Gut Microbiota: The Neglected Endocrine Organ

OCL, 2015

The gastro-intestinal tract hosts a complex microbial ecosystem, the gut microbiota, whose collective genome coding capacity exceeds that of the host genome. The gut microbiota is nowadays regarded as a full organ, likely to contribute to the development of pathologies when its dynamic balance is disrupted (dysbiosis). In the last decade, evidence emerged that the gut microbiota influences brain development and function. In particular, comparisons between germ-free and conventional laboratory rodents showed that the absence of the gut microbiota exacerbates the hypothalamic pituitary adrenal (HPA) system reactivity to stress and alters the anxiety-like behaviour. Furthermore, the dysfunctions observed in germ-free animals can be corrected if the gut microbiota is restored in early life but not in adulthood, suggesting a critical period for microbiota imprinting on the responsiveness to stress. The modes of action are still to be deciphered. They may involve transport of neuroactive bacterial metabolites to the brain through the bloodstream, stimulation of the vagus nerve or of entero-endocrine cells, or modulation of the immune system and, consequently, of the inflammatory status. The discovery that the gut microbiota regulates the neuroendocrine and behavioural responses to stress paves the way for the hypothesis that gut microbiota dysbioses could contribute to the pathophysiology of anxiety-related disorders. In this regard, treatments of anxiety-prone rodent strains with probiotics or antibiotics aimed at modifying their gut microbiota have shown an anxiolytic-like activity. Clinical trials are now needed to know if results obtained in preclinical studies can translate to humans. Keywords: Gut-brain axis / germ-free / probiotic / hypothalamic pituitary adrenal axis / anxiety Résumé-Effet du microbiote intestinal sur les réponses neuroendocrinienne et comportementale au stress. Le tractus gastro-intestinal héberge une communauté microbienne complexe appelée microbiote, dont le potentiel génétique excède celui de l'hôte en richesse et diversité. Le microbiote intestinal est considéré aujourd'hui comme un véritable organe, susceptible de contribuer au développement de pathologies si son équilibre est rompu (on parle alors de dysbiose). Au cours de la dernière décennie, des travaux ont commencé à mettre en évidence que le microbiote intestinal influençait le développement et le fonctionnement du cerveau. En particulier, des comparaisons entre rongeurs axéniques et conventionnels ont montré que l'absence de microbiote intestinal intensifiait la réponse au stress de l'axe corticotrope et modifiait le niveau d'anxiété. Ces anomalies ne peuvent être corrigées que si la restauration du microbiote chez les animaux axéniques intervient avant l'âge adulte. Ceci suggère l'existence d'une période critique du développement au cours de laquelle le microbiote influence la maturation des structures cérébrales impliquées dans la réponse au stress. Les mécanismes d'action ne sont pas encore complètement élucidés. Pourraient intervenir des métabolites microbiens neuro-actifs, atteignant le cerveau par voie sanguine, une stimulation des afférences intestinales du nerf vague, une stimulation des cellules endocrines de la paroi intestinale, ou une modulation du système immunitaire et, par conséquent, du statut inflammatoire de l'organisme. La découverte que le microbiote intestinal régule les réponses neuroendocrinienne et comportementale au stress conduit à l'hypothèse que des dysbioses du microbiote pourraient contribuer à la physiopathologie des troubles anxieux ou des troubles de l'humeur ayant une composante anxieuse. À cet égard, la modulation du microbiote intestinal avec des probiotiques ou des antibiotiques chez des lignées de rongeurs prédisposées à l'anxiété a un effet de type anxiolytique. Des essais cliniques sont maintenant nécessaires pour déterminer si ces résultats précliniques sont transposables à l'Homme.

