Complex Interactions Among Diet, Gastrointestinal Transit, and Gut Microbiota in Humanized Mice
TL;DR: Diet can affect GI transit through microbiota-dependent or microbiota-independent pathways, depending on the type of dietary change, and the effect of the microbiota on transit largely depends on the amount and type of polysaccharides present in the diet.
About: This article is published in Gastroenterology.The article was published on 2013-05-01 and is currently open access. It has received 368 citations till now. The article focuses on the topics: Gut flora.
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TL;DR: It is shown that changes in the microbiota of mice consuming a low-MAC diet and harbouring a human microbiota are largely reversible within a single generation, and that taxa driven to low abundance when dietary MACs are scarce are inefficiently transferred to the next generation and are at increased risk of becoming extinct within an isolated population.
Abstract: The gut is home to trillions of microorganisms that have fundamental roles in many aspects of human biology, including immune function and metabolism. The reduced diversity of the gut microbiota in Western populations compared to that in populations living traditional lifestyles presents the question of which factors have driven microbiota change during modernization. Microbiota-accessible carbohydrates (MACs) found in dietary fibre have a crucial involvement in shaping this microbial ecosystem, and are notably reduced in the Western diet (high in fat and simple carbohydrates, low in fibre) compared with a more traditional diet. Here we show that changes in the microbiota of mice consuming a low-MAC diet and harbouring a human microbiota are largely reversible within a single generation. However, over several generations, a low-MAC diet results in a progressive loss of diversity, which is not recoverable after the reintroduction of dietary MACs. To restore the microbiota to its original state requires the administration of missing taxa in combination with dietary MAC consumption. Our data illustrate that taxa driven to low abundance when dietary MACs are scarce are inefficiently transferred to the next generation, and are at increased risk of becoming extinct within an isolated population. As more diseases are linked to the Western microbiota and the microbiota is targeted therapeutically, microbiota reprogramming may need to involve strategies that incorporate dietary MACs as well as taxa not currently present in the Western gut.
1,123 citations
TL;DR: This Review will discuss microbiota–host cross-talk and intestinal microbiome signaling to extraintestinal organs, and review mechanisms of how this communication might contribute to host physiology and discuss how misconfigured signaling may contribute to different diseases.
Abstract: The ecosystem of the human gut consists of trillions of bacteria forming a bioreactor that is fueled by dietary macronutrients to produce bioactive compounds. These microbiota-derived metabolites signal to distant organs in the body, which enables the gut bacteria to connect to the immune and hormone system, to the brain (the gut-brain axis) and to host metabolism, as well as other functions of the host. This microbe-host communication is essential to maintain vital functions of the healthy host. Recently, however, the gut microbiota has been associated with a number of diseases, ranging from obesity and inflammatory diseases to behavioral and physiological abnormalities associated with neurodevelopmental disorders. In this Review, we will discuss microbiota-host cross-talk and intestinal microbiome signaling to extraintestinal organs. We will review mechanisms of how this communication might contribute to host physiology and discuss how misconfigured signaling might contribute to different diseases.
857 citations
TL;DR: Gut microbiota acting through SCFAs are important determinants of enteric 5‐HT production and homeostasis through an effect of short‐chain fatty acids on enterochromaffin cells.
Abstract: Gut microbiota alterations have been described in several diseases with altered gastrointestinal (GI) motility, and awareness is increasing regarding the role of the gut microbiome in modulating GI function. Serotonin [5-hydroxytryptamine (5-HT)] is a key regulator of GI motility and secretion. To determine the relationship among gut microbes, colonic contractility, and host serotonergic gene expression, we evaluated mice that were germ-free (GF) or humanized (HM; ex-GF colonized with human gut microbiota). 5-HT reduced contractile duration in both GF and HM colons. Microbiota from HM and conventionally raised (CR) mice significantly increased colonic mRNAs Tph1 [(tryptophan hydroxylase) 1, rate limiting for mucosal 5-HT synthesis; P < 0.01] and chromogranin A (neuroendocrine secretion; P < 0.01), with no effect on monoamine oxidase A (serotonin catabolism), serotonin receptor 5-HT4, or mouse serotonin transporter. HM and CR mice also had increased colonic Tph1 protein (P < 0.05) and 5-HT concentrations (GF, 17 ± 3 ng/mg; HM, 25 ± 2 ng/mg; and CR, 35 ± 3 ng/mg; P < 0.05). Enterochromaffin (EC) cell numbers (cells producing 5-HT) were unchanged. Short-chain fatty acids (SCFAs) promoted TPH1 transcription in BON cells (human EC cell model). Thus, gut microbiota acting through SCFAs are important determinants of enteric 5-HT production and homeostasis.
