Regulation of hepatic and systemic immune responses

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications & trials

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. We reported that these mice serve as better models for human responses than conventional laboratory mice in two preclinical studies (Science 2019, PMID: 31371577). Obesity and its consequences belong to the greatest challenges in healthcare. Disturbed gut microbiota is recognized as a key factor in the pathogenesis of obesity. Hypothesizing that the natural microbiome may exert protective effects, we investigated the effect of a wild-derived gut microbiome on weight gain and metabolic syndrome. We reported that mice with natural microbiota were protected against excessive weight gain, severe fatty liver disease and metabolic syndrome during a 10-week course of high-fat diet. A series of cross-fostering and co-housing experiments demonstrated that this phenotype is only transferable during the first weeks of life. 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. The protective phenotype is associated with increased secretion of metabolic hormones and increased energy expenditure through activation of brown adipose tissue (Nature Metabolism 2021, PMID: 34417593). In the current year we have extended these studies to additional types of diet and used metabolic chambers to assess the phenotype of the mice at different ambient temperatures. To explore the specific components of the natural microbiome that contribute to protection from obesity, we have devised techniques to reduce the complexity of the bacterial microbiome, and are examining the phenotype of these mice. To study coronavirus infections and the regulation of virus-induced inflammation in this mouse model we have established a cohort of old mice on different genetic backgrounds. These are mice being used to assess how the microbiome changes during the aging process and how it affects metabolic processes and immunosurveillance by innate and adaptive immune cells after coronavirus infections. These old mice with wild mouse microbiome are being challenged with coronaviruses in comparison to regular age mice. The translation of these results to humans may identify therapeutics that regulate metabolism and inflammation.