this relationship was amplified when the definition of plant-based patterns
encompassed fruits, vegetables, whole grains, legumes, and nuts. Similar conclusions have
been drawn elsewhere [194].
The above-mentioned foods share a common feature: bioactive compounds. Among
these, flavonoids are known as anti-diabetic bioactive compounds [188]. This property is
related to the modulatory effects on blood sugar transporters by enhancing insulin secretion,
reducing apoptosis, promoting the proliferation of pancreatic β-cells, reducing insulin
resistance, inflammation, oxidative stress in muscle, and promoting Glut-4 translocation
via PI3K/AKT and AMP-activated protein kinase (AMPK) pathways [195]. One of the
most common flavonoids, quercetin, induces activities similar to those of metformin in
muscle cells by activating AMPK pathways and thereby causing Glut-4 translocation [196].
However, quercetin also reduce proinflammatory cytokines, such as TNF-α, IL-6, and
IL-1b, and modulates certain transcriptional factors like NRf2 and NF-kB [197,198]. The
latter is essential, considering that accumulative evidence suggests that chronic activating
proinflammatory pathways in target cells of insulin action may contribute to obesity, insulin
resistance, and related metabolic disorders, including diabetes [199].
On the other hand, polyphenols are mostly found in tea, cocoa, and fruits, such
as apples, berries, and citrus, among other plant-derived foods. Polyphenols act in an
insulin-dependent manner by reducing β-cell apoptosis and oxidative stress, whilst stimu-
lating β-cell proliferation, insulin signaling, and pancreatic insulin secretion [200]. They
also act in an insulin-independent manner by inhibiting glucose absorption, digestive en-
zymes, and the formation of advanced glycation end-products, whilst regulating intestinal
microbiota and modifying the inflammatory response. Moreover, dietary polyphenols
ameliorate diabetic complications, such as vascular dysfunction and coronary diseases,
among others [200].
A previous meta-analysis found that a 5% decrease in type 2 diabetes risk was obtained
by a daily increase in anthocyanidin intake (7.5 mg) [201]. However, some studies present
inconclusive results. One possible explanation of their beneficial effects lies in PPARγ acti-
vation. Some plant phytochemicals, such as quercetin, resveratrol, genistein, or curcumin
affect inflammatory cascades by activating AMPK signaling via proteasomal activation
and by inactivating crucial transcription factors, which may explain most of the properties
attributed to PPARγ interaction. PPARγ represses inflammatory gene expression as in-
ducible nitric oxide synthase suppresses transcriptional factors AP-1 and NF-κB, modulates
mitogen-activated protein kinase (MAPK) activity, and influences glucose uptake [202].
Genistein, daidzein, and glycitein are the most active isoflavones and are mainly found
in soybeans. In fact, these bioactive compounds have been proven to reduce cancer and
decrease the risk of some chronic diseases like type 2 diabetes. Evidence on isoflavones re-
Nutrients 2023, 15, 3244 15 of 39

ducing type 2 diabetes risk is mainly derived from animal and cell culture studies [203,204].
Extrapolating these findings to humans should be done cautiously due to the inherent
limitations and differences of the biological context. Nonetheless, isoflavones have also
shown a positive effect in human trials. For instance, two months of genistein consumption
(50 mg/d) reduced insulin resistance in obese individuals, accompanied by a favorable
modulation of the gut microbiota composition. Furthermore, subjects showed reduced
metabolic endotoxemia and increased AMPK phosphorylation and genes expression in-
volved in fatty acid oxidation in skeletal muscle [205].
Additionally, a one-year intervention with flavan-3-ols and isoflavones (850 mg/d
and 100 mg/d, respectively) markedly reduced estimated peripheral insulin resistance
(HOMA-IR) and enhanced insulin sensitivity due to a notable decrease in insulin levels in
post-menopausal women with type 2 diabetes [206]. Moreover, genistein improved insulin
sensitivity, serum triglyceride concentrations, and delayed the onset of type 2 diabetes [207].
Previous evidence proposes that genistein may help delay the onset of type 2 diabetes and
improve different associated symptoms [207].
Finally, the whole-food plant-based diet has repeatedly shown benefits in this con-
text [193]. Three prospective cohort studies found an inverse association between a
healthy plant-based diet and type 2 diabetes, with 16,162 incident cases observed over
4,102,360 person-years of follow-up. These positive associations are related to antioxidants,
fiber, unsaturated fatty acids, magnesium, and low saturated fat content. This outcome
remains unchanged after the authors adjusted for body mass index [208]. In another large
sample, maintaining an overall PBD is linked with reduced longitudinal insulin resistance,
prediabetes risk, and type 2 diabetes. Further, the authors also concluded that the protective
role of this diet is beyond strict vegetarian or vegan diets and includes a high plant-based
diet and fewer animal-option foods [209].
Other authors concluded that a PBD accompanied by educational intervention could
significantly improve HbA1c levels, weight, and, therefore, diabetes management [210].
Jardine et al. [3] highlight that insulin resistance and the succeeding dysfunction in β-cell
serve as the key characteristics of the pathophysiology underlying type 2 diabetes. Along
with this, long-term intervention and even a single high-fat meal can cause postprandial
elevations in plasma glucose that can remain high for an extended period. This result is
similar to what was found by Parry et al. [211]. The authors specify that consuming a satu-
rated fat diet had a strong effect, improving intrahepatic triacylglycerol and exaggerating
postprandial glycemia. Thus, a PBD has the potential to reverse β-cell dysfunction and
peripheral insulin resistance in patients with type 2 diabetes [212], partly by improving
glycemic control, reducing lipid accumulation in muscle and liver, and/or improving
insulin sensitivity. This is important since a multi-adjusted analysis revealed that baseline
non-alcoholic fatty liver was associated with a 2.95 times higher risk of type 2 diabetes
within 10 years. The evidence has shown that a healthy plant-based diet has an inverse
association with non-alcoholic fatty liver. Conversely, an unhealthy plant-based diet, dis-
tinguished by low amounts of fiber, vitamins, or minerals, and more refined sugar or
sodium consumption due to the increase in ultra-processed foods, showed the opposite
results [213].

