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Significance The bacteria that live within the human gut play crucial roles in regulating our primary metabolism, protecting us from pathogens, and developing our immune system. Imbalances in bacterial community structure have been implicated in many diseases, such as Crohn’s disease, an inflammatory bowel disease. We found and characterized an inflammatory polysaccharide produced by the gut bacterium Ruminococcus gnavus, populations of which bloom during flares of symptoms in patients with Crohn’s disease. This molecule induces the production of inflammatory cytokines like TNFα by dendritic cells and may contribute to the association between R. gnavus and Crohn’s disease. This work establishes a plausible molecular mechanism that may explain the association between a member of the gut microbiome and an inflammatory disease., A substantial and increasing number of human diseases are associated with changes in the gut microbiota, and discovering the molecules and mechanisms underlying these associations represents a major research goal. Multiple studies associate Ruminococcus gnavus, a prevalent gut microbe, with Crohn’s disease, a major type of inflammatory bowel disease. We have found that R. gnavus synthesizes and secretes a complex glucorhamnan polysaccharide with a rhamnose backbone and glucose sidechains. Chemical and spectroscopic studies indicated that the glucorhamnan was largely a repeating unit of five sugars with a linear backbone formed from three rhamnose units and a short sidechain composed of two glucose units. The rhamnose backbone is made from 1,2- and 1,3-linked rhamnose units, and the sidechain has a terminal glucose linked to a 1,6-glucose. This glucorhamnan potently induces inflammatory cytokine (TNFα) secretion by dendritic cells, and TNFα secretion is dependent on toll-like receptor 4 (TLR4). We also identify a putative biosynthetic gene cluster for this molecule, which has the four biosynthetic genes needed to convert glucose to rhamnose and the five glycosyl transferases needed to build the repeating pentasaccharide unit of the inflammatory glucorhamnan.

The intestinal microbiota plays a crucial role in influencing the development of host immunity, and in turn the immune system also acts to regulate the microbiota through intestinal barrier maintenance and immune exclusion. Normally, these interactions are homeostatic, tightly controlled, and organized by both innate and adaptive immune responses. However, a combination of environmental exposures and genetic defects can result in a break in tolerance and intestinal homeostasis. The outcomes of these interactions at the mucosal interface have broad, systemic effects on host immunity and the development of chronic inflammatory or autoimmune disease. The underlying mechanisms and pathways the microbiota can utilize to regulate these diseases are just starting to emerge. Here, we discuss the recent evidence in this area describing the impact of microbiota-immune interactions during inflammation and autoimmunity, with a focus on barrier function and CD4+ T cell regulation.

Summary The human microbiome encodes extensive metabolic capabilities, but our understanding of the mechanisms linking gut microbes to human metabolism remains limited. Here, we focus on the conversion of cholesterol to the poorly absorbed sterol coprostanol by the gut microbiota to develop a framework for the identification of functional enzymes and microbes. By integrating paired metagenomics and metabolomics data from existing cohorts with biochemical knowledge and experimentation, we predict and validate a group of microbial cholesterol dehydrogenases that contribute to coprostanol formation. These enzymes are encoded by ismA genes in a clade of uncultured microorganisms, which are prevalent in geographically diverse human cohorts. Individuals harboring coprostanol-forming microbes have significantly lower fecal cholesterol levels and lower serum total cholesterol with effects comparable to those attributed to variations in lipid homeostasis genes. Thus, cholesterol metabolism by these microbes may play important roles in reducing intestinal and serum cholesterol concentrations, directly impacting human health., Graphical Abstract, Highlights • Bioinformatics enabled discovery of ismA, a microbial cholesterol dehydrogenase • Metagenomic species with ismA genes form coprostanol in microbial communities • ismA+ species are associated with decreased fecal and serum cholesterol in humans • Effect sizes of ismA+ species on serum cholesterol are on par with human genetics, The consequences of cholesterol metabolism by the gut microbiome were largely unknown. Kenny, Plichta et al. identified and characterized microbial cholesterol dehydrogenase enzymes encoded by uncultured metagenomic species of bacteria. The presence of these cholesterol-metabolizing bacteria is associated with decreased stool and serum total cholesterol in human cohorts.

Microbes living within host-associated microbial communities (microbiotas) rely on chemical communication to interact with surrounding organisms. These interactions serve many purposes, from supplying the multicellular host with nutrients to antagonizing invading pathogens, and breakdown of chemical signaling has potentially negative consequences for both the host and microbiota. Efforts to engineer microbes to take part in chemical interactions represent a promising strategy for modulating chemical signaling within these complex communities. In this review, we discuss prominent examples of chemical interactions found within host-associated microbial communities, with an emphasis on the plant-root microbiota and the intestinal microbiota of animals. We then highlight how an understanding of such interactions has guided efforts to engineer microbes to participate in chemical signaling in these habitats. We discuss engineering efforts in the context of chemical interactions that enable host colonization, promote host health, and exclude pathogens. Finally, we describe prominent challenges facing this field and propose new directions for future engineering efforts.