Suzanne Devkota

Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice

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 (TH1) 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.

Diet, microbes, and host genetics: the perfect storm in inflammatory bowel diseases

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.

Lymphotoxin regulates commensal responses to enable diet-induced obesity

Microbiota are essential for weight gain in mouse models of diet-induced obesity (DIO), but the pathways that cause the microbiota to induce weight gain are unknown. We report that mice deficient in lymphotoxin, a key molecule in gut immunity, were resistant to DIO. Ltbr−/− mice had different microbial community composition compared to their heterozygous littermates, including an overgrowth of segmented filamentous bacteria (SFB). Furthermore, cecal transplantation conferred leanness to germ-free recipients. Housing Ltbr−/− mice with their obese siblings rescued weight gain in Ltbr−/− mice, demonstrating the communicability of the obese phenotype. Ltbr−/− mice lacked interleukin 23 (IL-23) and IL-22, which can regulate SFB. Mice deficient in these pathways also resisted DIO, demonstrating that intact mucosal immunity guides diet-induced changes to the microbiota to enable obesity.

Regional Mucosa-Associated Microbiota Determine Physiological Expression of TLR2 and TLR4 in Murine Colon

Many colonic mucosal genes that are highly regulated by microbial signals are differentially expressed along the rostral-caudal axis. This would suggest that differences in regional microbiota exist, particularly mucosa-associated microbes that are less likely to be transient. We therefore explored this possibility by examining the bacterial populations associated with the normal proximal and distal colonic mucosa in context of host Toll-like receptors (TLR) expression in C57BL/6J mice housed in specific pathogen-free (SPF) and germ-free (GF) environments. 16S rRNA gene-based terminal restriction fragment length polymorphism (T-RFLP) and clone library analysis revealed significant differences in the community structure and diversity of the mucosa-associated microbiota located in the distal colon compared to proximal colon and stool, the latter two clustering closely. Differential expression of colonic TLR2 and TLR4 along the proximal-distal axis was also found in SPF mice, but not in GF mice, suggesting that enteric microbes are essential in maintaining the regional expression of these TLRs. TLR2 is more highly expressed in proximal colon and decreases in a gradient to distal while TLR4 expression is highest in distal colon and a gradient of decreased expression to proximal colon is observed. After transfaunation in GF mice, both regional colonization of mucosa-associated microbes and expression of TLRs in the mouse colon were reestablished. In addition, exposure of the distal colon to cecal (proximal) microbiota induced TLR2 expression. These results demonstrate that regional colonic mucosa-associated microbiota determine the region-specific expression of TLR2 and TLR4. Conversely, region-specific host assembly rules are essential in determining the structure and function of mucosa-associated microbial populations. We believe this type of host-microbial mutualism is pivotal to the maintenance of intestinal and immune homeostasis.

Composition of Dietary Fat Source Shapes Gut Microbiota Architecture and Alters Host Inflammatory Mediators in Mouse Adipose Tissue

BACKGROUND Growing evidence shows that dietary factors can dramatically alter the gut microbiome in ways that contribute to metabolic disturbance and progression of obesity. In this regard, mesenteric adipose tissue has been implicated in mediating these processes through the elaboration of proinflammatory adipokines. In this study, we examined the relationship of these events by determining the effects of dietary fat content and source on gut microbiota, as well as the effects on adipokine profiles of mesenteric and peripheral adipocytes. METHODS Adult male C57Bl/6 mice were fed milk fat-based, lard-based (saturated fatty acid sources), or safflower oil (polyunsaturated fatty acid)-based high-fat diets for 4 weeks. Body mass and food consumption were measured. Stool 16S ribosomal RNA (rRNA) was isolated and analyzed via terminal restriction fragment length polymorphism as well as variable V3-4 sequence tags via next-generation sequencing. Mesenteric and gonadal adipose samples were analyzed for both lipogenic and inflammatory mediators via quantitative real-time polymerase chain reaction. RESULTS High-fat feedings caused more weight gain with concomitant increases in caloric consumption relative to low-fat diets. In addition, each of the high-fat diets induced dramatic and specific 16S rRNA phylogenic profiles that were associated with different inflammatory and lipogenic mediator profiles of mesenteric and gonadal fat depots. CONCLUSIONS Our findings support the notion that dietary fat composition can both reshape the gut microbiota and alter host adipose tissue inflammatory/lipogenic profiles. They also demonstrate the interdependency of dietary fat source, commensal gut microbiota, and inflammatory profile of mesenteric fat that can collectively affect the host metabolic state.

Nutrition, microbiomes, and intestinal inflammation.

Purpose of review To present and evaluate the recent findings that contribute to our understanding of the functional impact of diet on the enteric microbiome and outcomes of disease. Recent findings Nutrients in excess and in deficiency have significant impact on gut microbial communities in both rodents and humans, acting directly on the microbiota or indirectly via altering host physiology. Furthermore, the effects of diet on the microbiome in determining health or disease can differ substantially depending on the age and environment of the individual. Summary Dietary compounds can have profound short-term and long-term effects on the assemblage of the gut microbiome, which in turn affects the host–microbe interactions critically important for intestinal, metabolic, and immune homeostasis. Until recently, the mechanisms underlying these effects were poorly understood. However, new insights have now been gained, made possible through the application of advanced technologies and bioinformatics, novel experimental models, and human research. As a result, our conceptual framework for understanding the impact of diet on the gut microbiome, health, and disease has advanced considerably, bringing the promise of better tools of risk assessment, diagnostics, and therapeutic intervention in an age of personalized medicine.

