Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus. The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons in the arcuate nucleus, which is accessible to peripheral hormones. Peptide YY3-36 (PYY3-36), a Y2R agonist, is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal. Here we show that peripheral injection of PYY3-36 in rats inhibits food intake and reduces weight gain. PYY3-36 also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY3-36 increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY3-36 inhibits food intake. PYY3-36 also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons. In humans, infusion of normal postprandial concentrations of PYY3-36 significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut–hypothalamic pathway.

BRIEF COMMUNICATION ARISING: Gut hormone PYY3-36 physiologically inhibits food intake

Metabolic syndrome, variously known also as syndrome X, insulin resistance, etc., is defined by WHO as a pathologic condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Though there is some variation in the definition by other health care organization, the differences are minor. With the successful conquest of communicable infectious diseases in most of the world, this new non-communicable disease (NCD) has become the major health hazard of modern world. Though it started in the Western world, with the spread of the Western lifestyle across the globe, it has become now a truly global problem. The prevalence of the metabolic syndrome is often more in the urban population of some developing countries than in its Western counterparts. The two basic forces spreading this malady are the increase in consumption of high calorie-low fiber fast food and the decrease in physical activity due to mechanized transportations and sedentary form of leisure time activities. The syndrome feeds into the spread of the diseases like type 2 diabetes, coronary diseases, stroke, and other disabilities. The total cost of the malady including the cost of health care and loss of potential economic activity is in trillions. The present trend is not sustainable unless a magic cure is found (unlikely) or concerted global/governmental/societal efforts are made to change the lifestyle that is promoting it. There are certainly some elements in the causation of the metabolic syndrome that cannot be changed but many are amenable for corrections and curtailments. For example, better urban planning to encourage active lifestyle, subsidizing consumption of whole grains and possible taxing high calorie snacks, restricting media advertisement of unhealthy food, etc. Revitalizing old fashion healthier lifestyle, promoting old-fashioned foods using healthy herbs rather than oil and sugar, and educating people about choosing healthy/wholesome food over junks are among the steps that can be considered.

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The Global Epidemic of the Metabolic Syndrome.

The human gastrointestinal (GI) tract harbours a complex and dynamic population of microorganisms, the gut microbiota, which exert a marked influence on the host during homeostasis and disease Multiple factors contribute to the establishment of the human gut microbiota during infancy Diet is considered as one of the main drivers in shaping the gut microbiota across the life time Intestinal bacteria play a crucial role in maintaining immune and metabolic homeostasis and protecting against pathogens Altered gut bacterial composition (dysbiosis) has been associated with the pathogenesis of many inflammatory diseases and infections The interpretation of these studies relies on a better understanding of inter-individual variations, heterogeneity of bacterial communities along and across the GI tract, functional redundancy and the need to distinguish cause from effect in states of dysbiosis This review summarises our current understanding of the development and composition of the human GI microbiota, and its impact on gut integrity and host health, underlying the need for mechanistic studies focusing on host–microbe interactions

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Introduction to the human gut microbiota

Observational findings achieved during the past two decades suggest that the intestinal microbiota may contribute to the metabolic health of the human host and, when aberrant, to the pathogenesis of various common metabolic disorders including obesity, type 2 diabetes, non-alcoholic liver disease, cardio-metabolic diseases and malnutrition. However, to gain a mechanistic understanding of how the gut microbiota affects host metabolism, research is moving from descriptive microbiota census analyses to cause-and-effect studies. Joint analyses of high-throughput human multi-omics data, including metagenomics and metabolomics data, together with measures of host physiology and mechanistic experiments in humans, animals and cells hold potential as initial steps in the identification of potential molecular mechanisms behind reported associations. In this Review, we discuss the current knowledge on how gut microbiota and derived microbial compounds may link to metabolism of the healthy host or to the pathogenesis of common metabolic diseases. We highlight examples of microbiota-targeted interventions aiming to optimize metabolic health, and we provide perspectives for future basic and translational investigations within the nascent and promising research field. In this Review, Fan and Pedersen discuss how the gut microbiota and derived microbial compounds may contribute to human metabolic health and to the pathogenesis of common metabolic diseases, and highlight examples of microbiota-targeted interventions aiming to optimize metabolic health.