Antonie van Leeuwenhoek, 2013

The microorganisms living in our gut have been a black box to us for a long time. However, with the recent advances in high throughput DNA sequencing technologies, it is now possible to assess virtually all microorganisms in our gut including non-culturable ones. With the use of powerful bioinformatics tools to deal with multivariate analyses of huge amounts of data from metagenomics, metatranscriptomics, metabolomics, we now start to gain some important insights into these tiny gut inhabitants. Our knowledge is increasing about who they are, to some extent, what they do and how they affect our health. Gut microbiota have a broad spectrum of possible effects on health, from preventing serious diseases, improving immune system and gut health to stimulating the brain centers responsible for appetite and food intake control. Further, we may be on the verge of being capable of manipulating the gut microbiota by diet control to possibly improve our health. Diets consisting of different components that are fermentable by microbiota are substrates for different kinds of microbes in the gut. Thus, diet control can be used to favor the growth of some selected gut inhabitants. Nowadays, the gut microbiota is taken into account as a separate organ in human body and their activities and metabolites in gut have many physiological and neurological effects. In this mini-review, we discuss the diversity of gut microbiota, the technologies used to assess them, factors that affect microbial composition and metabolites that affect human physiology, and their potential applications in satiety control via the gut-brain axis.

Pharmacology & Therapeutics, 2011

a b s t r a c t a r t i c l e i n f o Keywords: Gut microbiota LPS Obesity/type 2 diabetes Gut permeability Inflammation Endocannabinoid system Obesity, type-2 diabetes and low-grade inflammation are becoming worldwide epidemics. In this regard, the literature provides a novel concept that we call "MicrObesity" (Microbes and Obesity), which is devoted to deciphering the specific role of dysbiosis and its impact on host metabolism and energy storage. In the present review, we discuss novel findings that may partly explain how the microbial community participates in the development of the fat mass development, insulin resistance and low-grade inflammation that characterise obesity. In recent years, numerous mechanisms have been proposed and several proteins identified. Amongst the key players involved in the control of fat mass development, Fasting induced adipose factor, AMP-activated protein kinase, G-protein coupled receptor 41 and G-protein coupled receptor 43 have been linked to gut microbiota. In addition, the discovery that low-grade inflammation might be directly linked to the gut microbiota through metabolic endotoxaemia (elevated plasma lipopolysaccharide levels) has led to the identification of novel mechanisms involved in the control of the gut barrier. Amongst these, the impacts of glucagon-like peptide-2, the endocannabinoid system and specific bacteria (e.g., Bifidobacterium spp.) have been investigated. Moreover, the advent of probiotic and prebiotic treatments appears to be a promising "pharmaco-nutritional" approach to reversing the host metabolic alterations linked to the dysbiosis observed in obesity. Although novel powerful molecular system biology approaches have offered great insight into this "small world within", more studies are needed to unravel how specific changes in the gut microbial community might affect or counteract the development of obesity and related disorders.

Behavioural Pharmacology, 2019

Stress is a nonspecific response of the body to any demand imposed upon it, disrupting the body homoeostasis and manifested with symptoms such as anxiety, depression or even headache. These responses are quite frequent in the present competitive world. The aim of this review is to explore the effect of stress on gut microbiota. First, we summarize evidence of where the microbiota composition has changed as a response to a stressful situation, and thereby the effect of the stress response. Likewise, we review different interventions that can modulate microbiota and could modulate the stress according to the underlying mechanisms whereby the gut–brain axis influences stress. Finally, we review both preclinical and clinical studies that provide evidence of the effect of gut modulation on stress. In conclusion, the influence of stress on gut microbiota and gut microbiota on stress modulation is clear for different stressors, but although the preclinical evidence is so extensive, the cli...

Journal of Medicinal Food, 2014

The human gut microbiome impacts human brain health in numerous ways: (1) Structural bacterial components such as lipopolysaccharides provide low-grade tonic stimulation of the innate immune system. Excessive stimulation due to bacterial dysbiosis, small intestinal bacterial overgrowth, or increased intestinal permeability may produce systemic and/or central nervous system inflammation. (2) Bacterial proteins may cross-react with human antigens to stimulate dysfunctional responses of the adaptive immune system. (3) Bacterial enzymes may produce neurotoxic metabolites such as Dlactic acid and ammonia. Even beneficial metabolites such as short-chain fatty acids may exert neurotoxicity. (4) Gut microbes can produce hormones and neurotransmitters that are identical to those produced by humans. Bacterial receptors for these hormones influence microbial growth and virulence. (5) Gut bacteria directly stimulate afferent neurons of the enteric nervous system to send signals to the brain via the vagus nerve. Through these varied mechanisms, gut microbes shape the architecture of sleep and stress reactivity of the hypothalamic-pituitary-adrenal axis. They influence memory, mood, and cognition and are clinically and therapeutically relevant to a range of disorders, including alcoholism, chronic fatigue syndrome, fibromyalgia, and restless legs syndrome. Their role in multiple sclerosis and the neurologic manifestations of celiac disease is being studied. Nutritional tools for altering the gut microbiome therapeutically include changes in diet, probiotics, and prebiotics. KEY WORDS: D-lactic acid endotoxin microbial endocrinology microbiome prebiotics probiotics short-chain fatty acids trimethylamine oxide (TMAO)

