Microbiota-Gut-Brain Axis: Modulator of Host Metabolism and Appetite.
TL;DR: Understanding the mechanisms in which the gut microbiota can influence host appetite and metabolism will provide a better understanding of conditions wherein appetite is dysregulated, such as obesity and other metabolic or eating disorders, leading to novel biotherapeutic strategies.
Abstract: The gut harbors an enormous diversity of microbes that are essential for the maintenance of homeostasis in health and disease. A growing body of evidence supports the role of this microbiota in influencing host appetite and food intake. Individual species within the gut microbiota are under selective pressure arising from nutrients available and other bacterial species present. Each bacterial species within the gut aims to increase its own fitness, habitat, and survival via specific fermentation of dietary nutrients and secretion of metabolites, many of which can influence host appetite and eating behavior by directly affecting nutrient sensing and appetite and satiety-regulating systems. These include microbiota-produced neuroactives and short-chain fatty acids. In addition, the gut microbiota is able to manipulate intestinal barrier function, interact with bile acid metabolism, modulate the immune system, and influence host antigen production, thus indirectly affecting eating behavior. A growing body of evidence indicates that there is a crucial role for the microbiota in regulating different aspects of eating-related behavior, as well as behavioral comorbidities of eating and metabolic disorders. The importance of intestinal microbiota composition has now been shown in obesity, anorexia nervosa, and forms of severe acute malnutrition. Understanding the mechanisms in which the gut microbiota can influence host appetite and metabolism will provide a better understanding of conditions wherein appetite is dysregulated, such as obesity and other metabolic or eating disorders, leading to novel biotherapeutic strategies.
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TL;DR: Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.
Abstract: The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within ...
1,775 citations
TL;DR: The present knowledge on the properties of butyrate, especially its potential effects and mechanisms involved in intestinal health and obesity, are summarized.
542 citations
TL;DR: 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, informing the development of microbiota‐targeted therapies for stress‐related disorders.
Abstract: 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 therapies for stress-related disorders. Abstract There is a growing recognition of the involvement of the gastrointestinal microbiota in the regulation of physiology and behaviour. Microbiota-derived metabolites play a central role in the communication between microbes and their host, with short-chain fatty acids (SCFAs) being perhaps the most studied. SCFAs are primarily derived from fermentation of dietary fibres and play a pivotal role in host gut, metabolic and immune function. All these factors have previously been demonstrated to be adversely affected by stress. Therefore, we sought to assess whether SCFA supplementation could counteract the enduring effects of chronic psychosocial stress. C57BL/6J male mice received oral supplementation of a mixture of the three principle SCFAs (acetate, propionate and butyrate). One week later, mice underwent 3 weeks of repeated psychosocial stress, followed by a comprehensive behavioural analysis. Finally, plasma corticosterone, faecal SCFAs and caecal microbiota composition were assessed. SCFA treatment alleviated psychosocial stress-induced alterations in reward-seeking behaviour, and increased responsiveness to an acute stressor and in vivo intestinal permeability. In addition, SCFAs exhibited behavioural test-specific antidepressant and anxiolytic effects, which were not present when mice had also undergone psychosocial stress. Stress-induced increases in body weight gain, faecal SCFAs and the colonic gene expression of the SCFA receptors free fatty acid receptors 2 and 3 remained unaffected by SCFA supplementation. Moreover, there were no collateral effects on caecal microbiota composition. Taken together, these data show that SCFA supplementation alleviates selective and enduring alterations induced by repeated psychosocial stress and these data may inform future research into microbiota-targeted therapies for stress-related disorders.
382 citations
TL;DR: The gut microbiota is discussed as a regulator of anxiety and depression, the role of gut-derived peptides as signaling molecules in microbiome–gut–brain communication is explored, and gut peptide concentrations vary according to the composition of the intestinal microbiota.
313 citations
TL;DR: In this review, several representative NDCs are introduced, and their chemical components, structures, and physiological functions, including promotion of the proliferation of butyrate-producing bacteria and enhancement ofbutyrate production are discussed.
Abstract: Nondigestible carbohydrates (NDCs) are fermentation substrates in the colon after escaping digestion in the upper gastrointestinal tract. Among NDCs, resistant starch is not hydrolyzed by pancreatic amylases but can be degraded by enzymes produced by large intestinal bacteria, including clostridia, bacteroides, and bifidobacteria. Nonstarch polysaccharides, such as pectin, guar gum, alginate, arabinoxylan, and inulin fructans, and nondigestible oligosaccharides and their derivatives, can also be fermented by beneficial bacteria in the large intestine. Butyrate is one of the most important metabolites produced through gastrointestinal microbial fermentation and functions as a major energy source for colonocytes by directly affecting the growth and differentiation of colonocytes. Moreover, butyrate has various physiological effects, including enhancement of intestinal barrier function and mucosal immunity. In this review, several representative NDCs are introduced, and their chemical components, structures, and physiological functions, including promotion of the proliferation of butyrate-producing bacteria and enhancement of butyrate production, are discussed. We also describe the strategies for achieving directional accumulation of colonic butyrate based on endogenous generation mechanisms.
