Background: Well-balanced interactions between gut microbiota and the immune system are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). Toll-like receptor 4 (TLR4) functions as a sensor mediating the crosstalk between the intestinal commensal microbiome and host immunity, but the influence of TLR4 on the shaping of intestinal microbiota and immune responses during colon inflammation remains poorly characterized. We investigated whether the different susceptibilities to colitis between wild-type (WT) and TLR4^−/− mice were gut microbiota-dependent and aimed to identify the potential immunity modulation mechanism. Methods: We performed antibiotic depletion of the microbiota, cohousing experiments, and faecal microbiota transplantation (FMT) in WT and TLR4^−/− mice to assess the influence of TLR4 on intestinal microbial ecology. 16S rRNA sequencing was performed to dissect microbial discrepancies, and dysbiosis-associated immune perturbation was investigated by flow cytometry. Akkermansia muciniphila (A. muciniphila)-mediated immune modulation was confirmed through the T-cell transfer colitis model and bone marrow chimaera construction. Results: TLR4^−/− mice experienced enhanced susceptibility to DSS-induced colitis. 16S rRNA sequencing showed notable discrepancy in the gut microbiota between WT and TLR4^−/− mice. In particular, A. muciniphila contributed most to distinguishing the two groups. The T-cell transfer colitis model and bone marrow transplantation (BMT) consistently demonstrated that A. muciniphila ameliorated colitis by upregulating RORγt⁺ Treg cell-mediated immune responses. Mucosal biopsies from human manifested parallel outcomes with colon tissue from WT mice, as evidenced by the positive correlation between TLR4 expression and intestinal A. muciniphila colonization during homeostasis. Conclusions: Our results demonstrate a novel protective role of TLR4 against intestinal inflammation, wherein it can modulate A. muciniphila-associated immune responses. These findings provide a new perspective on host-commensal symbiosis, which may be beneficial for developing potential therapeutic strategies. Graphical

Background: The endoglycosidase heparanase which degrades heparan sulfate proteoglycans, exerts a pro-inflammatory mediator in various inflammatory disorders. However, the function and underlying mechanism of heparanase in acute pancreatitis remain poorly understood. Here, we investigated the interplay between heparanase and the gut microbiota in the development of acute pancreatitis. Methods: Acute pancreatitis was induced in wild-type and heparanase-transgenic mice by administration of caerulein. The differences in gut microbiota were analyzed by 16S ribosomal RNA sequencing. Antibiotic cocktail experiment, fecal microbiota transplantation, and cohousing experiments were used to assess the role of gut microbiota. Results: As compared with wild-type mice, acute pancreatitis was exacerbated in heparanase-transgenic mice. Moreover, the gut microbiota differed between heparanase-transgenic and wild-type mice. Heparanase exacerbated acute pancreatitis in a gut microbiota-dependent manner. Specially, the commensal Parabacteroides contributed most to distinguish the differences between wild-type and heparanase-transgenic mice. Administration of Parabacteroides alleviated acute pancreatitis in wild-type and heparanase-transgenic mice. In addition, Parabacteroides produced acetate to alleviate heparanase-exacerbated acute pancreatitis through reducing neutrophil infiltration. Conclusions: The gut–pancreas axis played an important role in the development of acute pancreatitis and the acetate produced by Parabacteroides may be beneficial for acute pancreatitis treatment.

Intrahepatic cholestasis of pregnancy (ICP) is a female pregnancy-specific disorder that is characterized by increased serum bile acid and adverse fetal outcomes. The aetiology and mechanism of ICP are poorly understood; thus, existing therapies have been largely empiric. Here we show that the gut microbiome differed significantly between individuals with ICP and healthy pregnant women, and that colonization with gut microbiome from ICP patients was sufficient to induce cholestasis in mice. The gut microbiomes of ICP patients were primarily characterized by Bacteroides fragilis (B. fragilis), and B. fragilis was able to promote ICP by inhibiting FXR signaling via its BSH activity to modulate bile acid metabolism. B. fragilis-mediated FXR signaling inhibition was responsible for excessive bile acid synthesis and interrupted hepatic bile excretion to ultimately promote the initiation of ICP. We propose that modulation of the gut microbiota-bile acid-FXR axis may be of value for ICP treatment.

Nonalcoholic steatohepatitis (NASH) has been linked with the gut-liver axis. Here, we investigate the potential for repurposing disulfiram (DSF), a drug commonly used to treat chronic alcoholism, for NASH. Using a mouse model, we show that DSF ameliorates NASH in a gut microbiota-dependent manner. DSF modulates the gut microbiota and directly inhibits the growth of Clostridium. Administration of Clostridium abolishes the ameliorating effects of DSF on NASH. Mechanistically, DSF reduces Clostridium-mediated 7α-dehydroxylation activity to suppress secondary bile acid biosynthesis, which in turn activates hepatic farnesoid X receptor signaling to ameliorate NASH. To assess the effect of DSF on human gut microbiota, we performed a self-controlled clinical trial (ChiCTR2100048035), including 23 healthy volunteers who received 250 mg-qd DSF for 7 days. The primary objective outcomes were to assess the effects of the intervention on the diversity, composition and functional profile of gut microbiota. The pilot study shows that DSF also reduces Clostridium-mediated 7α-dehydroxylation activity. All volunteers tolerated DSF well and there were no serious adverse events in the 7-day follow-up period. Transferring fecal microbiota obtained from DSF-treated humans into germ-free mice ameliorates NASH. Collectively, the observations of similar ameliorating effects of DSF on mice and humans suggest that DSF ameliorates NASH by modulating the gut microbiota and bile acid metabolism.

The gut microbiota plays a crucial role in the development of the immune system and confers benefits or disease susceptibility to the host. Emerging studies have indicated the gut microbiota could affect pulmonary health and disease through cross talk between the gut microbiota and the lungs. Gut microbiota dysbiosis could lead to acute or chronic lung disease, such as asthma, tuberculosis, and lung cancer. In addition, the composition of the gut microbiota may be associated with different lung diseases, the prevalence of which also varies by age.

The MiT/TFE transcription factors play a pivotal role in the regulation of autophagy and lysosomal biogenesis. The subcellular localization and activity of MiT/TFE proteins are primarily regulated through phosphorylation. And the phosphorylated protein is retained in the cytoplasm and subsequently translocates to the nucleus upon dephosphorylation, where it stimulates the expression of hundreds of genes, leading to lysosomal biogenesis and autophagy induction. The transcription factor-mediated lysosome-to-nucleus signaling can be directly controlled by several signaling molecules involved in the mTORC1, PKC, and AKT pathways. MiT/TFE family members have attracted much attention owing to their intracellular clearance of pathogenic factors in numerous diseases. Recently, multiple studies have also revealed the MiT/TFE proteins as master regulators of cellular metabolic reprogramming, converging on autophagic and lysosomal function and playing a critical role in cancer, suggesting that novel therapeutic strategies could be based on the modulation of MiT/TFE family member activity. Here, we present an overview of the latest research on MiT/TFE transcriptional factors and their potential mechanisms in cancer.