3.2. Hypertension
Hypertension may be considered a chronic disease and is a risk factor for other dis-
eases. Its incidence depends on modifiable risk factors (e.g., smoking, diet, drinking, or
sedentarism/physical inactivity) and non-modifiable risk factors (e.g., genetic predispo-
sition). As such, a diet or following a healthy foods pattern can be crucial for prevention
and treatment. A healthy plant-based diet has shown positive results in both hypertensive
and non-hypertensive people. In a 3-year prospective study with 1546 non-hypertensive
individuals spanning the age range of 20 to 70, higher phytochemicals-rich foods consump-
tion was linked with a lower risk of developing hypertension [214]. In a large study with
13,771 participants, the authors demonstrated that only in male individuals was an increase
Nutrients 2023, 15, 3244 16 of 39

in antioxidants, vitamins, and phytochemicals correlated significantly with a reduction in

CRP, systolic, and diastolic blood pressure (SBP/DBP, respectively) [215].
Previous studies showed that vegetarians, especially vegans, have lower SBP and DBP,
and less hypertension than omnivores [216,217]. In a 4-week study, participants changed
their diets to a PBD. The authors observed changes in nutrient intake, reducing saturated fat,
cholesterol, protein, and some vitamins and minerals such as sodium, vitamin D, or vitamin
B12. However, after four weeks, vitamin C, folate, dietary fiber, magnesium, vitamin A, and
potassium significantly increased. Different measured biomarkers changed significantly,
such as total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, insulin, HbA1c,
and hs-CRP. However, glucose levels and total cholesterol/HDL ratio remained unchanged.
The main findings highlight that SBP and DBP clinically and significantly changed after
four weeks in a PBD. Interestingly, there were notable and marked declines in both blood
pressure medication usage and serum lipids [218].
Berries can positively affect vascular function and reduce hypertension via their phyto-
chemical anthocyanins. Previous studies have reported that a higher intake of anthocyanins
and flavones is inversely associated with lower arterial stiffness in women through the
significant reduction in central SBP, suggesting that incorporating one to two portions of
berries daily (44 mg anthocyanins) could be relevant to reducing cardiovascular disease
risk [219]. Fairlie-Jones et al. [220] stated that anthocyanins consumption from foods or
extracts significantly enhanced vascular health. FMD, as an indicator of vascular function,
is considered the gold-standard non-invasive vascular reactivity measure and has improved
after acute or chronic anthocyanidins consumption.
Supporting this, other authors have highlighted that anthocyanin is an inexpensive,
accessible, and effective approach to controlling atherosclerosis, cardiovascular risk, and
cardiovascular aging. They can exert their effects mainly by improving endothelial func-
tion, managing oxidative stress, and inhibiting certain enzymes such as cyclooxygenase-
1 and cyclooxygenase-2, which exert antihypertensive, antiatherogenic, antithrombotic,
antiglycation, and anti-inflammatory activities, and ameliorate dyslipidemia and arterial
stiffness [221]. Furthermore, a recent study [178] claimed that the main mechanism is
an increase in endothelial-derived nitric oxide, which enhances endothelium-dependent
vasorelaxation and prevents calcium-induced vascular smooth muscle contraction induced
by endothelial nitric oxide synthase.
Conversely, high dietary sodium consumption is one of the significant harmful agents
that impairs blood pressure homeostasis. According to the WHO, an intake of 5 g or more of
sodium per day is considered excessive. This has been strongly connected to elevated blood
pressure and the start of hypertension and its related cardiovascular complications [222].
The International Society of Hypertension Global Hypertension Practice Guidelines
recommend reducing dietary salt intake and increasing the availability of fresh fruits and
vegetables. The support for this lies in the physiological function of potassium in sodium
homeostasis [223,224]. However, not all evidence supports this association [225]. An earlier
study explained the theoretical mechanism referring to the capacity of potassium to modify
central or peripheral neural mechanisms that regulate blood pressure. Additionally, high-
potassium diets can lower blood pressure by relaxing the vascular smooth muscle and
directly decreasing peripheral vascular resistance [226].
Furthermore, the “Renal Potassium Switch” (RPS) can be activated or inhibited de-
pending on dietary potassium consumption. When potassium consumption is low, RPS
activates the NaCl cotransporter (NCC) in the distal convoluted tubule. Interestingly,
increased potassium intake decreases blood pressure by ~10 mmHg, which coincides with
NCC inactivation. A high salt intake in animals significantly elevated blood pressure but
not when the RPS was inactive [227,228]. Along with this, another study supported the
positive function of potassium in regulating blood pressure and/or hypertension [229].
It was explained previously that small changes in serum potassium can cause endothelium-
dependent vasodilation by hyperpolarizing the endothelial and vascular smooth muscle
cells. A high-potassium diet may also enhance vascular integrity on increased tension
Nutrients 2023, 15, 3244 17 of 39

due to hypertension. A high-potassium diet substantially reduced wall thickening in

the very large or small arteries of spontaneous hypertension rats (SHR). In a previous
analysis, a four-week increase in potassium consumption potentiates AngII-stimulated
aldosterone secretion without affecting systemic cardiovascular hemodynamics in healthy
normotensive men. This indicates that the antihypertensive effect of potassium is mediated
by its diuretic effect [230]. In addition to maintaining normal plasma potassium levels,
these natriuretic effects contribute to the blood pressure-lowering effect of high potassium
intake. The result of a potassium-deficient diet at the expense of increased sodium retention
has been linked to the pathogenesis of salt-sensitive hypertension [231].
A PBD may reduce blood pressure, body mass index, and lower sodium levels whilst
increasing potassium content in foods. Also, its function has been analyzed in terms of
improving NO bioavailability and the beneficial effect on the microbiome [5]. A recent
study highlights the relevance of opting for a healthy plant-based diet in preventing
hypertension. The authors found that 2244 individuals, based on a community cohort of
5636 men and women between 40–69 years, developed hypertension in a 14-year follow-
up period. However, according to a healthy plant-based diet, the highest versus lowest
quintiles exhibited significant differences. Those in the highest quintile of a healthy plant-
based diet had a 35% lower incidence of hypertension, while an unhealthy plant-based diet
showed a 44% greater hypertension incidence [232].

