SUMMARY Many of the immune and metabolic changes occurring during normal pregnancy also describe metabolic syndrome. Gut microbiota can cause symptoms of metabolic syndrome in non-pregnant hosts: To explore their role in pregnancy, here we characterized fecal bacteria of 91 pregnant women of varying pre-pregnancy BMIs and gestational diabetes status, and their infants. Similarities between infant-mother microbiotas increased with children’s age, and the infant microbiota was unaffected by mother health status. Gut microbiota changed dramatically from first (T1) to third (T3) trimesters, with vast expansion of diversity between mothers, an overall increase in Proteobacteria and Actinobacteria, and reduced richness. T3 stool showed strongest signs of inflammation and energy loss, however microbiome gene repertoires were constant between trimesters. When transferred to germ-free mice, T3 microbiota induced greater adiposity and insulin insensitivity compared to T1. Our findings indicate that host-microbial interactions impacting host metabolism can occur, and may be beneficial, in pregnancy.

Metabolic syndrome is a group of obesity-related metabolic abnormalities that increase an individual’s risk of developing type 2 diabetes and cardiovascular disease. Here, we show that mice genetically deficient in Toll-like receptor 5 (TLR5), a component of the innate immune system that is expressed in the gut mucosa and that helps defend against infection, exhibit hyperphagia and develop hallmark features of metabolic syndrome, including hyperlipidemia, hypertension, insulin resistance, and increased adiposity. These metabolic changes correlated with changes in the composition of the gut microbiota, and transfer of the gut microbiota from TLR5-deficient mice to wild-type germ-free mice conferred many features of metabolic syndrome to the recipients. Food restriction prevented obesity, but not insulin resistance, in the TLR5-deficient mice. These results support the emerging view that the gut microbiota contributes to metabolic disease and suggest that malfunction of the innate immune system may promote the development of metabolic syndrome.

SUMMARY Colitis results from breakdown of homeostasis between intestinal microbiota and the mucosal immune system, with both environmental and genetic influencing factors. Flagellin receptor TLR5-deficient mice (T5KO) display elevated intestinal pro-inflammatory gene expression and colitis with incomplete penetrance, providing a genetically sensitized system to study the contribution of microbiota to driving colitis. Both colitic and non-colitic T5KO exhibited transiently unstable microbiotas, with lasting differences in colitic T5KO while their non-colitic siblings stabilized their microbiotas to resemble wild-type mice. Transient high levels of Proteobacteria, especially Enterobacteria species including E. coli, observed in close proximity to the gut epithelium was a striking feature of colitic microbiota. A Crohn’s disease-associated E. coli strain induced chronic colitis in T5KO, which persisted well after the exogenously introduced bacterial species had been eliminated. Thus, an innate immune deficiency can result in unstable gut microbiota associated with low-grade inflammation and harboring Proteobacteria can drive and/or instigate chronic colitis.

SUMMARY Gut mucosal barrier breakdown and inflammation have been associated with high levels of flagellin, the principal bacterial flagellar protein. Although several gut commensals can produce flagella, flagellin levels are low in the healthy gut, suggesting the existence of control mechanisms. We find that mice lacking the flagellin receptor Toll-like receptor (TLR) 5 exhibit a profound loss of flagellin-specific immunoglobulins (Ig) despite higher total Ig levels in the gut. Ribotyping of IgA-coated cecal microbiota showed Proteobacteria evading antibody coating in the TLR5−/− gut. A diversity of microbiome members over-expressed flagellar genes in the TLR5−/− host. Proteobacteria and Firmicutes penetrated small intestinal villi, and flagellated bacteria breached the colonic mucosal barrier. In vitro, flagellin-specific Ig inhibited bacterial motility and down-regulated flagellar gene expression. Thus, innate-immunity directed development of flagellin-specific adaptive immune responses can modulate the microbiome’s production of flagella in a three-way interaction that helps to maintain mucosal barrier integrity and homeostasis.

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