Carrageenan-Induced Colonic Inflammation Is Reduced in Bcl10 Null Mice and Increased in IL-10-Deficient Mice

The common food additive carrageenan is a known activator of inflammation in mammalian tissues and stimulates both the canonical and noncanonical pathways of NF-κB activation. Exposure to low concentrations of carrageenan (10 μg/mL in the water supply) has produced glucose intolerance, insulin resistance, and impaired insulin signaling in C57BL/6 mice. B-cell leukemia/lymphoma 10 (Bcl10) is a mediator of inflammatory signals from Toll-like receptor (TLR) 4 in myeloid and epithelial cells. Since the TLR4 signaling pathway is activated in diabetes and by carrageenan, we addressed systemic and intestinal inflammatory responses following carrageenan exposure in Bcl10 wild type, heterozygous, and null mice. Fecal calprotectin and circulating keratinocyte chemokine (KC), nuclear RelA and RelB, phospho(Thr559)-NF-κB-inducing kinase (NIK), and phospho(Ser36)-IκBα in the colonic epithelial cells were significantly less (P < 0.001) in the carrageenan-treated Bcl10 null mice than in controls. IL-10-deficient mice exposed to carrageenan in a germ-free environment showed an increase in activation of the canonical pathway of NF-κB (RelA) activation, but without increase in RelB or phospho-Bcl10, and exogenous IL-10 inhibited only the canonical pathway of NF-κB activation in cultured colonic cells. These findings demonstrate a Bcl10 requirement for maximum development of carrageenan-induced inflammation and lack of complete suppression by IL-10 of carrageenan-induced inflammation.

The role of diet in triggering human inflammatory disorders in the modern age

Previously uncommon human inflammatory disorders are emerging with alarming frequency, possibly triggered by environmental factors introduced through Westernization. This review highlights how Western diets heighten the inflammatory state promoting development of disease. Evidence that this can occur directly or indirectly through perturbations of host-microbe interactions are reviewed.

Diet-induced expansion of pathobionts in experimental colitis: implications for tailored therapies.

Evidence presented in our recent study and elsewhere suggests that the interplay of dietary macronutrients with the intestinal lumen alters the microbial environment, and thus host-microbe interactions, in ways that are not always in a favorable, mutualistic fashion. Specifically, in inflammatory bowel diseases (IBD), experimental and clinical observations have implicated a detrimental impact of environmental/microbial factors on the etiopathogenesis of IBD in individuals with a background of genetic susceptibility to the disease.1 Thus, now more than ever, we are realizing that specific intestinal microbes can metabolize and react to a wide array of dietary compositions that, in turn, markedly alter microbial populations. We aimed to understand if certain dietary fats that are prevalent in Western diets are capable of precipitating colonic inflammation through their actions on the enteric microbiota. On a background of genetic susceptibility, these microbial changes can impact host immune homeostasis and increase risk for disease. Here we elaborate on our findings and their potential implications for future medical care.

Increased ratio of dietary carbohydrate to protein shifts the focus of metabolic signaling from skeletal muscle to adipose

BackgroundThe Dietary Reference Intakes (DRI) established acceptable macronutrient distribution ranges (AMDR) for carbohydrates and protein, however little is known about differences in glycemic regulations and metabolic signaling across this range. This study examined metabolic outcomes associated with intake of two diets differing in carbohydrate:protein ratios representing the upper and lower ends of the AMDR.MethodsAdult, male rats were fed either a high carbohydrate (CHO) diet (60% of energy from carbohydrates, 12% protein, 28% fat; n = 30) or a high protein (PRO) diet (35% carbohydrate, 35% protein, 30% fat; n = 30). Rats were meal-fed 3x/d the respective diets for 10 d and then terminated after overnight food deprivation or 30, 60, 90, 120 min post-prandial (PP). Plasma was collected at each of these points to provide a time course for glucose, insulin and C-peptide. Skeletal muscle and adipose tissues were collected at 0, 30 and 90 min for measurements of basal, early and delayed activation of Akt, p70S6K and Erk 1/2. Data were analyzed by two-way ANOVA.ResultsThe CHO group produced a consistently elevated response in plasma glucose, insulin and C-peptide following the meal through the 120 min time course. In addition, Akt and Erk 1/2 activation in adipose was much higher than in skeletal muscle. Conversely, the PRO group PP glucose response was minimal and insulin maintained a response similar to a biphasic pattern. Tissue responses for the PRO group were greater for Akt and p70S6K signaling in skeletal muscle compared with adipose.ConclusionTaken together these data suggest that altering CHO:PRO ratios within the AMDR produce different glycemic response patterns accompanied by differential metabolic signaling in skeletal muscle and adipose.