3.3. Dyslipidemia
Koh et al. [233] identified dyslipidemia as a prominent risk factor for ASCVD, a condi-
tion marked by the imbalance of atherogenic and protective lipids, such as triglycerides,
LDL cholesterol, and HDL cholesterol. Statins are standard treatment, as they inhibit
the critical step in cholesterol synthesis: the conversion of 3-hydroxy-3-methylglutaryl
coenzyme A (HMGC) to mevalonate by HMGC reductase. This gives statins a potent
lipid-lowering effect that reduces cardiovascular risk and decreases mortality (reducing
LDL cholesterol by ≥50%). However, statins have many common side effects ranging from
musculoskeletal symptoms, increased risk of diabetes, and higher rates of hemorrhagic
stroke [234].
Considering that mentioned above, a PBD has shown multiple beneficial effects on
dyslipidemia without adverse side effects. In a recent pilot, dietitian-led, vegan 12-week
program, the results showed a significant reduction in LDL cholesterol and LDL particles,
with a decreasing trend in very low lipoprotein density and chylomicron particles. These
beneficial changes have been attributed to the observed decrease in inflammation, as
measured by GlycA [235]. GlycA is considered a novel marker related to systemic and
subclinical vascular inflammation [236], a significant consequence of dyslipidemia that
affects others’ pathogenesis. In a study of 38 Romanian subjects who adopted a PBD for at
least one year, the authors observed that 75% of subjects with elevated TG succeeded in
normalizing them, as well as individuals with high LDL cholesterol levels, where 72.7%
from the borderline elevated level became optimal. The total cholesterol/HDL ratio shifted
from elevated to optimum levels in 78.6% of the cases [237].
One of the plant-based source components that plays an essential role in health is fiber.
Different studies have evaluated dietary fiber’s benefits for reducing LDL cholesterol. In
1999, with 67 controlled clinical trials, it was reported that other soluble fibers could reduce
total and LDL cholesterol to a similar extent. For instance, the consumption of 3 g of soluble
oat fiber reduces LDL cholesterol by <0.13 mmol/L [238].
A recent meta-analysis found that foods high in unsaturated and low in saturated
and trans fatty acids with added plant sterols/stanols and high in soluble fiber at least
moderately reduce LDL cholesterol [239]. This has also been published in a previous study
concluding that a low glycemic index and at least 23 g of fiber a day can help to improve
dyslipidemia in subjects with type 2 diabetes. A particular finding in this study was that
the changes were not dependent on altering energy intake or body composition. This is
important because most beneficial effects could eventually be overshadowed or mixed with
Nutrients 2023, 15, 3244 18 of 39

improving body composition, particularly the decrease in fat mass or improvement in the
percentage of total body fat [240].
The mechanism by which fiber improves cardiovascular health is not fully understood.
It has been proposed that fiber could modify cholesterol metabolism by directly interacting
with pancreatic lipase, binding to bile acids, increasing intraluminal viscosity, intestinal
microbiota secreting fermentation products that modulate hepatic fatty acid synthesis,
changes in intestinal motility, and increasing satiety that results in to lower overall energy
intake [238,241]. Soluble fiber directly affects serum cholesterol and LDL cholesterol
levels by binding bile acids in the small intestine and increasing their excretion in the
feces [242]. This trapping of cholesterol and bile acids in the small intestine reduces
absorption/reabsorption [243]. SCFA complements this effect.
Soluble fiber is resistant to hydrolysis in the small intestine but is fermented by gut
microbiota in the large intestine. In this context, a previous study observed that SCFA
reduces cholesterol levels by negating the counteractive induction of hepatic cholesterol
synthesis caused by increased bile acid excretion [244]. Also, it appears that SCFA plays a
role in the production of Apo-A I, which could consequently improve the functionality of
the serum HDL fraction [245]. This is relevant as HDL performs the opposite action to LDL
(reverse cholesterol transport). The absorption of SCFAs such as propionic acid has been
shown to decrease cholesterol synthesis in the liver, thus reducing plasma cholesterol and
increasing sodium and water absorption into the colonic mucosal cells.
Further, dietary saponins directly inhibit cholesterol absorption in the small intestine
and indirectly inhibit the reabsorption of bile acids to lower plasma cholesterol. Addition-
ally, phytochemicals have been shown to decrease LDL levels, which signal cholesterol
build-up, thus indicating that phytochemicals can also be used to reduce blood cholesterol
levels [246]. Therefore, if cholesterol absorption from the diet is reduced, physiological adap-
tations must be generated to maintain levels within normal ranges. Lütjohann et al. [247]
observed that lacto-vegetarians absorbed 44% less dietary cholesterol but synthesized 22%
more cholesterol, while vegans absorbed 90% less dietary cholesterol, synthesized 35%
more cholesterol, and had a similar plasma total cholesterol but a 13% lower plasma LDL
cholesterol than omnivores. The authors concluded that the reduction of LDL cholesterol
was significant only in vegans.
On the other hand, not all studies found a PBD to be beneficial for hypertriglyc-
eridemia [9]. However, the outcomes were positive when specific foods such as walnuts
were tested. Indeed, walnut consumption has shown notable improvements in triglyceride
levels, particularly among overweight/obese individuals, with men experiencing more
significant results than women. Nonetheless, a subgroup analysis reflects much-lowering
effects, comparing individuals with comorbidities versus healthy subjects [248]. Thus, the
different or negative impacts could be related to the “type of diet”.
As we mentioned at the beginning, according to the literature, two types of PBD
exist: healthy and unhealthy. In this line, a plant-based diet index (PDI), which separates
healthy plant-based diet options (i.e., fruits, whole grains, vegetables, legumes, nuts,
coffee, and tea) from less healthy plant-based diet options (i.e., refined grains, potatoes,
sugar-sweetened beverages, sweets and desserts, salty foods), was evaluated. The authors
found that those in the highest quintile of PDI and consuming a healthy plant-based
diet consumed more carbohydrates (including fiber), vitamins, and minerals but less
cholesterol, protein, and fat. In this study’s follow-up of 29,313 person-years, the incidence
of dyslipidemia was significantly lower in healthy plant-based diets than in unhealthy
plant-based diets, comparing the highest and lowest quintiles. In fact, one standard
deviation of PDI and healthy PDI was associated with a 9% and 16% lower risk of incident
dyslipidemia, respectively, and one standard deviation of unhealthy PDI was associated
with a 16% higher risk of dyslipidemia after adjustment for confounders effects. While PDI
and a healthy plant-based diet were inversely connected with hypertriglyceridemia, an
unhealthy plant-based diet was associated with all lipid disorders. Interestingly, this strong
association remained after adjustment for anti-dyslipidemia medication [249].
Nutrients 2023, 15, 3244 19 of 39

