Regulation of hepatic and systemic immune responses

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

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Abstract

Over millions of years the microbiota of mammals co-evolved with their hosts, resulting in a symbiotic host-microbe relationship that is critical to host physiology. At all phases of life, the microbiota and the host immune response shape each other. However, standard laboratory mice are lacking many of the microbes and pathogens that have co-evolved with mammals in the natural world. To mitigate this problem, we previously established mouse models that combined the tractable genetics of C57BL/6 mice with the natural microbiota (bacteria, viruses, fungi, mites and protozoa) of wild mice. This was achieved by transferring embryos from conventional C57/BL6 mice into pseudopregnant wild mice. We reported that these mice serve as better models for human responses than conventional laboratory mice in two preclinical studies (Science 2019, PMID: 31371577). The offspring were used to generate a mouse colony that is now maintained over 5 years. In the past year, we assessed the stability of the microbiome using serial samples from this colony, in combination with detailed characterization and serial assessments of immune responses. We demonstrated that mice with natural microbiota maintain an enhanced immune status with more myeloid cells and antibody-producing B cells than standard laboratory mice. In addition, their effector cells (natural killer cells and T cells) have more cytotoxic molecules and produce greater amounts of cytokines. We continued to study innate and adaptive immune cells after coronavirus infections, and have identified measures of protection in mice with wild-type microbiome as compared to mice with standard microbiome. Finally, we have continued to study the mechanisms that protect mice with wild-type microbiome from high-fat diet induced obesity. We previously reported in a series of cross-fostering and co-housing experiments demonstrated that this phenotype is only transferable during the first weeks of life (Nature Metabolism 2021, PMID: 34417593). In adult mice, neither transfer nor severe disturbance of the wild-type microbiome by treatment with antibiotics modifies the metabolic response to high-fat diet. In the current year we have extended these studies to investigating in more detail the timing of microbiome exposure, immune response maturation, and brown adipose tissue development. We have also assessed the extent of beiging/browning of white adipose tissue, and characterized the brown adipose tissue in more detail. Results from these studies are currently being analyzed. The translation of these studies to humans may identify therapeutics that regulate metabolism and inflammation.