Psychoneuroendocrinology, 2014

Background and aims: Establishment of the gut microbiota is one of the most important events in early life and emerging evidence indicates that the gut microbiota influences several aspects of brain functioning, including reactivity to stress. To better understand how the gut microbiota contributes to a vulnerability to the stress-related psychiatric disorders, we investigated the relationship between the gut microbiota, anxiety-like behavior and HPA axis activity in stresssensitive rodents. We also analyzed the monoamine neurotransmitters in the brain upper structures involved in the regulation of stress and anxiety. Methods: Germfree (GF) and specific pathogen free (SPF) F344 male rats were first subjected to neurological tests to rule out sensorimotor impairments as confounding factors. Then, we

Pathology and Laboratory Medicine International, 2017

Purpose of review: We have established that many metabolic biomes exist within the complex mammalian gut. Substantial metabolism occurs within these biomes and is called co-metabolism of the host and resident microorganisms. This gut-brain-endocrine metabolic interaction emphasizes how bacteria can affect the brain and the hormonal axes in the process of co-metabolism. This review highlights new findings in this regard. Recent findings: In this review, we explore how the gut microbiota affect the development and regulation of the hypothalamic-pituitary-adrenal axis and neurochemistry from mental health and behavioral health to memory, depression, mood, anxiety, obesity, and the development of the blood-brain barrier. Summary: This review describes the implications of the findings for clinical practice or research. Interaction of small molecules within these biomes is now described collectively as a "metabolic interactome". Metabolites of the gut-brain-endocrine axis and our overall gut health constantly shape the host phenotype in ways previously unimagined, and this niche represents potential targets for treatment and drug design, since the interaction or biochemical interplay results in net metabolite production and/or end products to exercise either positive or negative effects on human health.

Proceedings of the Nutrition Society, 2014

A healthy gut microbiota plays many crucial functions in the host, being involved in the correct development and functioning of the immune system, assisting in the digestion of certain foods and in the production of health-beneficial bioactive metabolites or ‘pharmabiotics’. These include bioactive lipids (including SCFA and conjugated linoleic acid) antimicrobials and exopolysaccharides in addition to nutrients, including vitamins B and K. Alterations in the composition of the gut microbiota and reductions in microbial diversity are highlighted in many disease states, possibly rendering the host susceptible to infection and consequently negatively affecting innate immune function. Evidence is also emerging of microbially produced molecules with neuroactive functions that can have influences across the brain–gut axis. For example, γ-aminobutyric acid, serotonin, catecholamines and acetylcholine may modulate neural signalling within the enteric nervous system, when released in the in...

The Journal of Physiology, 2018

Key points Chronic (psychosocial) stress changes gut microbiota composition, as well as inducing behavioural and physiological deficits. The microbial metabolites short‐chain fatty acids (SCFAs) have been implicated in gastrointestinal functional, (neuro)immune regulation and host metabolism, but their role in stress‐induced behavioural and physiological alterations is poorly understood. Administration of SCFAs to mice undergoing psychosocial stress alleviates enduring alterations in anhedonia and heightened stress‐responsiveness, as well as stress‐induced increases in intestinal permeability. In contrast, chronic stress‐induced alterations in body weight gain, faecal SCFAs and the gene expression of the SCFA receptors FFAR2 and FFAR3 remained unaffected by SCFA supplementation. These results present novel insights into mechanisms underpinning the influence of the gut microbiota on brain homeostasis, behaviour and host metabolism, informing the development of microbiota‐targeted the...

Frontiers in Endocrinology