Additionally, previous evidence has shown that quinoa could decrease weight gain,
improve lipid profile, and improve capacity to respond to oxidative stress, mainly due to
saponins content [250]. Another study also showed decreased LDL cholesterol and TG after
30 days of quinoa bar consumption [251]. This has been supported previously [252]. Here,
the authors found a 36% reduction in TG levels after 12 weeks of 50 g of quinoa consump-
tion. The mechanism by which quinoa exhibits these benefits is not fully comprehended.
However, their effects are related to fiber content, reduction in dietary fat absorption due
to increased lipid content in feces, and/or bile acid activity. One crucial detail is that these
changes in triglyceride reduction levels were comparable to the reduction evidenced in
pharmacologic therapy that used 40% nicotinic acid, 35% fibrates, and 20% statins. Finally,
Table 2 displays a summary of findings on NCCD and MetS, Figure 2 provides a compre-
hensive overview addressing the overall advantages of adopting a plant-based diet, and
Figure 3 provides a synthesis addressing the general effects of adopting a plant-based food
pattern against specific chronic non-communicable diseases.

Table 2. NCCD and MetS (pre-clinical, clinical, prospective, or follow-up human studies summary).

Study Analysis Resume of Main Results Found

IR/IS DB * GI VF TG WC BW BMI BP HDL LDL
[185] Flavonoids x ↑ x x x x x x x x x
[188] Lifelong PBD adherence x ↑ x x x x x x x x x
[191] PBD x ↑ x x x x x x x x x
[197] Polyphenols ↑ ↑ x x x x x x x x x
[202] Genistein ↑ x x x x x x x x x x
Flavan-3-ols and
[203] ↑ x x x x x x x x x x
isoflavones
[204] Genistein ↑ ↑ x x ↓ x x x x x x
[205] PBD x ↑ x x x x x x x x x
[206] PBD ↑ ↑ x x x x x x x x x
[209] PBD ↑ x x x x x x x x x x
[211] PBD x x x x x x x x ↑ x x
PBD (results observed
[212] x x x x x x x x ↑ x x
only in males)
[213,214] PBD x x x x x x x x ↑ x x
[215] Diet change to PBD ↑ x = x = ↓ ↓ ↑ ↓ ↓
Berries anthocyanin
[216] x x x x x x x x ↑ x x
(women)
Healthy PBD vs.
[229] x x x x x x x x ↑ x x
Unhealthy PBD
[232] Vegan diet x x x x x x x x x x ↓
[234] PBD x x x x ↓ x x x x x ↓
Vegans vs.
[244] x x x x x x x x x x ↓
Lacto-vegetarians
Walnut’s intake (results
[245] x x x x ↓ x x x x x
men > women)
Quinoa bar consumption
[248] x x x x ↓ x x x x x ↓
(30 days)
[250] Blueberries ↑ x x x x x x x x x x
Nutrients 2023, 15, 3244 20 of 39

Table 2. Cont.

Study Analysis Resume of Main Results Found

Berberine (plant-derived
[253] ↑ x ↑ x x x x x x x x
compound)
[254–256] Polyphenols ↑ x ↑ x x x x x x x x
Strawberry and cranberry
[257] ↑ x x x x x x x x x x
polyphenols
[258] Grape polyphenols ↑ x x x x x x x x x x
[259] Fruits and vegetables x x x ↓ ↓ x x x x x x
Pesco-vegetarian and
[260] x x x x x ↑ ↑ ↑ x x x
vegetarians
[261] PBD adherence x x x x x ↑ x ↑ x x x
[262] x x x x x x x x ↑ x x
PBD adherence and
[263] x x x x x x x x = x x
high-flavonoid intake
[264] x x x x x x x x ↑ x x
[246] PBD adherence x x x x ↑ x x x x ↓ x
[265] PBD adherence x x x x ↑ x x x x x x
Vegetarians vs.
[266] x x x x ↓ x x x ↓ x ↓
omnivores
[267] PBD adherence x x x x ↓ x x x x ↓ ↓
[268] Tomato x x x x x x x x x ↑ x
Pakistani and American
[269] x x x x x x x x x ↑ x
almonds
[270] Strawberry anthocyanin ↑ x x x x x x x x x x
IR/IS: insulin resistance or insulin sensitivity; DB: diabetes or diabetic complications; GI: glucose intake; VF:
visceral fat; TG: triglycerides; WC: waist circumference; BW: body weight; BMI: body mass index; BP: blood
pressure; HDL: high-density lipoprotein; LDL: low-density lipoprotein; PBD: plant-based diet; NCCD: non-
communicable chronic diseases. For more details see the main text. x: not measured or not informed; Arrow
Nutrients 2023, 15, x FOR PEER REVIEW
down (↓): decrease or negative association; Arrow up (↑): improvement or positive association; Equal21 of (=):
sign 41
without change; Green box: positive change; Red box: negative change. Yellow box: no change. * Diabetes: type 1
or type 2 diabetes.

