The role of the gut microbiome in susceptibility to Mycobacterium tuberculosis

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PROJECT SUMMARY Tuberculosis (TB) is a deadly infectious disease that kills over 1.7 million people per year. The majority of individuals are able to control Mycobacterium tuberculosis (Mtb) infection, yet others are extremely vulnerable. Life-threatening disease symptoms, including extreme weight loss or cachexia, are also heterogenous across individuals. Immunocompromised people are particularly susceptible to TB, and less extreme variations in immune system function may also contribute to susceptibility. The mammalian gut microbiome is a complex community of microbes with extreme variation across individuals. Gut microbiome composition impacts immune function and susceptibility to a variety of pathogens. Our pilot data suggests that genetically identical mice with distinct gut microbiomes have altered ability to control Mtb infection. In this proposal we will interrogate the role of the microbiome in Mtb control and cachexia. First, we will expand our comparison of mice from different housing conditions to determine the extent of variation in Mtb burden. To confirm the role of the microbiome in Mtb infection control, we will transplant fecal microbiomes of interest into germ-free mice and repeat Mtb infection. We will also profile the immune response to infection in each case. Second, we will explore the role of the gut microbiome in mediating TB associated cachexia by measuring microbial and metabolic changes over time in genetically identical mice with diverse microbiomes. In follow up, we will isolate gut bacteria of interest from these microbiomes to investigate how microbial metabolism may impact immune function. This proposal will open up a new area of research to probe the role of the gut microbiome in the pathogenesis of TB. This research has the potential to identify new microbial and host directed therapeutic targets for TB prophylaxis and treatment.