Project description:The gut microbiota impacts many aspects of host biology including immune function. One hypothesis is that microbial communities induce epigenetic changes with accompanying alterations in chromatin accessibility, providing a mechanism that allows a community to have sustained host effects even in the face of its structural or functional variation. We used ATAC-seq to define chromatin accessibility in predicted enhancer regions of intestinal αβ+ and γδ+ intraepithelial lymphocytes (IELs) purified from germ-free mice, their conventionally-raised (CONV-R) counterparts, and mice reared GF and then colonized with a CONV-R gut microbiota at the end of the suckling-weaning transition. Characterizing genes adjacent to traditional enhancers and super-enhancers revealed signaling networks, metabolic pathways, and enhancer-associated transcription factors affected by the microbiota. Our results support the notion that epigenetic modifications help define microbial community-affiliated functional features of host immune cell lineages.
Project description:Microbial sequencing revealed progressive reduction of gut microbiota that showed some differences in the two ABX groups compared to untreated controls. Interestingly, duration of ABX was associated with a gradual disappearance of the CD4+ and CD4+CD8+ subset of gut intraepithelial lymphocytes (IELs). This IEL subset is microbiota-dependent and is absent in germ-free mice. Relative abundance of Lactobacillus reuteri correlated with frequencies of CD4+CD8+ IELs and reduced EAU. Notably, IELs in culture suppressed antigen-specific activation of autoreactive T cells.
Project description:Gut intraepithelial lymphocytes (IELs) are one of the few immune cell populations in the body that expresses glucagon-like 1 receptors (GLP-1R). To test the potential effects of GLP-1 on the gut microbiota through the gut IEL GLP-1R, we performed 16s rRNA seq on the DNA isolated from the fecal pellet of Lck-Cre; Glp1rfl/fl mice (Glp1rTcell-/-) or controls (Glp1rTcell+/+) fed a high-fat diet (HFD) for 12 weeks followed by 1 week of HFD plus semaglutide (10 ug/kg) or vehicle treatment. Fecal pellets from a group of age-matched, sex-matched control mice were included as a chow control group.
Project description:Acetaminophen is a widely used antipyretic and analgesic drug, and its overdose is the leading cause of drug-induced acute liver failure. This study aimed to investigate the effect and mechanism of Lacticaseibacillus casei Shirota (LcS), an extensively used and highly studied probiotic, on acetaminophen-induced acute liver injury. C57BL/6 mice were gavaged with LcS suspension or saline once daily for 7 days before the acute liver injury was induced via intraperitoneal injection of 300 mg/kg acetaminophen. The results showed that LcS significantly decreased acetaminophen-induced liver and ileum injury, as demonstrated by reductions in the increases in aspartate aminotransferase, total bile acids, total bilirubin, indirect bilirubin and hepatic cell necrosis. Moreover, LcS alleviated the acetaminophen-induced intestinal mucosal permeability, elevation in serum IL-1α and lipopolysaccharide, and decreased levels of serum eosinophil chemokine (eotaxin) and hepatic glutathione levels. Furthermore, analysis of the gut microbiota and metabolome showed that LcS reduced the acetaminophen-enriched levels of Cyanobacteria, Oxyphotobacteria, long-chain fatty acids, cholesterol and sugars in the gut. Additionally, the transcriptome and proteomics showed that LcS mitigated the downregulation of metabolism and immune pathways as well as glutathione formation during acetaminophen-induced acute liver injury. This is the first study showing that pretreatment with LcS alleviates acetaminophen-enriched acute liver injury, and it provides a reference for the application of LcS.