Interplay between intestinal microbiota and PRDM16‐mediated metabolic regulation of intestinal stem and progenitor cells

Abstract

Distinct metabolic programs regulate intestinal stem cell renewal and differentiation. However, the mechanisms that rewire metabolism during differentiation are poorly defined. Previously, we have shown that the transcription factor PRDM16 is a critical regulator of intestinal metabolism and differentiation. Acute deletion of Prdm16 in adult mice causes intestinal wasting, apoptosis, and an accumulation of poorly differentiated cells in the small intestinal crypt, primarily in the duodenum and proximal jejunum. PRDM16 has emerged as a regulator of metabolic signaling in multiple tissues including thermogenic adipose tissue and the small intestine. RNA‐seq and tracer metabolomic studies show that PRDM16 regulates fatty acid oxidation (FAO) in the intestinal crypt, leading to impaired differentiation of stem and transit amplifying cells into mature cells.Our current studies have focused on the effects of the intestinal microbiota, which produces significant quantities of metabolites that could affect cells in the digestive tract. We postulated that altering the microbiome of mice in the context of Prdm16 deletion could modify the phenotype. Strikingly, pre‐treatment of animals with an antibiotic cocktail including ampicillin, neomycin, vancomycin and metronidazole almost completely rescues the Prdm16 deletion phenotype. While deletion of Prdm16 typically leads to death within 10 days, antibiotic treated mice survive at least 12 weeks after deletion. An early hallmark of the Prdm16‐deletion phenotype is the induction of the p53 pathway in the crypt. Apoptotic cells are present in high numbers, particularly in transit amplifying progenitors. Gene expression profiling of isolated small intestinal crypts indicates that the early p53 signature that is typical of Prdm16 deletion does not develop in antibiotic treated mice. Furthermore, pretreatment of mice with antibiotics prevents the severe defects normally observed when Prdm16 is deleted ex vivo in organoid cultures. However, treatment of organoids with the same antibiotics only in culture does not lead to a phenotypic rescue. We are currently characterizing how deletion of Prdm16 alters the intestinal microbiota and the effects that those changes could have on metabolite levels in the tissue. Overall, these studies aim to understand how changes in metabolic signaling can affect stem and progenitor cell behaviors and how the microbiome and, potentially, antibiotics themselves can affect the function of the intestine.