Figure 3. AA brief
brief description
descriptionof
ofPBD
PBDbenefits
benefitsfor
forNCCD
NCCDand andMetS.
MetS.NRf2:
NRf2:nuclear factor
nuclear erythroid
factor 2-
erythroid
related factor
2-related factor2;2;NF-kB:
NF-kB: nuclear factor-κB;ROS:
nuclear factor-κB; ROS:reactive
reactiveoxygen
oxygen species;
species; SBP:
SBP: systolic
systolic blood
blood pres-
pressure;
sure; DBP:
DBP: diastolic
diastolic bloodblood pressure;
pressure; Apo-A Apo-A I: apolipoprotein
I: apolipoprotein A I;triglycerides.
A I; TG: TG: triglycerides.

4. A Plant-Based Diet and Metabolic Syndrome

4.1. Insulin Resistance (Fasting Blood Sugar)
The relationship between high fasting blood sugar (hyperglycemia) and insulin re-
sistance (IR) is consistent. IR is a pathological condition in which cells fail to respond nor-
Nutrients 2023, 15, 3244 21 of 39

4. A Plant-Based Diet and Metabolic Syndrome

4.1. Insulin Resistance (Fasting Blood Sugar)
The relationship between high fasting blood sugar (hyperglycemia) and insulin resis-
tance (IR) is consistent. IR is a pathological condition in which cells fail to respond normally
to insulin. Consequently, this leads to elevated blood glucose levels, often accompanied by
hyperinsulinemia and hyperglycemia. In this condition, pancreatic β-cells secrete excessive
insulin to maintain normal blood sugar levels.
The principal function of insulin in skeletal muscle is to stimulate glucose uptake by
inducing the translocation of the specific glucose transporter GLUT4 from the cytoplasm
to the plasma membrane. Upon binding to GLUT4, insulin initiates a signaling cascade
to phosphorylate and activates the Insulin Receptor Substrate (IRS), leading to the activa-
tion of various protein kinases (PI3 kinase, Pdk1, and Akt). Activated Akt moves to the
plasma membrane and phosphorylates Akt Substrate of 160 kDa (AS160). AS160 initiates
GLUT4 translocation, allowing for glucose influx into skeletal muscle. This glucose is then
undergoing glycolysis and thus blood glucose levels are lowered.
A previous study has demonstrated that both acute blueberry consumption and short-
term blueberry supplementation have beneficial effects on glucose regulation and insulin
balance in sedentary individuals, presumably mediated through gastrointestinal enzyme
inhibition and incretins secretion [271]. Prioritizing plant sources to the detriment of tra-
ditional animal alternatives results in lower IR and a lower risk of prediabetes and type
2 diabetes [272]. Similarly, Kahleova et al. [212] found in a 16-week randomized clinical
intervention that β-cell function and fasting insulin resistance were improved by a qualita-
tive change in macronutrient composition with no limit on energy intake in overweight
individuals with no history of diabetes. HOMA-IR is considered an effective indicator of
IR since it provides an estimate of fasting glucose and insulin serum concentrations [273].
Further, previous studies have extensively demonstrated that AMPK stimulation can
improve health in different contexts. The AMPK signaling pathway provides an alternative
to the insulin-dependent glucose uptake pathway in muscle by activating phosphatidyl-
inositol-3 kinase (PI3-K) and PKB/Akt [253]. Data support that AMPK inhibits Rab-GTPase
activating proteins AS160 (TBC1D4) and TBC1D1, which triggers Glut-4 trafficking to the
plasma membrane [274]. Firstly, related to the stimulation of Glut-4 translocation and
AMPK activation, a previous study demonstrated that anthocyanin-rich extract from black
rice promotes glucose uptake by increasing Glut-4 expression in the plasma membrane in
C2C12 myotubes via activation of the PI3K/Akt and AMPK/p38 MAPK pathways [275].
Furthermore, resveratrol, a naturally occurring phytochemical, increases glucose uptake in
insulin-resistant 3T3-L1 adipocytes by increasing pAkt phosphorylation and downstream
AMPK activation. In another study, berberine, a natural plant-derived compound, can
indirectly activate AMPK. Furthermore, a berberine derivative demonstrated enhanced
insulin sensitivity and reduced adiposity in vivo in high-fat diet rats [254].
On the other hand, in recent years, PPAR has gained significant interest due to its
potential role as an essential regulator of glucose metabolism and insulin sensitivity. PPAR-
α activation stimulates pancreatic islet β-cells, potentiating glucose-stimulated insulin
secretion. On the contrary, PPAR-α deficiency in a mouse model of obesity-related in-
sulin resistance leads to reduced insulin secretion by pancreatic β-cells in response to
glucose [255]. This improvement in insulin sensitivity has been theorized in the modifica-
tion of signaling due to a decrease in ectopic lipids in non-adipose tissues and a decrease
in circulating fatty acids and triglycerides, seen in animal models [256]. Furthermore,
PPARγ activation in type 2 diabetic patients results in a marked improvement in insulin
and glucose parameters by modifying whole-body insulin sensitivity.
Given this, diet-induced PPAR downregulation can be viewed as a negative effect. For
instance, a high-fat diet can negatively affect the activity or expression of PPAR, favoring
several complications, such as IR. However, some bioactive plant components, like the
polyphenols present in coffee, rice, berries, and others, can modulate this pathway, increas-
ing PPARα and γ mRNA [257]. Polyphenols have a positive effect on insulin sensitivity
Nutrients 2023, 15, 3244 22 of 39

and improve IR by way of several mechanisms, including lowering postprandial glucose,