Gut microbiota in human metabolic health and disease.

High-throughput technologies have revolutionized medical research. The advent of genotyping arrays enabled large-scale genome-wide association studies and methods for examining global transcript levels, which gave rise to the field of "integrative genetics". Other omics technologies, such as proteomics and metabolomics, are now often incorporated into the everyday methodology of biological researchers. In this review, we provide an overview of such omics technologies and focus on methods for their integration across multiple omics layers. As compared to studies of a single omics type, multi-omics offers the opportunity to understand the flow of information that underlies disease.

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Multi-omics approaches to disease.

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Author Correction: Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms

To the Editor — We read with interest the article by Depommier et al. reporting improved insulin sensitivity, reduced cholesterol levels and decreased white blood cell counts in humans with metabolic syndrome after supplementation with Akkermansia muciniphila1. Although the authors carried out elaborate laboratory experiments to test their concepts, we feel that this study lacks in the fundamental information for a phase 1 human trial report. The predictor—A. muciniphila treatment—and the outcomes—obesity, metabolic syndrome and diabetes—are affected by lifestyle factors, glucose levels and diet, forming a complex confounding relationship. Thus, these factors must be considered even in a phase 1 trial, in which the main purpose is safety assessment. Without this consideration (or adjustment), the metabolic improvements reported by Depommier and colleagues may be an example of Simpson’s paradox (which posits that when confounding factor(s) are not adjusted for, they can generate opposing and seemingly paradoxical results). If the observed results are a product of Simpson’s paradox, stratifying the results according to the levels of diet and exercise will cause the observed beneficial effects to disappear. Randomization alone does not balance all the confounding factors, unless the sample size is sufficiently large2. A diet rich in polyphenols, polydextrose, butyrate and inulin is reported to increase A. muciniphila abundance3. Butyrate and other short-chain fatty acids from high-fiber diets play an important role in gut mucosa health4, improve insulin resistance4 and gut permeability5 and affect the mucin layer, which is the substrate for A. muciniphila6. Thus, it is highly likely that diet will affect the abundance of A. muciniphila and reduce metabolic inflammation as well5. Therefore, phase 1 trials such as this one must follow the standard human phase 1 trial reporting format to show that confounding factors would not have biased their results, as was recently reported by Bajaj et al.7. Without elucidating the balanced confounding factors at baseline, the report may contain potentially biased results and trigger the lay media to produce flash headlines that may mislead the public. Notably, the health benefits of the A. muciniphila membrane protein Amuc_1100 were more pronounced than those of live A. muciniphila1. Hence, supplementation with Amuc_1100 rather than live bacteria will be more appropriate in future research. Additionally, we suggest that phase 2 and 3 trials should have a crossover design to mitigate any bias stemming from the imbalance in confounding factors in the parallel group design. We sincerely hope that Amuc_1100 can curtail the obesity pandemic worldwide. The investigators should realize that confounding must be balanced at baseline; otherwise the results will be biased. Also, blinding will not balance the confounding. ❐

Reply to 'Simpson's paradox in proof-of-concept studies'.

Abstract Background Excessive hedonic consumption is one of the main drivers for weight gain. Identifying contributors of this dysregulation would help to tackle obesity. The gut microbiome is altered during obesity and regulates host metabolism including food intake. Results By using fecal material transplantation (FMT) from lean or obese mice into recipient mice, we demonstrated that gut microbes play a role in the regulation of food reward (i.e., wanting and learning processes associated with hedonic food intake) and could be responsible for excessive motivation to obtain sucrose pellets and alterations in dopaminergic and opioid markers in reward-related brain areas. Through untargeted metabolomic approach, we identified the 3-(3’-hydroxyphenyl)propanoic acid (33HPP) as highly positively correlated with the motivation. By administrating 33HPP in mice, we revealed its effects on food reward. Conclusions Our data suggest that targeting the gut microbiota and its metabolites would be an interesting therapeutic strategy for compulsive eating, preventing inappropriate hedonic food intake. 

Clara Depommier

Papers

Author Correction: Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms

Reply to 'Simpson's paradox in proof-of-concept studies'.

Obese-associated gut microbes and derived phenolic metabolite as mediators of excessive motivation for food reward