Carbohydrate Structure Controls on Human Gut Microbial Ecology

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Low gut microbiota diversity is associated with many chronic diseases including metabolic syndrome, type II diabetes, irritable bowel syndrome, inflammatory bowel disease (IBD), and colorectal cancer. The human costs are staggering and increasing; IBD, alone, impacts 3.1 million Americans, causing lower quality of life, high hospitalization rates, and healthcare costs of over $6.8 billion, especially among those of low socioeconomic status. Westernization of diet is correlated with reduced gut microbial diversity compared to that of traditional diets. Recently, research groups have determined that this loss of gut microbial species is linked to the high- fat, low-fiber Western diet, in mice, these extinctions compound over generations, and higher consumption of fermentable dietary fibers modestly increases gut microbiome diversity. Complicating understanding of fiber influences on the gut microbiome is that, although often combined into a single category, dietary fibers are actually a diverse set of molecularly-distinct carbohydrate structures. Though microbes are known to exclude each other in competition for growth on simple substrates (e.g., glucose), little is known about how complex substrates affect the ecology of microbial communities. Because such complex substrates are too large to directly be imported through the cell envelope, external degradative enzymes must first act to convert components of the complex substrate into a transportable form that can be imported into the enzyme- producing cell; until then, the hydrolyzed products remain available to any microbe. Thus, external degradation of complex substrates by specific microbes that encode the degradative enzymes has the capacity to produce “public goods” that cross-feed other organisms lacking the ability to consume the complex substrate. This is especially true of polysaccharides, as carbohydrates are composed of many different types of glycosyl residues connected by diverse types of bonds. The human gut is an environment rich in complex polysaccharides, and the structural complexity of these substrates suggest the possibility that organisms might be able to co-exist in consuming a complex substrate. This may be one mechanism preserving or increasing microbial diversity in the colon. Here, we describe an integrated experimental and modeling approach in three interconnected projects to identify gut microbe traits that influence competitiveness for complex carbohydrates, determine hydrolysis and transport traits important for polysaccharide response in vivo, and elucidate and model microbe-host metabolic interactions in carbohydrate fermentation. We employ a combination of in vitro ecological experiments, mechanistic and genome-scale metabolic in silico models, chemical biology-based probing using oligosaccharide mimics, and microfluidic systems for high-throughput screening of carbohydrate- microbiota-host interactions to achieve these ends. The goal of my work is to identify the principles governing how carbohydrate structure controls the gut microbiota and human physiology, to enable rational design of carbohydrates and dietary strategies to manage gut microbiota diversity and function for improved health.