774 citations
Cites background or methods or result from "Complex Interactions Among Diet, Ga..."
...HM mice were generated (colonized) at 4–6weeks of ageby gavagewith 300ml of a 1:1 suspension of prereduced PBS and fecal microbiota from a healthy human donor (a 49-yr-oldman) or at age 8 weeks using material from a second donor (a 37-year-old man), as described previously (10)....
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...Colonization of GF mice with human-derived bacteria is associated with increased colonic contractility in vivo and increased concentrations of 5-hydroxyindoleacetic acid (a surrogate marker of serotonin) in stool (10)....
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...This result contrasts with a previous study (10) that reported greater colonic contractility invivo in consciousHMmicecompared toGFmice, likely reflecting differences in in vivo and ex vivo experimental design....
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...First, response to exogenous, luminal 5-HT was similar between GF and HM groups, suggesting that previously reported differences in whole-gut transit times and colonic contractility (10) are not due to aprimary deficit in the ability of the GFneuromuscularapparatus to senseandrespond to5-HT....
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...Colonization of germ-free (GF) mice with normal human- or mousederived fecal microbiota significantly accelerates wholegut transit, an effect that can be partially blocked by systemic pharmacologic antagonism of 5-HT3/4 receptors (10)....
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TL;DR: This review clarifies how the gut microbiota regulates Trp metabolism and identifies the underlying molecular mechanisms of these interactions.
Abstract: The gut microbiota influences the health of the host, especially with regard to gut immune homeostasis and the intestinal immune response. In addition to serving as a nutrient enhancer, L-tryptophan (Trp) plays crucial roles in the balance between intestinal immune tolerance and gut microbiota maintenance. Recent discoveries have underscored that changes in the microbiota modulate the host immune system by modulating Trp metabolism. Moreover, Trp, endogenous Trp metabolites (kynurenines, serotonin, and melatonin), and bacterial Trp metabolites (indole, indolic acid, skatole, and tryptamine) have profound effects on gut microbial composition, microbial metabolism, the host's immune system, the host-microbiome interface, and host immune system-intestinal microbiota interactions. The aryl hydrocarbon receptor (AhR) mediates the regulation of intestinal immunity by Trp metabolites (as ligands of AhR), which is beneficial for immune homeostasis. Among Trp metabolites, AhR ligands consist of endogenous metabolites, including kynurenine, kynurenic acid, xanthurenic acid, and cinnabarinic acid, and bacterial metabolites, including indole, indole propionic acid, indole acetic acid, skatole, and tryptamine. Additional factors, such as aging, stress, probiotics, and diseases (spondyloarthritis, irritable bowel syndrome, inflammatory bowel disease, colorectal cancer), which are associated with variability in Trp metabolism, can influence Trp-microbiome-immune system interactions in the gut and also play roles in regulating gut immunity. This review clarifies how the gut microbiota regulates Trp metabolism and identifies the underlying molecular mechanisms of these interactions. Increased mechanistic insight into how the microbiota modulates the intestinal immune system through Trp metabolism may allow for the identification of innovative microbiota-based diagnostics, as well as appropriate nutritional supplementation of Trp to prevent or alleviate intestinal inflammation. Moreover, this review provides new insight regarding the influence of the gut microbiota on Trp metabolism. Additional comprehensive analyses of targeted Trp metabolites (including endogenous and bacterial metabolites) are essential for experimental preciseness, as the influence of the gut microbiota cannot be neglected, and may explain contradictory results in the literature.
687 citations
Cites background from "Complex Interactions Among Diet, Ga..."
...Colonization of GF animals with the gut microbiota from humans or other mice can significantly increase gut motility, and this can be partially blocked by a pharmacologic antagonist of serotonin receptors (Kashyap et al., 2013)....
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TL;DR: Differentiating between an optimal microbiota, one that increases disease risk, and one that is causative or potentiates disease will be required to further understand both the etiology and possible treatments for health problems related to microbiota dysbiosis.
572 citations
Cites background from "Complex Interactions Among Diet, Ga..."
