Microbiota-derived metabolites and the regulation of host immunity and inflammation

PROJECT SUMMARY
Soil-transmitted helminth infections are estimated to infected two billion people worldwide, remaining one of the
most neglected groups of infectious diseases and a significant public health and economic challenge. Infected
individuals can suffer from malnutrition, growth retardation, impaired cognitive function, anemia and severe
immunopathology as a result of chronic inflammation. Immunity to helminth parasites is dependent on type 2
inflammatory responses, characterized by activation of T helper type 2 (Th2) cells, group 2 innate lymphoid cells
(ILC2), eosinophils, alternatively-activated macrophages, and B cell production of IgE and IgG. These protective
type 2 responses are influenced by genetic and environmental factors, including diet and microbiota-derived
metabolites. Therefore, further studies are urgently needed to understand the mechanistic basis of how these
factors influence type 2 immune responses to improve strategies to treat and prevent allergic diseases and
intestinal helminth infections. The microbiota is the source of various metabolites which can exert their effects at
the site of absorption (intestine), as well at distant sites such as brain via bloodstream. Since various dietary
components, including dietary fiber, influence the composition of the microbiota and the types of metabolites the
microbiota produces, many of the effects of diet on immune cells can be mediated via the microbiota. However,
the influence of dietary fiber on microbiota-derived metabolites and their roles in regulating type 2
immunity and inflammation in the context of allergic responses or helminth infection remain poorly
defined. Our new preliminary studies in mice employing untargeted comparative metabolomic analyses
identified that a high fiber diet drives a significant shift in the composition of the microbiota and remarkable
changes in the levels of microbiota-derived metabolites. This metabolic reprogramming was associated with the
development of a proinflammatory type 2 immune response, characterized by activation of group 2 innate
lymphoid cells (ILC2s), accumulation of eosinophils, and accelerated parasite expulsion in a murine model of
helminth infection. Based on these preliminary data, we hypothesize that high fiber diet-induced modulation of
microbiota-derived metabolites promotes ILC2-induced type 2 inflammation and immunity to helminth parasite
infection. Based on these preliminary data, studies outlined in Aim 1 will test which microbiota-derived
metabolites activate ILC2s and trigger eosinophilia and type 2 inflammation to promote anti-parasite immunity.
In Aim 2, we will employ chemical and genetic approaches to test how the microbiota-intrinsic bile acid metabolic
pathway regulates dietary fiber-induced type 2 inflammation and immunity to infection. Upon successful
completion of our proposed aims, we expect to contribute to a fundamentally new understanding of the biology
of fiber diet, microbiota-derived metabolites, and ILC2s in regulating type 2 inflammation and anti-helminth
immunity.

Grant Number: 5R01AI172027-04
NIH Institute/Center: NIH
Principal Investigator: David Artis