Advancing the fitness of gut commensal bacteria

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Abstract

Nutrient starvation of beneficial bacteria helps them colonize the human gut

Abstract

Improving the colonization, survival, and persistence of beneficial microbes in the human gut holds great therapeutic potential because they play critical roles in health and disease. In particular, gut commensal bacteria harbor many genes that have no homologs in the hosts that they inhabit, and so they enable various functions that are not encoded in host genomes. For mammals, these functions include energy extraction from otherwise indigestible dietary fibers, vitamin production, and resistance to pathogens. Disruption of the human gut microbiota is associated with metabolic disorders, immune deficiencies, altered susceptibility to pharmacological agents, mental health problems, and some types of cancer. To harness the benefits of gut commensals as probiotics, it is critical to identify bacterial determinants and host conditions, such as diet and eating patterns (e.g., fasting), that advance their fitness.

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A genomic view of the human-Bacteroides thetaiotaomicron symbiosis.

Jian Xu, Magnus Bjursell, Jason Himrod … (2003)

The human gut is colonized with a vast community of indigenous microorganisms that help shape our biology. Here, we present the complete genome sequence of the Gram-negative anaerobe Bacteroides thetaiotaomicron, a dominant member of our normal distal intestinal microbiota. Its 4779-member proteome includes an elaborate apparatus for acquiring and hydrolyzing otherwise indigestible dietary polysaccharides and an associated environment-sensing system consisting of a large repertoire of extracytoplasmic function sigma factors and one- and two-component signal transduction systems. These and other expanded paralogous groups shed light on the molecular mechanisms underlying symbiotic host-bacterial relationships in our intestine.

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Genetic determinants of in vivo fitness and diet responsiveness in multiple human gut Bacteroides.

Meng-Meng Wu, Nathan P McNulty, Dmitry A. Rodionov … (2015)

Libraries of tens of thousands of transposon mutants generated from each of four human gut Bacteroides strains, two representing the same species, were introduced simultaneously into gnotobiotic mice together with 11 other wild-type strains to generate a 15-member artificial human gut microbiota. Mice received one of two distinct diets monotonously, or both in different ordered sequences. Quantifying the abundance of mutants in different diet contexts allowed gene-level characterization of fitness determinants, niche, stability, and resilience and yielded a prebiotic (arabinoxylan) that allowed targeted manipulation of the community. The approach described is generalizable and should be useful for defining mechanisms critical for sustaining and/or approaches for deliberately reconfiguring the highly adaptive and durable relationship between the human gut microbiota and host in ways that promote wellness.

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A hybrid two-component system protein of a prominent human gut symbiont couples glycan sensing in vivo to carbohydrate metabolism.

H-Y Chiang, Robert E Sonnenburg, D Manchester … (2006)

Bacteroides thetaiotaomicron is a prominent member of our normal adult intestinal microbial community and a useful model for studying the foundations of human-bacterial mutualism in our densely populated distal gut microbiota. A central question is how members of this microbiota sense nutrients and implement an appropriate metabolic response. B. thetaiotaomicron contains a large number of glycoside hydrolases not represented in our own proteome, plus a markedly expanded collection of hybrid two-component system (HTCS) proteins that incorporate all domains found in classical two-component environmental sensors into one polypeptide. To understand the role of HTCS in nutrient sensing, we used B. thetaiotaomicron GeneChips to characterize their expression in gnotobiotic mice consuming polysaccharide-rich or -deficient diets. One HTCS, BT3172, was selected for further analysis because it is induced in vivo by polysaccharides, and its absence reduces B. thetaiotaomicron fitness in polysaccharide-rich diet-fed mice. Functional genomic and biochemical analyses of WT and BT3172-deficient strains in vivo and in vitro disclosed that alpha-mannosides induce BT3172 expression, which in turn induces expression of secreted alpha-mannosidases. Yeast two-hybrid screens revealed that the cytoplasmic portion of BT3172's sensor domain serves as a scaffold for recruiting glucose-6-phosphate isomerase and dehydrogenase. These interactions are a unique feature of BT3172 and specific for the cytoplasmic face of its sensor domain. Loss of BT3172 reduces glycolytic pathway activity in vitro and in vivo. Thus, this HTCS functions as a metabolic reaction center, coupling nutrient sensing to dynamic regulation of monosaccharide metabolism. An expanded repertoire of HTCS proteins with diversified sensor domains may be one reason for B. thetaiotaomicron's success in our intestinal ecosystem.