220 citations
References
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11 Jun 2013
113,134 citations
TL;DR: It is demonstrated through metagenomic and biochemical analyses that changes in the relative abundance of the Bacteroidetes and Firmicutes affect the metabolic potential of the mouse gut microbiota and indicates that the obese microbiome has an increased capacity to harvest energy from the diet.
Abstract: The worldwide obesity epidemic is stimulating efforts to identify host and environmental factors that affect energy balance. Comparisons of the distal gut microbiota of genetically obese mice and their lean littermates, as well as those of obese and lean human volunteers have revealed that obesity is associated with changes in the relative abundance of the two dominant bacterial divisions, the Bacteroidetes and the Firmicutes. Here we demonstrate through metagenomic and biochemical analyses that these changes affect the metabolic potential of the mouse gut microbiota. Our results indicate that the obese microbiome has an increased capacity to harvest energy from the diet. Furthermore, this trait is transmissible: colonization of germ-free mice with an 'obese microbiota' results in a significantly greater increase in total body fat than colonization with a 'lean microbiota'. These results identify the gut microbiota as an additional contributing factor to the pathophysiology of obesity.
10,126 citations
"Microbiota-Gut-Brain Axis: Modulato..." refers background in this paper
...As such, the ‘‘obese’’ gut microbiota has an increased capacity for energy harvest through SCFA production (86)....
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...Indeed, colonization of GF mice with a gut microbiota originating from an obese human resulted in a substantial increase in total body fat compared with a lean gut microbiota (86)....
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...fermentation of nonhost-digestible dietary fibers by the gut microbiota and can provide #10% of total daily caloric intake (86, 192)....
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...Shortly after this, it was discovered that there was a different gut microbial ecology associated with obesity (84, 85), and that the gut microbiota connected with obesity was associated with an increased capacity for dietary energy harvest (86)....
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...Numerous studies have reported that overweight and obese individuals have increased SCFA concentrations (86, 95, 189, 190), even though this is not always consistently reported (191)....
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TL;DR: The Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals are described, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species.
Abstract: To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, ~150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively
9,268 citations
"Microbiota-Gut-Brain Axis: Modulato..." refers background in this paper
...The majority of the composition of the gut microbiota is composed of the phyla Firmicutes (including Lactobacillus, Clostridium, and Enterococcus) and Bacteroidetes (including Bacteroides), with less from the phyla Actinobacteria (Bifidobacteria), Proteobacteria (Escherichia coli), Fusobacteria, Verrucomicrobia, and Cyanobacteria (6, 89)....
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TL;DR: It is shown that the relative proportion of Bacteroidetes is decreased in obese people by comparison with lean people, and that this proportion increases with weight loss on two types of low-calorie diet.
Abstract: Two groups of beneficial bacteria are dominant in the human gut, the Bacteroidetes and the Firmicutes. Here we show that the relative proportion of Bacteroidetes is decreased in obese people by comparison with lean people, and that this proportion increases with weight loss on two types of low-calorie diet. Our findings indicate that obesity has a microbial component, which might have potential therapeutic implications.
7,550 citations
"Microbiota-Gut-Brain Axis: Modulato..." refers background in this paper
...Shortly after this, it was discovered that there was a different gut microbial ecology associated with obesity (84, 85), and that the gut microbiota connected with obesity was associated with an increased capacity for dietary energy harvest (86)....
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...In regard to obesity, phylum-level changes, such as increased Actinobacteria (14) and Firmicutes and decreased Bacteroidetes, have been reported (84), as well as genus-level changes (16)....
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TL;DR: A majority of the bacterial sequences corresponded to uncultivated species and novel microorganisms, and significant intersubject variability and differences between stool and mucosa community composition were discovered.
Abstract: The human endogenous intestinal microflora is an essential “organ” in providing nourishment, regulating epithelial development, and instructing innate immunity; yet, surprisingly, basic features remain poorly described. We examined 13,355 prokaryotic ribosomal RNA gene sequences from multiple colonic mucosal sites and feces of healthy subjects to improve our understanding of gut microbial diversity. A majority of the bacterial sequences corresponded to uncultivated species and novel microorganisms. We discovered significant intersubject variability and differences between stool and mucosa community composition. Characterization of this immensely diverse ecosystem is the first step in elucidating its role in health and disease.
7,049 citations
"Microbiota-Gut-Brain Axis: Modulato..." refers background in this paper
...More startling is the fact that the cumulative amount of unique genes in the gut microbiota, the microbiome, is 100-fold higher than that of the human genome, further indicating its significance (6)....
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...The majority of the composition of the gut microbiota is composed of the phyla Firmicutes (including Lactobacillus, Clostridium, and Enterococcus) and Bacteroidetes (including Bacteroides), with less from the phyla Actinobacteria (Bifidobacteria), Proteobacteria (Escherichia coli), Fusobacteria, Verrucomicrobia, and Cyanobacteria (6, 89)....
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