modulating glucose transport, affecting insulin signaling pathways, and protecting against
damage to insulin-secreting pancreatic β-cells [276]. In fact, synergistic metabolic action
between exercise and polyphenols consumption from grapes counteracts anthropometric
and metabolic impairments. It increases insulin sensitivity, probably via lipid oxidation
enhancement and glycogen utilization reduction. Although this study was performed
in animals, the amount of polyphenols consumed by the specific grape is equivalent to
nutritional amounts ingested daily by humans [258].
Moreover, in a study of IR nondiabetic adults, the 6-week consumption of strawberry
and cranberry polyphenols showed that the consumption of 333 mg polyphenols might
improve insulin sensitivity and prevent an increase in compensatory insulin secretion with-
out affecting plasma lipids, CRP, proinflammatory cytokines, or antioxidant capacity [270].
This result is in line with a previous study that evaluated daily dietary bioactive supple-
mentation in freeze-dried whole blueberry powder. The authors found an improvement in
insulin sensitivity in obese, nondiabetic, and insulin-resistant participants after six weeks,
independent of any changes in inflammatory biomarkers or adiposity [277]. Different other
studies have found similar results [278,279].
Inflammatory signaling pathways are associated with the activation of TLRs. TLRs
are transmembrane proteins that regulate the innate immune response in various patho-
physiological states like sepsis and cardiovascular disease [280]. TLR signaling triggers
transforming growth factor β activating kinase 1 activation and, subsequently, also MAPK
and NF-κB [281]. NF-κB regulates the transcription of inflammatory cytokines such as
TNF, IL-6, and IL-1 [282]. TLR2 and TLR4 are involved in inflammation and insulin re-
sistance [283] in human skeletal muscle cells [284]. Interestingly, in mice, the absence of
TLR2 and TLR4 from the plasma membrane protects against obesity and IR [285], which
generated a lot of interest in the TLRs as possible therapeutic targets in the fight against
obesity and IR. A recent review identified some plant extracts as potential modulators of
TLRs controlling inflammation and the immune response [259]. Counteracting the nega-
tive effects of chronic low-grade inflammation may result in beneficial effects in different
pathological states such as insulin resistance.

4.2. Visceral Obesity and Waist Circumference

A recent study reported that greater adherence to a healthy plant-based pattern,
but not an unhealthy one, was linked with lower visceral adipose tissue, accounting
for several potential confounding variables [260,286]. This outcome aligns with a Dutch
study comparing sweet snacks against fruit and vegetable consumption. While the first
was associated with hepatic triglyceride content, consuming fruits and vegetables was
negatively related to visceral fat and liver fat content (triglycerides) [261]. The theoretical
mechanism of these positive results is partly in energy consumption, considering that a
PBD is high in fiber [287] and higher in antioxidants. In the case of fiber, it can help increase
satiety with little or no calorie intake.
On the other hand, antioxidants can reduce inflammation related to visceral adiposity.
A healthy and unhealthy plant-based diet have marked differences in the amounts of sugar,
glycemic index, and energy intake with the theoretical capacity to increase weight and,
consequently, waist circumference.
A recent study [263] performed on older Australian women showed that body weight,
body mass index, and waist circumference were significantly lower in pesco-vegetarian
and vegetarians than meat-eaters. Moreover, among meat-eaters, subjects that consume
meat regularly or several times a week, compared with those consuming meat two or fewer
times a week, present higher body weight, body mass index, and waist circumference. To
be detailed, in a dose-dependent meat intake, for every increase in the category of weekly
meat intake, an associated 2.6 kg increase in body weight, a 0.9 kg/m2 increase in body
mass index, and a 2–3 cm increase in waist circumference were reported. Although this
evidence does not qualify as a PBD, it is essential to highlight that meat consumption
Nutrients 2023, 15, 3244 23 of 39

frequency was the primary factor involved in the main results. Another study that included
9633 participants showed that greater adherence to a PBD was associated with lower body
mass index, waist circumference, fat mass index, and body fat percentage across a median
follow-up period of 7.1 years [262]. This result has been previously supported by other
authors [288].

4.3. High-Blood Pressure

High blood pressure is universally known as a risk factor for several chronic diseases,
such as hypertension. In a recent meta-analysis [6], the authors concluded that a PBD
reduced SBP and DBP. The authors established that a high fruit and vegetable diet was as-
sociated with a mean reduction in SBP. Although some studies did not observe a consistent
association between fruit and vegetable consumption and improved blood pressure in older
age [264], the central body of evidence has found positive results. For instance, healthy
PDI is associated with lower blood pressure, while unhealthy PDI is adversely related to
blood pressure. A PBD rich in vegetables and whole grains and limited in refined grains,
sugar-sweetened beverages, and total meat may contribute to these associations [289]. In a
study by Stefler et al. [264], the preference for vegetable consumption involves preserved
or cooked vegetables instead of having them raw, and including salt during both types
of procedures might counteract the positive benefits of these foods. Additionally, the
authors mentioned some study limitations that could explain the lack of clear association.
Nevertheless, other studies have found the benefits of fruit and/or vegetable intake for
blood pressure.
In this line, it has been hypothesized that fiber, different nutrients, bioactive compo-
nents, and plant-sourced foods, such as fruits and/or vegetables, can exert their benefits
on blood pressure due to the improvement in baroreflex sensitivity [290], endothelial-
dependent vasodilatation related to high-flavonoid intake [291], and the inhibition of
inflammation and oxidative stress response [265,266]. In a study on cranberry juice and
vascular function, patients with coronary artery disease registered a reduction in carotid-
femoral pulse wave velocity, a clinically relevant measure of arterial stiffness [292].

4.4. Hypertriglyceridemia
A PBD has widely demonstrated several benefits related to MetS. For instance, in a
recent South Korean prospective cohort study [293] comparing the highest with the lowest
quintiles of an unhealthy plant-based diet linked to greater intake versus lower intake, in a
follow-up of 8 years, the highest quintile had a 50% higher risk of developing MetS. After
adjusting for body mass index, those in the highest quintile of an unhealthy plant-based diet
had a 24% to 46% higher risk of four out of five individual components of MetS, including
hypertriglyceridemia. These results have been recently supported, detailing that greater
adherence to PDI or healthy PDI was associated with a lower risk of incident dyslipidemia.
In contrast, greater adherence to unhealthy PDI was associated with a higher risk.
Moreover, the authors detailed that PDI was inversely associated with low HDL
cholesterol among women, while among men a greater adherence to PDI was inversely
associated with hypertriglyceridemia [249]. Based on Korean food patterns, the authors
reported that the lipid composition from a PBD leads to less absorption and conversion
to blood cholesterol and reduced triglyceride concentration. This is because plant foods
are rich in compounds for preventing dyslipidemia, such as dietary fiber, phytosterols,
antioxidants, and polyphenols.
On the other hand, although some studies did not refer to a PBD, the reduction in
animal-based food has also shown positive effects. Teixeira et al. [294], in a comparison
between vegetarians and omnivores, found that different indicators such as blood pressure,
fasting plasma glucose, total cholesterol, LDL cholesterol, and triglycerides were lower
among vegetarians. In fact, the authors complemented the results, highlighting that an
unbalanced omnivorous diet with excess animal protein and fat may be implicated, to a
Nutrients 2023, 15, 3244 24 of 39

