Project description:Obesity is associated with an increased risk of mucosal infections; however, the mechanistic basis of this phenomenon remains incompletely defined. Intestinal mucus barrier systems normally prevent infections, but are sensitive to changes in the luminal environment. Here we demonstrate that mice exposed to an obesogenic Western-style diet (WSD) suffer regiospecific failure of the mucus barrier in the small intestinal jejunum caused by diet-induced mucus condensation, which occurs independently of microbiota alterations. Mucus barrier disruption due to either WSD exposure or chromosomal Muc2 deletion results in collapse of the commensal jejunal microbiota, which in turn sensitises mice to atypical jejunal colonization by the enteric pathogen Citrobacter rodentium. We identify the jejunal mucus layer as a microbial habitat, and link the regiospecific mucus dependency of the microbiota to fundamental properties of the jejunal niche. Together, our data identifies a symbiotic mucus-microbiota relationship that normally prevents jejunal pathogen colonization, but is highly sensitive to disruption by exposure to a Western-style diet.
Project description:We profiled transcriptome and chromatin landscapes in jejunal mouse intestinal epithelial cells (IECs) from mice reared in the absence (Germ Free or GF) or presence (Conventionalized or CV) of microbiota. We show that microbiota colonization results in changes in histone modifications at hundreds of enhancers that are associated with microbiota-regulated genes. Furthermore, we show that microbiota colonization is associated with a drastic genome-wide reduction in Hnf4a and Hnf4g binding.
Project description:Alterations in intestinal microbiota and intestinal short chain fatty acids profiles have been associated with the pathophysiology of obesity and insulin resistance. Whether intestinal microbiota dysbiosis is a causative factor in humans remains to be clarified We examined the effect of fecal microbial infusion from lean donors on the intestinal microbiota composition, glucose metabolism and small intestinal gene expression. Male subjects with metabolic syndrome underwent bowel lavage and were randomised to allogenic (from male lean donors with BMI<23 kg/m2, n=9) or autologous (reinfusion of own feces, n=9) fecal microbial transplant. Insulin sensitivity and fecal short chain fatty acid harvest were measured at baseline and 6 weeks after infusion. Intestinal microbiota composition was determined in fecal samples and jejunal mucosal biopsies were also analyzed for the host transcriptional response. Insulin sensitivity significantly improved six weeks after allogenic fecal microbial infusion (median Rd: from 26.2 to 45.3 μmol/kg.min, p<0.05). Allogenic fecal microbial infusion increased the overall amount of intestinal butyrate producing microbiota and enhanced fecal harvest of butyrate. Moreover, the transcriptome analysis of jejunal mucosal samples revealed an increased expression of genes involved in a G-protein receptor signalling cascade and subsequently in glucose homeostasis. Lean donor microbial infusion improves insulin sensitivity and levels of butyrate-producing and other intestinal microbiota in subjects with the metabolic syndrome. We propose a model wherein these bacteria provide an attractive therapeutic target for insulin resistance in humans. (Netherlands Trial Register NTR1776).
Project description:An early settlement of a complex gut microbiota can protect against gastro-intestinal dysbiosis, but the effects of neonatal microbiota colonization on the gut barrier upon the further encounter of favorable bacteria or not, are largely unknown. The jejunal transcriptome of differently perfused intestinal loops of 12 caesarian-derived pigs previously associated with microbiota of different complexity was studied. Pigs received pasteurized sow colostrum at birth (d0), 2 mL of starter microbiota (10^7 CFU of each Lactob. Amylovorus (LAM), Clostr. glycolicum, and Parabacteroides spp.) on d1-d3 of age and either a placebo inoculant (simple association, SA) or an inoculant consisting of diluted feces of an adult sow (complex association, CA) on d3-d4 of age. On days 26-37 of age, jejunal loops were perfused for 8 h with either enterotoxigenic E. coli F4 (ETEC), F4 fimbriae (F4), LAM or saline (CTRL) and jejunal samples were obtained from each piglet immediately afterwards.
