Regulation of hepatic and systemic immune responses

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

The following research is based on the hypothesis that conventional laboratory mice lack many microbes that have co-evolved in a mutually beneficial relationship with mammals in the natural world. They also lack many of the pathogens that free-living mammals are exposed to starting at an early age. To restore the natural microbiome and maintain the C57BL/6 background of inbred laboratory mice, C57BL/6 embryos were transferred into wild mice and the resulting offspring were used to establish a colony. This approach allowed the vertical transfer of microbiota and pathogens at multiple body sites (Science 2019, PMID: 31371577). The microbiome affected the frequency, activation and differentiation status of innate and adaptive immune cell populations as studied by mass cytometry, and transcriptome analysis. Importantly mice with natural microbiota predicted human immune responses in two studies, whereas conventional laboratory mice did not (Science 2019, PMID: 31371577). This research provides a path towards developing mouse models that better recapitulate complex physiological phenomena found in the natural world. Given the wide-ranging effects of the microbiome on host physiology it is likely that this approach will benefit many research fields including immunology, metabolism and endocrinology. In the current year we completed a study on the effect of the wild-type microbiome on metabolism. We show that a wild-derived microbiome protected conventional C57BL/6 mice from excessive weight gain, severe fatty liver disease and metabolic syndrome during a 10-week course of diet (choline-deficient, 45% of calories are derived from fat). This phenotype was transferable only during the first two weeks of life through co-housing or fostering. During adult life, neither transfer nor antibiotic-mediated depletion of the wild-derived microbiome modified the metabolic response to increased caloric intake. The protective phenotype was due to increased metabolism evidenced by higher temperature, reduced hepatic lipogenesis and increased energy expenditure in brown adipose tissue. Additional collaborative studies with Dr. Belkaids lab, NIAID, demonstrated that the wild-type microbiome confers colonization resistance against other bacteria by altering bile acid metabolism. The increased utilization of the bile acid taurine potentiates the production of sulfide, which inhibits the cellular respiration that many host-invading pathogens depend on. Finally, we are using mice with wild-type microbiota to study to immune-mediated inflammation after coronavirus infections in different organs. These studies are designed to (i) assess whether age-dependent disease severity after coronavirus infection is driven by microbiota and past pathogen/antigen exposure, and identify the underlying mechanisms, (ii) study the organ-specific modulation of coronavirus-induced inflammation by the microbiome and its specific kingdoms, and (iii) use mice with natural microbiota as a preclinical model to screen immunomodulatory compounds that mitigate hyperinflammatory responses / cytokine storm in humans.