great extent, in the development of non-communicable diseases and conditions, especially

cardiovascular risk.
The consumption of dietary fiber of those who opt for a PBD and those who follow a
traditional Western diet differs significantly. In this context, dietary fiber has been evaluated
in the reduction of postprandial triglycerides response [295]. The beneficial mechanism of
this property is strongly attributed to its viscosity, which effectively slows down gastric
emptying and disrupts the emulsification of fats and the formation of micelles in the
gastrointestinal tract. This is achieved by reducing the availability of circulating bile acids.
Also, soluble fiber can be fermented by the gut microbiota to release metabolites such as
SCFA, which upregulate genes PPARα and PPAR-γ coactivator-1α (PGC-1α) involved in
lipid metabolism and the regulation of postprandial triglycerides response.

4.5. Dyslipidemia (Low HDL Cholesterol)

Generally, HDL cholesterol is considered a healthy biomarker due to its ability to
reverse cholesterol transport and reduce cardiovascular risk. This cardioprotective function
is supported by theoretical mechanisms, such as the regulation of cholesterol efflux, where
apolipoprotein A-I (Apo-A I), the main component of HDL, is mainly responsible for
reverse cholesterol transport through the macrophage ATP-binding cassette transporter
ABCA. Another mechanism lies in the modulation of inflammation, antioxidant, and
vasoprotective effects [296]. However, according to Kosmas et al. [297], HDL functionality
is more critical in atheroprotection than circulating HDL cholesterol levels. In fact, plasma
HDL constitutes a heterogeneous group of particles with diverse structures and biological
activity and, under certain conditions, may become proinflammatory. Further, Apo-A I
can be damaged by oxidative mechanisms, which render the protein less able to promote
cholesterol efflux. Navab et al. [296] complement this information by pointing out that a
modification of the protein components of HDL can convert it from an anti-inflammatory
to a proinflammatory particle.
Very high HDL cholesterol could be more harmful than harmless; several previous
investigations have reported that the elevation of HDL cholesterol could result in a cardio-
vascular risk factor [298,299]. This relationship between high HDL cholesterol levels and
mortality risk has been observed even at >80 mg/100 mL, although the authors reported
that it was related to men, not women [300]. Both extremely high and low HDL cholesterol
are associated with an increased mortality risk [301].
These paradoxical results’ mechanisms and theoretical explanations can be attributed
to two main factors. Firstly, some genetic disorders raise HDL cholesterol, such as primary
familial or secondary hyperalphalipoproteinemia, mainly resulting in the overproduction
or variants of apolipoprotein C-III (Apo-C III) due to a mutation in Apo-A I. These compli-
cations promote HDL cholesterol dysfunction, stimulate smooth muscle cell proliferation,
facilitate the interaction between monocytes and endothelial cells, and alter platelet activity,
all triggering atherosclerosis [298,299,301]. Secondly, a previous study [302] has shown that
a moderate to high HDL concentration impairs human endothelial progenitor cells and
related angiogenesis by activating rho-associated kinase pathways in healthy subjects. The
authors found that, although oxidized LDL reduces the cell viability of late-growing EPCs
derived from healthy human peripheral blood in a dose-dependent relationship, HDL alone
might not be enough to counteract this negative effect and might even be paradoxically
impaired at high concentrations (400–800 µg/mL, equivalent to 40–80 mg/dL in humans).
Some evidence has indicated that vegans, vegetarians, or PBD reduce total, LDL, and
HDL cholesterol compared to omnivores in observational and clinical studies [9]. Along
with this, some authors have found that a short-term, very low carbohydrate diet has
been associated with an increase in HDL cholesterol in normal-weight normolipidemic
women [303]. However, a low carbohydrate plant-based diet (eco-atkins) was evaluated
in hyperlipidemic subjects. The result demonstrated a greater reduction in Apo-B, Apo-A
I, LDL, and HDL cholesterol compared to a high carbohydrate diet, resulting in better
context in which to improve heart disease risk factors [304]. This discrepancy of findings
Nutrients 2023, 15, 3244 25 of 39

might generate a confounding analysis in evaluating a PBD, cardiovascular risk, and