...For example, host genotype can dictate alteration of mucus structures, such as the absence of alpha-1-2 fucose residues in the mucus of nonsecretor individuals that lack alpha-1-2fucosyltransferase activity in the intestine (Kashyap et al., 2013b)....
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...Highly controlled experiments in mice have shown that the quantity and type of carbohydrates that feed the microbiota alter simplified and complex microbial communities (Faith et al., 2011; Kashyap et al., 2013a; Sonnenburg et al., 2010; Turnbaugh et al., 2009b)....
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...In mice, reduction of dietary fiber has a direct effect on microbiota diversity and short-chain fatty acid production; the latter is an indication that indeed the dietary fiber includes MACs (Kashyap et al., 2013b; Trompette et al., 2014)....
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...In addition, the term dietary fiber encompasses the carbohydrates that are fermentable by an individual’s microbiota plus those that remain unfermented and serve a bulking role (Kashyap et al., 2013a)....
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References
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TL;DR: An overview of the analysis pipeline and links to raw data and processed output from the runs with and without denoising are provided.
Abstract: Supplementary Figure 1 Overview of the analysis pipeline. Supplementary Table 1 Details of conventionally raised and conventionalized mouse samples. Supplementary Discussion Expanded discussion of QIIME analyses presented in the main text; Sequencing of 16S rRNA gene amplicons; QIIME analysis notes; Expanded Figure 1 legend; Links to raw data and processed output from the runs with and without denoising.
28,911 citations
TL;DR: Alternative enterotype states are associated with long-term diet, particularly protein and animal fat (Bacteroides) versus carbohydrates (Prevotella) and other enterotypes distinguished primarily by levels of Bacteroide and Prevotella.
Abstract: Diet strongly affects human health, partly by modulating gut microbiome composition. We used diet inventories and 16S rDNA sequencing to characterize fecal samples from 98 individuals. Fecal communities clustered into enterotypes distinguished primarily by levels of Bacteroides and Prevotella. Enterotypes were strongly associated with long-term diets, particularly protein and animal fat (Bacteroides) versus carbohydrates (Prevotella). A controlled-feeding study of 10 subjects showed that microbiome composition changed detectably within 24 hours of initiating a high-fat/low-fiber or low-fat/high-fiber diet, but that enterotype identity remained stable during the 10-day study. Thus, alternative enterotype states are associated with long-term diet.
5,174 citations
TL;DR: New studies are revealing how the gut microbiota has coevolved with us and how it manipulates and complements the authors' biology in ways that are mutually beneficial.
Abstract: The distal human intestine represents an anaerobic bioreactor programmed with an enormous population of bacteria, dominated by relatively few divisions that are highly diverse at the strain/subspecies level. This microbiota and its collective genomes (microbiome) provide us with genetic and metabolic attributes we have not been required to evolve on our own, including the ability to harvest otherwise inaccessible nutrients. New studies are revealing how the gut microbiota has coevolved with us and how it manipulates and complements our biology in ways that are mutually beneficial. We are also starting to understand how certain keystone members of the microbiota operate to maintain the stability and functional adaptability of this microbial organ.
4,526 citations
TL;DR: The advances in modeling and analysis of gut microbiota will further the authors' knowledge of their role in health and disease, allowing customization of existing and future therapeutic and prophylactic modalities.
Abstract: Gut microbiota is an assortment of microorganisms inhabiting the length and width of the mammalian gastrointestinal tract. The composition of this microbial community is host specific, evolving throughout an individual's lifetime and susceptible to both exogenous and endogenous modifications. Recent renewed interest in the structure and function of this "organ" has illuminated its central position in health and disease. The microbiota is intimately involved in numerous aspects of normal host physiology, from nutritional status to behavior and stress response. Additionally, they can be a central or a contributing cause of many diseases, affecting both near and far organ systems. The overall balance in the composition of the gut microbial community, as well as the presence or absence of key species capable of effecting specific responses, is important in ensuring homeostasis or lack thereof at the intestinal mucosa and beyond. The mechanisms through which microbiota exerts its beneficial or detrimental influences remain largely undefined, but include elaboration of signaling molecules and recognition of bacterial epitopes by both intestinal epithelial and mucosal immune cells. The advances in modeling and analysis of gut microbiota will further our knowledge of their role in health and disease, allowing customization of existing and future therapeutic and prophylactic modalities.
3,077 citations