Project description:Antibiotics have long-lasting consequences on the gut microbiota with the potential to impact host physiology and health. However, little is known about the transgenerational impact of an antibiotic-perturbed microbiota. Here we demonstrated that adult pregnant female mice inoculated with a gut microbial community shaped by antibiotic exposure passed on their dysbiotic microbiota to their offspring. This dysbiotic microbiota remained distinct from controls for at least 5 months in the offspring without any continued exposure to antibiotics. By using IL-10 deficient mice, which are genetically susceptible to colitis, we showed mice that received an antibiotic-perturbed gut microbiota from their mothers had increased risk of colitis. Taken together, our findings indicate that the consequences of antibiotic exposure affecting the gut microbiota can extend to a second generation.
Project description:The gut microbiota is a key environmental determinant of mammalian metabolism. Regulation of white adipose tissue (WAT) by the gut microbiota is a critical process that maintains metabolic fitness, while dysbiosis contributes to the development of obesity and insulin resistance (IR). However, how the gut microbiota controls WAT functions remain largely unknown. Herein, we show that tryptophan-derived metabolites produced by the microbiota control the expression of the miR-181 family in white adipocytes to regulate energy expenditure and insulin sensitivity. Moreover, we show that dysregulation of the microbiota-miR-181 axis is required for the development of obesity, IR, and WAT inflammation. Thus, our results indicate that regulation of miRNA levels in WAT by microbiota-derived cues is a central mechanism by which host metabolism is tuned in response to dietary and environmental changes. As MIR-181 is dysregulated in WAT from obese human individuals, the MIR-181 family may represent a potential therapeutic target to modulate WAT function in the context of obesity.
Project description:Microbial RNAseq analysis of cecal and fecal samples collected from mice colonized with the microbiota of human twins discordant for obesity. Samples were colleted at the time of sacrifice, or 15 days after colonization from mice gavaged with uncultured or cultured fecal microbiota from the lean twins or their obese co-twins. Samples were sequenced using Illumina HiSeq technology, with 101 paired end chemistry. Comparisson of microbial gene expression between the microbiota of lean and obese twins fed a Low fat, rich in plant polysaccharide diet.
Project description:Emerging knowledge shows the importance of early life events in programming the intestinal mucosal immune system and development of the intestinal barrier function. These processes depend heavily on close interactions between gut microbiota and host cells in the intestinal mucosa. In turn, development of the intestinal microbiota is largely dependent on available nutrients and substrates required for the specific microbial community structures to expand. It is currently not known what the specificities are of intestinal microbial community structures in relation to the programming of the intestinal mucosal immune system and development of the intestinal barrier function. The objective of the present study was to investigate the effect of a nutritional intervention on intestinal development of suckling piglets by daily oral administration of fructooligosaccharides (FOS) over a period of 12 days. At the microbiota community level a clear “bifidogenic” effect of the FOS administration was observed in colon digesta at day 14. The former, however, did not translate into significant changes of local gene expression in the colonic mucosa. In the jejunum, significant changes were observed for microbiota composition at day 14, and microbiota diversity at day 25. In addition, significant differentially expressed gene sets in mucosal tissues of jejunum were identified at both days 14 and 25 of age. At the age of 14 days, lower activity of cell cycle-related processes and a higher activity of extracellular matrix processes were observed in jejunal scrapings of piglets supplemented with FOS compared to control piglets. At day 25, lower activity of immune-related processes in jejunal tissue were seen in piglets supplemented with FOS. Histological parameters, villi height and crypt depth, were significantly different at day 25 between the experimental and control group, where piglets supplemented with FOS had higher villi and deeper crypts. We conclude that oral FOS administration during the suckling period of piglets has significant bifidogenic effects on the microbiota in the colon and on gene expression in jejunal mucosa scrapings. We hypothesize that FOS supplementation of suckling piglets results in a higher butyrate production in the colon due to the increase in bifidobacteria and lactobacilli in the hindgut. We further speculate that a higher butyrate production in colonic digesta relates to changes in gene expression in the jejunum by thus far unknown mechanisms.