Impact of gut microbial metabolism on host breath volatiles

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Project Summary/Abstract The gut microbiome has been implicated in various diseases such as inflammatory bowel disease, asthma, and neurodegenerative diseases. Despite the progress made in the studies of these diseases, there remains remarkable heterogeneity in patient presentation and prognosis. The interindividual variability in gut microbiome composition and metabolic functions may in part explain the interindividual variability in disease. Characterization of the gut microbiome is typically carried out using metagenomic sequencing or marker gene sequencing of the V4 16S sequence of bacteria in stool; however, these methods are not always possible in a clinical setting. Human stool must be acquired, properly stored, and is often not readily available at the site and time of collection for a clinical study. Metabolomic analysis of stool or urine also provides information about the functions of the bacteria present in the gut microbiome, however there is yet an even more convenient sample that carries information relevant to human health. In this project I propose to investigate the breath volatile profile as a medium for characterizing the gut microbiome. There are over 800 volatile organic compounds (VOC) that have been detected in human breath, some of them unexplained by host cellular metabolism. I hypothesize that the gut microbiota contributes otherwise unexplained VOCs to the host breath VOC profile. In Specific Aim 1 I will characterize the breath VOC profile of gnotobiotic mice to test the effect of gut microbiome composition on the breath VOC profile. In Specific Aim 2 I will show that bacterial metabolism directly produces VOCs that are absorbed by the host and excreted in breath with a monocolonized gnotobiotic mouse model. Finally, in Specific Aim 3, I will determine the effect of the microbiome on human breath by comparing the results of metagenomic sequencing of human stool with human breath VOCs collected as part of a recently completed clinical study. This investigation will take place at Washington University in St. Louis, a renowned institution for microbiome research, in the laboratory of Dr. Andrew Kau, an expert in the study of the microbiome and its interactions with the host. To supplement my training and expertise, I will collaborate with the laboratory of Dr. Audrey Odom- John, an expert in breath volatile profiling. Further supporting my mentorship team, Dr. Gautam Dantas will provide excellent advice as a co-sponsor and the chairperson of my thesis committee. This excellent training environment will ensure the research plan proposed provides rigorous scientific training for me as future physician-scientist.