HDL cholesterol.
Regarding these findings, some authors have evaluated the total cholesterol/HDL
cholesterol ratio (T/H-r) as a predictor of cardiovascular disease. Previous studies estab-
lished that this ratio has a better predictive value than the isolated parameters in vascular
risk. In fact, when there is no reliable calculation of LDL cholesterol, it is preferable to use
the T/H-r [305]. An earlier study has supported this and indicated that T/H-r is a superior
measure of risk for coronary heart disease compared with either total cholesterol or LDL
cholesterol levels [306]. A recent large study [267] has sustained this finding. Although non-
HDL cholesterol is linearly related to ischemic heart disease and may be easier to calculate,
T/H-r represents a higher predictability as a clinical predictor than non-HDL cholesterol.
In addition, Quispe et al. [307] reported that the potential clinical utility of T/H-r is most
apparent among individuals in whom TC/HDL-C levels are inconsistent with their other
lipid parameters (i.e., LDL cholesterol and non-HDL cholesterol). Discordance was more
pronounced in those with high triglycerides and low HDL cholesterol levels, characteristic
of patients with insulin resistance, diabetes, and MetS, who also have a higher prevalence
of LDL and Apo-B particles that are cholesterol depleted.
Considering the information above, the lower T/H-r, the better. Bleda et al. [308] found
that improvement of nitrite levels is associated with decreased T/H-r values in peripheral
artery disease patients, resulting in endothelial dysfunction recovery. In this line, a previous
study demonstrated that a low fat, plant-based lifestyle intervention reduced HDL levels
but this was not as great as the decrease in LDL and TC, resulting in improvements in
the T/H-r of −3.2% and the LDL/HDL ratio of −5.3% [309]. According to the authors,
even when HDL levels decreased, other indicators of cardiovascular risk improved, raising
the question of whether HDL levels are a suitable predictor of cardiovascular risk in
this population.
In subjects who do not consume a typical Western diet or have a diagnosis of MetS, it
may not be appropriate in clinical practice or research to apply lifestyle interventions that
promote a plant-based eating pattern. It is relevant to mention that, although 323 partici-
pants classified as having MetS at program entry no longer had this status after 30 days,
112 participants acquired the MetS classification because of reduced HDL levels. Regard-
ing HDL levels, the mean value changed by −8.7% from 54.84 (baseline) to 50.07 (post-
intervention), considering the average value within the normal ranges. Supporting this, a
previous meta-analysis suggested that the T/H-r was more predictive than HDL or non-
HDL cholesterol sub-fractions and two times more predictive than total cholesterol [310].
Taking this into account, HDL has components with anti-inflammatory functions, such
as Apo-A I and paraoxonase 1. At the same time, the proinflammatory action lies mainly
in Apo-A II and Apo-C III. Regarding the latter, four prospective cohort studies indicated
that Apo-C III might mark a subfraction of HDL associated with a higher risk of coronary
heart disease [311]. This finding raises the question of whether the reduction in HDL may
decrease in part the proinflammatory component of this particle.
The presence or absence of Apo-C III in HDL could be responsible for opposite
outcomes related to cardiovascular risk. For instance, HDL that lacks Apo-C III inhibits
the monocyte-endothelial cell interaction, leading to a lowered inflammatory response.
In contrast, HDL with Apo-C III did not diminish this interaction [268]. Previous studies
have provided supporting evidence that certain drugs aimed at improving health can
increase HDL cholesterol levels but do not effectively reduce coronary atherosclerosis [269].
In this study, using the CEPT (cholesteryl ester transfer protein) inhibitor after one-year
of treatment increased HDL cholesterol by approximately 60%, while LDL cholesterol
decreased by about 20%. However, there was no significant reduction in the progression of
coronary atherosclerosis according to the percent atheroma volume, the primary efficacy
measure. Another study has found similar results with a different drug [312]. Given that,
for people who follow a healthy plant-based diet, reducing HDL cholesterol could not be
Nutrients 2023, 15, 3244 26 of 39

as harmful as those who suffer from a chronic disease. The decrease in HDL cholesterol is
likely less of a concern and the need to increase these levels is less critical.
Nonetheless, some plant foods have shown a positive relationship with improving
HDL cholesterol levels. In a randomized, single-blinded, controlled clinical trial [313],
tomato consumption showed an independent positive association with HDL cholesterol.
In an isocaloric diet, subjects were randomized to receive 300 g of cucumber (control
group) or two uncooked Roma tomatoes daily for four weeks. The results indicated
that subjects with initial low HDL cholesterol who ate tomato changed their levels from
36.5 ± 7.5 mg/dL to 41.6 ± 6.9 mg/dL. Another study evaluating a specific plant food
also found a positive association [314]. The authors found that 10 g/day consumed before
breakfast can increase HDL cholesterol and improve other markers of abnormal lipid
metabolism in coronary artery disease patients with low initial HDL cholesterol levels. At
weeks 6 and 12, HDL cholesterol was 12–14% and 14–16% higher, referring to Pakistani
and American almonds, respectively.
Furthermore, a more recent meta-analysis [315] reported that avocado consumption
significantly increased HDL cholesterol with significant heterogeneity. This remained
consistent in sensitivity and subgroup analyses. Therefore, although HDL cholesterol has
been declared for decades as an essential indicator to protect our health, in some contexts
where different health factors are present, such as physical activity or healthy eating habits,
the subtle reduction of this component might not be a problem because a whole-food
plant-based diet is considered more protective. Finally, Table 2 displays a summary of
findings on NCCD and MetS, while Figure 2 shows a brief description of PBD benefits for
NCCD and MetS, and Figure 3 provides a comprehensive overview addressing the overall
advantages of adopting a plant-based diet.

5. Conclusions
Over the past two decades, a substantial body of consistent evidence has emerged at
the cellular and molecular level, elucidating the numerous benefits of a plant-based diet
(PBD) for preventing and mitigating conditions such as atherosclerosis, chronic noncommu-
nicable diseases, and metabolic syndrome. It is paramount to prioritize the consumption of
quality, natural, and fermented foods to fully harness the health potential of this dietary
approach. With guidance from qualified professionals to ensure optimal nutrition, any
concerns regarding potential nutritional deficiencies can be effectively addressed through
diverse and well-planned food choices. This specialist support enables individuals to adopt
a PBD at any stage of life, allowing them to reap its benefits while minimizing potential
risks. Consequently, a plant-based diet offers a promising outlook for improving the health
and well-being of the global population, with its protective effects mediated by bioactive
compounds. It is crucial for both the public and researchers to recognize the significance
of this evidence and its implications for nutrition science and public health. As our un-
derstanding of the underlying mechanisms of a PBD continues to expand, there remain
exciting areas within this field of study to explore and uncover.

Author Contributions: H.P.-J. conceived and designed the review and wrote the initial draft. C.C.-M.
contributed to the conceptualization of the design and critically reviewed the manuscript. All other
authors provided valuable insights and feedback to enhance the final version. All authors have read
and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
Nutrients 2023, 15, 3244 27 of 39

Abbreviations

AMPK AMP-activated protein kinase

DHA docosahexaenoic acid
EPA eicosapentaenoic acid
FMD flow-mediated dilatation
HDL high-density lipoprotein
LDL low-density lipoprotein
MetS metabolic syndrome
PBD plant-based diet
PDI plant-based diet index
PUFAs polyunsaturated fatty acids
TMAO trimethylamine N-oxide
SCFAs short-chain fatty acids
TNF-α tumor necrosis factor-alpha
ABC ATP-binding cassette
ASCVD atherosclerotic cardiovascular disease

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