Elucidating mechanisms of microbiome-diet modulation of host homeostasis

Abstract

Industrialization and advances in technology over the last half-millennium have led to dramatic changes in human society. The diet of our ancestors, once rich in plant matter of extraordinary chemical diversity, has been replaced with a heavily processed diet. Similarly, the rise of urban centers has resulted in an environment devoid of many microbial and chemical exposures around which our ancestors evolved. This rapid shift in human society is sharply correlated with two facets of modern human health: an extensive restructuring of the human gut microbiome and a dramatic increase in the incidence of chronic inflammatory diseases and infection. The gut microbiome is an incredibly complex ecosystem of microorganisms residing in the chemically complex milieu that is the gut.

Diet has emerged as instrumental in driving the composition and dynamics of the gut microbiome, and in the development of diverse human diseases. While the impact of dietary carbohydrates (fiber) on the gut microbiome and human health is well characterized, there is a dearth of information as to how plant small molecules (phytochemicals) and other xenobiotics, many of which are thought to be bioactive, interact with or are transformed by the gut microbiome to affect human health. The dynamic interplay between multiple biotic and abiotic factors in this ecosystem makes deconvoluting molecular mechanism challenging using next-generational community profiling tools that profile community structure alone. This research aims to synergize bottoms-up and top-down approaches to define the landscape of phytochemical metabolism by the gut microbiome as a lever on human health.

Chapter 2 describes the characterization of phytochemical glycoside metabolism across diverse gut bacteria, discovery of the genetic and molecular basis for differential glycoside catabolism across both gut bacteria and phytochemical substrates and the identification of a phytochemical-specific bacterial catabolic enzyme, and identification of two phytochemical-derived microbial metabolites with novel bioactivities: protection from experimental colitis and selective antagonism of C. difficile. Chapter 3 describes the identification of a novel small intestinal factor that regulates oral tolerance via modulation of both the microbiome and immune components of the gut, discovery of a dietary microbial tryptophan catabolic pathway that generates food allergy-protective Treg-reactive metabolites, and therapeutic intervention against this factor protecting against loss of tolerance in both early life and adulthood. Together, these findings demonstrate novel microbiome-diet axes wherein gut bacterial catabolism of dietary xenobiotics generates chemically-diverse metabolites that regulate the development of both local (inflammatory bowel disease; enteric C. difficile infection) and global (food allergy) disease processes. Furthermore, these findings emphasize the importance of reducing both the host and microbial components of the gut microbiome to their most basic, tractable parts—microbes, genes, and molecules to mechanistically identify tractable elements for therapeutic intervention.