A commensal-derived exopolysaccharide regulates ILC3-mediated diseases

Abstract The gut microbiota plays a fundamental role in controlling many facets of human physiology, with impacts on the immune system being chief among them. Although there have been increasing successes in identifying disease-regulating commensal bacteria, the mechanisms by which they work remain poorly understood. We previously identified Clostridium immunis, a new human-derived commensal bacterial species that modulates colitis. Here we identify the immunological factors and specific bacterial determinant required for its disease modulating activity. We find that C. immunis directly regulates the effector function of group 3 innate lymphoid cells (ILC3s), with altered levels of IL-22 and GM-CSF in states of health and inflammation, respectively. This impact on ILC3s serves as a common immunological node for modulation of visceral adiposity and intestinal inflammation. Surprisingly, the two bacterial species most closely related to C. immunis lack this ILC3-modulating activity. Guided by comparative genomics, we purified an exopolysaccharide (EPS) that recapitulates the immunomodulatory activity of C. immunis in vitro and in vivo. Structural analysis revealed that phosphocholine on the EPS correlated with activity, and deletion of the C. immunis phosphocholine biosynthesis locus (LicABC) resulted in functionally inactive EPS. Our results reveal that a phosphocholine moiety present on a bacterial polysaccharide is critically required to orchestrate ILC3 effector function and regulate intestinal homeostasis. Considered together, we provide genetic and structural insight into how a human commensal bacterium provides a unique immunomodulatory function. Supported by a predoctoral fellowship from the American Heart Association (897275), a postgraduate scholarship from the Tan Kah Kee Foundation, and a Development Grant from the National University of Singapore (to C.Y.T) Supported by grants from NIH (NIH R03 AI142341), The Hartwell Foundation, and as a Translating Duke Health Scholar and as a Whitehead Scholar (to N.K.S.).