Autoimmune hepatitis (AIH) is an immune-mediated inflammatory liver disease with unclear pathogenesis. The gut microbiota and intestinal barrier play an essential role in AIH. Polymeric immunoglobulin receptor (pIgR) is a central component of mucosal immunity. Herein, we aimed to test the hypothesis that pIgR plays a pivotal role in maintaining gut microbiota homeostasis and gut barrier integrity in an AIH mouse model. The expression of intestinal pIgR shows the variation tendency of falling after rising with the aggravation of experimental AIH (EAH). The deletion of Pigr exacerbates liver damage in EAH. Furthermore, we identified a distinct microbiota profile of Pigr-deficient EAH mice, with a significant increased aboundance in the Oscillospiraceae family, particularly the Anaeromassilibacillus genus. Such a situation occurs because the loss of Pigr inhibits MEK/ERK, a key signal pathway whereby pIgR transports immunoglobulin A (IgA), resulting in reduced IgA secretion, which leads to the destruction of intestinal epithelial tight junction proteins and intestinal flora disturbance. Increased intestinal leakage causes increased translocation of bacteria to the liver, thus aggravating liver inflammation in EAH. Treatment with the Lactobacillus rhamnosus GG supernatant reverses liver damage in EAH mice but loses its protective effect without pIgR. Our study identifies that intestinal pIgR is a critical regulator of the adaptive response to S100-induced alterations in gut flora and the gut barrier function, which closely correlates with liver injury. Intestinal upregulation of pIgR could be a novel approach for treating AIH.

Immune-mediated liver injury (ILI) is a condition where an aberrant immune response due to various triggers causes the destruction of hepatocytes. Fibroblast growth factor 4 (FGF4) was recently identified as a hepatoprotective cytokine; however, its role in ILI remains unclear. In patients with autoimmune hepatitis (type of ILI) and mouse models of concanavalin A (ConA)- or S-100-induced ILI, we observed a biphasic pattern in hepatic FGF4 expression, characterized by an initial increase followed by a return to basal levels. Hepatic FGF4 deficiency activated the mitochondria-associated intrinsic apoptotic pathway, aggravating hepatocellular apoptosis. This led to intrahepatic immune hyper-reactivity, inflammation accentuation, and subsequent liver injury in both ILI models. Conversely, administration of recombinant FGF4 reduced hepatocellular apoptosis and rectified immune imbalance, thereby mitigating liver damage. The beneficial effects of FGF4 were mediated by hepatocellular FGF receptor 4, which activated the Ca²⁺/calmodulin-dependent protein kinasekinase 2 (CaMKKβ) and its downstream phosphatase and tensin homologue-induced putative kinase 1 (PINK1)-dependent B-cell lymphoma 2-like protein 1-isoform L (Bcl-X_L) signalling axis in the mitochondria. Hence, FGF4 serves as an early response factor and plays a protective role against ILI, suggesting a therapeutic potential of FGF4 and its analogue for treating clinical immune disorder-related liver injuries.

Background: Research into the “gut–lung” axis links gut microbiota to pulmonary artery hypertension (PAH). However, the mechanisms by which gut microbiota influence PAH remain unclear. We aimed to investigate the causal relationship between the gut microbiota and PAH using Mendelian randomization analysis, identify key microbiota and metabolites, and explore the regulatory role of associated genes in PAH pathogenesis. Methods and Results: We examined the association between gut microbiota taxa and PAH using inverse variance weighted 2‐sample Mendelian randomization analysis, Mendelian randomization–Egger, weighted median, and weighted mode methods. Additionally, we identified PAH‐regulating genes in the intestinal microbiome using bioinformatics tools and validated their expression levels in the lung tissue of hypoxia‐induced PAH mice models by quantitative reverse transcription polymerase chain reaction. Eleven gut microbiota taxa were associated with PAH. The order Clostridiales and genera Eubacterium fissicatena group, Lachnospiraceae UCG004 , and Ruminococcaceae UCG002 were positively associated with PAH, whereas the order Bifidobacteriales; family Bifidobacteriaceae; and genera Eubacterium eligens group , Sutterella, Methanobrevibacter , Sellimonas , and Tyzzerella3 were negatively associated with PAH, with some exhibiting bidirectional causality. These microbiota modulate 24 metabolites, including palmitoylcholine, oleoylcholine, and 3,7‐dimethylurate, to influence PAH. Hypoxia‐induced PAH mice had significantly downregulated 1,4,5‐trisphosphate receptor type 2, degrading enzyme, nuclear receptor‐interacting protein 1, and growth factor‐binding protein 1 in lung tissues, indicating their potential role in PAH regulation. Conclusions: These findings suggest that gut microbiota composition and associated metabolites contribute to PAH development by regulating lung tissue gene expression. Our findings have implications for advancing gut microbiota‐based PAH diagnostic technologies and targeted therapies.

Objective: Cryptococcal meningitis (CM) is a not rare condition in HIV-negative patients. Here, we describe the clinical characteristics, possible risk factors, and outcomes of HIV-negative patients with CM. Methods: Medical records from 99 HIV-negative patients with CM admitted to our hospital from 2010 to 2021 were reviewed systematically. We compared the clinical features and outcomes between patients with underlying diseases and otherwise healthy hosts. Results: The 99 HIV-negative CM patients had a mean age at presentation of 56.2 ± 16.2 years, and the female-to-male ratio was 77:22. A total of 52 (52.5%) CM patients had underlying conditions, and 47 patients (47.5%) had no underlying conditions. Kidney transplant represented the most frequent underlying condition (11.1%), followed by rheumatic disease (10.1%) and hematological diseases (9.1%). Compared to patients without underlying conditions, those with underlying conditions had significantly more fever, more steroid therapy, higher serum creatinine, and lower albumin, IgG, hemoglobin, and platelets (p < 0.05 for each). CM patients without underlying conditions had significantly more alcohol abuse than those with underlying conditions (31.9% vs. 9.6%, p = 0.011). By logistic regression analysis, male gender (OR = 3.16, p = 0.001), higher CSF WBC (OR = 2.88, p = 0.005), and protein (OR = 2.82, p = 0.002) were significantly associated with mortality. Conclusion: Patients with underlying conditions had a similar mortality to patients without underlying conditions. Alcohol abuse was a probable risk factor for CM for previously healthy patients. Male gender, higher CSF WBC, and protein were significantly associated with mortality.