The incidence of inflammatory bowel diseases (IBD), as well as other inflammatory conditions, has dramatically increased over the past half century. While many studies have shown that IBD exhibits a ...genetic component via genome-wide association studies, genetic drift alone cannot account for this increase, and other factors, such as those found in the environment must play a role, suggesting a “multiple hit” phenomenon that precipitates disease. One major environmental factor, dietary intake, has shifted to a high fat, high carbohydrate Western-type diet in developing nations, nearly in direct correlation with the increasing incidence of IBD. Recent evidence suggests that specific changes in dietary intake have led to a shift in the composite human gut microbiota, resulting in the emergence of pathobionts that can thrive under specific conditions. In the genetically susceptible host, the emerging pathobionts can lead to increasing incidence and severity of IBD and other inflammatory disorders. Since the gut microbiota is plastic and responds to dietary modulations, the use of probiotics, prebiotics, and/or dietary alterations are all intriguing complementary therapeutic approaches to alleviate IBD symptoms. However, the interactions are complex and it is unlikely that a one-size-fits all approach can be utilized across all populations affected by IBD. Exploration into and thoroughly understanding the interactions between host and microbes, primarily in the genetically susceptible host, will help define strategies that can be tailored to an individual as we move towards an era of personalized medicine to treat IBD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The composite human gut microbiomes of Western populations have changed over the past century, brought on by new environmental triggers that often have a negative impact on human health. Diets high ...in saturated fats and refined sugars and low in fiber are leading candidates for these events and for triggering the increased prevalence of immune-mediated diseases like inflammatory bowel disease (IBD). Our studies have shown that consumption of a 'Western' diet high in saturated (milk-derived) fat (MF) or n-6 polyunsaturated (safflower oil) fat have similar effects on the structure of the colonic microbiome of wild-type and IL- 10(-/-) mice, characterized by increased Bacteroidetes and decreased Firmicutes. However, the MF diet uniquely promotes the expansion of an immunogenic sulfite-reducing pathobiont, Bilophila wadsworthia, a member of the Deltaproteobacteria and minor component of the gut microbiome. This bacterial bloom results from a MF diet-induced shift in hepatic conjugation of bile acids, from glycocholic to taurocholic (TC) acid, which is important for solubilizing the more hydrophobic MF diet. However, it is also responsible for delivery of taurine-derived sulfur to the distal bowel, promoting the assemblage of bile-tolerant microbes such as B. wadsworthia. The bloom of this species promotes a Th1-mediated immune response and the development of colitis in IL-10(-/-) mice. A similar bloom of B. wadsworthia is seen when IL-10(-/-) mice are fed a low-fat diet supplemented with TC. B. wadsworthia colonization of monoassociated germ-free IL-10(-/-) mice was dependent on the host consuming either a high-saturated MF diet or the gavage with TC. Together, these data provide a plausible explanation for the link between diseases such as IBD and dietary-mediated selection of gut microbial pathobionts in genetically susceptible hosts. With this knowledge, it may be possible to mitigate the bloom of these types of pathobionts by modifying the conjugation states of bile acids.
The composite human microbiome of Western populations has probably changed over the past century, brought on by new environmental triggers that often have a negative impact on human health. Here we ...show that consumption of a diet high in saturated (milk-derived) fat, but not polyunsaturated (safflower oil) fat, changes the conditions for microbial assemblage and promotes the expansion of a low-abundance, sulphite-reducing pathobiont, Bilophila wadsworthia. This was associated with a pro-inflammatory T helper type 1 (T(H)1) immune response and increased incidence of colitis in genetically susceptible Il10(−/−), but not wild-type mice. These effects are mediated by milk-derived-fat-promoted taurine conjugation of hepatic bile acids, which increases the availability of organic sulphur used by sulphite-reducing microorganisms like B. wadsworthia. When mice were fed a low-fat diet supplemented with taurocholic acid, but not with glycocholic acid, for example, a bloom of B. wadsworthia and development of colitis were observed in Il10(−/−) mice. Together these data show that dietary fats, by promoting changes in host bile acid composition, can markedly alter conditions for gut microbial assemblage, resulting in dysbiosis that can perturb immune homeostasis. The data provide a plausible mechanistic basis by which Western-type diets high in certain saturated fats might increase the prevalence of complex immune-mediated diseases like inflammatory bowel disease in genetically susceptible hosts.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A mysterious feature of Crohn’s disease (CD) is the extra-intestinal manifestation of “creeping fat” (CrF), defined as expansion of mesenteric adipose tissue around the inflamed and fibrotic ...intestine. In the current study, we explore whether microbial translocation in CD serves as a central cue for CrF development. We discovered a subset of mucosal-associated gut bacteria that consistently translocated and remained viable in CrF in CD ileal surgical resections, and identified Clostridium innocuum as a signature of this consortium with strain variation between mucosal and adipose isolates, suggesting preference for lipid-rich environments. Single-cell RNA sequencing characterized CrF as both pro-fibrotic and pro-adipogenic with a rich milieu of activated immune cells responding to microbial stimuli, which we confirm in gnotobiotic mice colonized with C. innocuum. Ex vivo validation of expression patterns suggests C. innocuum stimulates tissue remodeling via M2 macrophages, leading to an adipose tissue barrier that serves to prevent systemic dissemination of bacteria.
