ena-STUDY-WASHINGTON UNIVERSITY CENTER FOR GENOME SCIENCES-21-05-2014-21:17:20:256-278
Effects of cholera on the human gut microbiota, and interactions between human gut microbes and Vibrio cholerae.
Given the global burden of diarrheal diseases, it is important to understand how members of the gut microbiota affect the risk for, the course of, and recovery from disease.  This is true for young children when the gut microbiota is being assembled, as well as for adults.  Recent culture-independent analyses of the fecal microbiota of healthy Bangladeshi infants and children, sampled monthly from birth through the second year of life, have identified a group of age-discriminatory bacterial taxa that together define a normal program of postnatal development (maturation) of the gut microbiota. The acute voluminous diarrhea caused by Vibrio cholerae represents a dramatic example of enteropathogen invasion and gut microbial community disruption.  We have conducted a detailed time-series metagenomic study of the fecal microbiota during the acute diarrheal and recovery phases of cholera in a cohort of Bangladeshi adults living in an area with a very high burden of disease. Recovery is characterized by a pattern of accumulation of bacterial taxa that mirrors the normal pattern of assembly/maturation of the microbiota in healthy Bangladeshi children. To define underlying mechanisms, we created an artificial community of 14 sequenced human gut bacterial species in gnotobiotic mice, composed of taxa that directly correlate with recovery from cholera and that are indicative of normal microbiota maturation in healthy Bangladeshi children. One of these age-discriminatory species, Ruminococcus obeum, exhibited consistent increases in its relative abundance upon V. cholerae infection of the mice. Follow-up mono- and bi-colonization studies established that R. obeum restricts V. cholerae colonization. RNA-Seq of the community’s meta-transcriptome, combined with assays of autoinducer-2 (AI-2) production and function, revealed that expression of R. obeum luxS (AI-2 synthase) and AI-2 production increase significantly with V. cholerae invasion, and that R. obeum AI-2 causes quorum-sensing mediated repression of toxin co-regulated pilus, a primary V. cholerae colonization factor. Co-colonization experiments in gnotobiotic mice established that R. obeum AI-2 reduces Vibrio colonization/pathogenicity through a novel pathway that does not depend on the canonical V. cholerae AI-2 sensor, LuxP.
Given the global burden of diarrheal diseases, it is important to understand how members of the gut microbiota affect the risk for, the course of, and recovery from disease.  This is true for young children when the gut microbiota is being assembled, as well as for adults.  Recent culture-independent analyses of the fecal microbiota of healthy Bangladeshi infants and children, sampled monthly from birth through the second year of life, have identified a group of age-discriminatory bacterial taxa that together define a normal program of postnatal development (maturation) of the gut microbiota. The acute voluminous diarrhea caused by Vibrio cholerae represents a dramatic example of enteropathogen invasion and gut microbial community disruption.  We have conducted a detailed time-series metagenomic study of the fecal microbiota during the acute diarrheal and recovery phases of cholera in a cohort of Bangladeshi adults living in an area with a very high burden of disease. Recovery is characterized by a pattern of accumulation of bacterial taxa that mirrors the normal pattern of assembly/maturation of the microbiota in healthy Bangladeshi children. To define underlying mechanisms, we created an artificial community of 14 sequenced human gut bacterial species in gnotobiotic mice, composed of taxa that directly correlate with recovery from cholera and that are indicative of normal microbiota maturation in healthy Bangladeshi children. One of these age-discriminatory species, Ruminococcus obeum, exhibited consistent increases in its relative abundance upon V. cholerae infection of the mice. Follow-up mono- and bi-colonization studies established that R. obeum restricts V. cholerae colonization. RNA-Seq of the community’s meta-transcriptome, combined with assays of autoinducer-2 (AI-2) production and function, revealed that expression of R. obeum luxS (AI-2 synthase) and AI-2 production increase significantly with V. cholerae invasion, and that R. obeum AI-2 causes quorum-sensing mediated repression of toxin co-regulated pilus, a primary V. cholerae colonization factor. Co-colonization experiments in gnotobiotic mice established that R. obeum AI-2 reduces Vibrio colonization/pathogenicity through a novel pathway that does not depend on the canonical V. cholerae AI-2 sensor, LuxP.