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•Gut bacterial translocation to mesenteric adipose tissue (MAT) naturally occurs•MAT from Crohn’s disease (CD) harbors a bacterial consortium defined by C. innocuum•These bacteria in CD promote restructuring of MAT and formation of “creeping fat”•Creeping fat expansion and fibrosis prevent systemic translocation of gut bacteria
Ha et al. provide evidence that, in humans with inflammatory bowel disease, the phenomenon known as “creeping fat” is a protective response where mesenteric adipose tissue migrates (or “creeps”) to sites of gut barrier dysfunction to prevent systemic dissemination of potentially harmful bacterial antigens that have translocated across the barrier from the gut lumen.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Interactions of diet, gut microbiota, and host genetics play important roles in the development of obesity and insulin resistance. Here, we have investigated the molecular links between gut ...microbiota, insulin resistance, and glucose metabolism in 3 inbred mouse strains with differing susceptibilities to metabolic syndrome using diet and antibiotic treatment. Antibiotic treatment altered intestinal microbiota, decreased tissue inflammation, improved insulin signaling in basal and stimulated states, and improved glucose metabolism in obesity- and diabetes-prone C57BL/6J mice on a high-fat diet (HFD). Many of these changes were reproduced by the transfer of gut microbiota from antibiotic-treated donors to germ-free or germ-depleted mice. These physiological changes closely correlated with changes in serum bile acids and levels of the antiinflammatory bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and were partially recapitulated by treatment with a TGR5 agonist. In contrast, antibiotic treatment of HFD-fed, obesity-resistant 129S1 and obesity-prone 129S6 mice did not improve metabolism, despite changes in microbiota and bile acids. These mice also failed to show a reduction in inflammatory gene expression in response to the TGR5 agonist. Thus, changes in bile acid and inflammatory signaling, insulin resistance, and glucose metabolism driven by an HFD can be modified by antibiotic-induced changes in gut microbiota; however, these effects depend on important interactions with the host's genetic background and inflammatory potential.
Abstract Background The last 50–100 years has been marked by a sharp rise in so-called “Western-diseases” in those countries that have experienced major industrial advances and shifts towards ...urbanized living. These diseases include obesity, type 2 diabetes, inflammatory bowel diseases, and food allergies in which chronic dysregulation of metabolic and/or immune processes appear to be involved, and are likely a byproduct of new environmental influences on our ancient genome. What we now appreciate is that this genome consists of both human and co-evolved microbial genes of the trillions of microbes residing in our body. Together, host–microbe interactions may be determined by the changing diets and behaviors of the Western lifestyle, influencing the etiopathogenesis of “new-age” diseases. Scope of review This review takes an anthropological approach to the potential interplay of the host and its gut microbiome in the post-industrialization rise in chronic inflammatory and metabolic diseases. The discussion highlights both the changes in diet and the physical environment that have co-occurred with these diseases and the latest evidence demonstrating the role of host–microbe interactions in understanding biological responses to the changing environment. Major conclusions Technological advances that have led to changes in agriculture and engineering have altered our eating and living behaviors in ways never before possible in human history. These changes also have altered the bacterial communities within the human body in ways that are seemingly linked with the rise of many intestinal and systemic metabolic and inflammatory diseases. Insights into the mechanisms of this reciprocal exchange between the environment and the human gut microbiome may offer potential to attenuate the chronic health conditions that derail quality of life. This article is part of a special issue on microbiota.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Chronic dietary protein-restriction can create essential amino acid deficiencies and induce metabolic adaptation through the hepatic FGF21 pathway which serves to maintain host fitness during ...prolonged states of nutritional imbalance. Similarly, the gut microbiome undergoes metabolic adaptations when dietary nutrients are added or withdrawn. Here we confirm previous reports that dietary protein-restriction triggers the hepatic FGF21 adaptive metabolic pathway and further demonstrate that this response is mediated by the gut microbiome and can be tuned through dietary supplementation of fibers that alter the gut microbiome. In the absence of a gut microbiome, we discover that FGF21 is de-sensitized to the effect of protein-restriction. These data suggest that host-intrinsic adaptive pathways to chronic dietary protein-restriction, such as the hepatic FGF21 pathway, may in-fact be responding first to adaptive metabolic changes in the gut microbiome.
Microbiome-based signatures of disease have focused primarily on the bacterial component of the microbiome for numerous reasons, including ease of sample preparation and depth of the curated ...bacterial database. However, even more numerous than bacteria are the bacteriophages of the viral portion of the microbiome, which have emerged with identifiable disease signatures in other diseases, such as inflammatory bowel diseases. Here, G. D. Hannigan, M. B. Duhaime, M. T. Ruffin, IV, C. C. Koumpouras, and P. D. Schloss (mBio 9:e02248-18, https://doi.org/10.1128/mBio.02248-18) present a study that explores the potential bacteriophage signatures in patients with colorectal cancer (CRC) and the associated changes in bacterial signatures. Sampling from a cross section of 60 patients at different stages of CRC in addition to 30 healthy controls, this study highlights the need for greater exploration into the virome, including the "dark matter" of diverse forms that viruses assume in the gastrointestinal tract.
For more than a century, the prenatal environment was considered sterile. Over the last few years, findings obtained with next-generation sequencing approaches from samples of the placenta, the ...amniotic fluid, meconium, and even fetal tissues have challenged the dogma of a sterile womb, and additional reports have emerged that used culture, microscopy, and quantitative PCR to support the presence of a low-biomass microbial community at prenatal sites. Given the substantial implications of prenatal exposure to microbes for the development and health of the host, the findings have gathered substantial interest from academics, high impact journals, the public press, and funding agencies. However, an increasing number of studies have challenged the prenatal microbiome identifying contamination as a major issue, and scientists that remained skeptical have pointed to inconsistencies with in utero colonization, the impact of c-sections on early microbiome assembly, and the ability to generate germ-free mammals. A lively academic controversy has emerged on the existence of the wider importance of prenatal microbial communities. Microbiome has asked experts to discuss these issues and provide their thoughts on the implications. To allow for a broader perspective of this discussion, we have specifically selected scientists, who have a long-standing expertise in microbiome sciences but who have not directly been involved in the debate so far.
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