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Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease that can progress to liver fibrosis. Recent clinical advance suggests a reversibility of liver fibrosis, but the cellular and molecular mechanisms underlying NASH resolution remain unclarified. Here, using a murine diet-induced NASH and the subsequent resolution model, we demonstrate direct roles of CD8 + tissue-resident memory CD8 + T (CD8 + Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69 + CD103 − CD8 + Trm cell enrichment in NASH resolution livers. The reduction of liver CD8 + Trm cells, maintained by tissue IL-15, significantly delayed fibrosis resolution, while adoptive transfer of these cells protected mice from fibrosis progression. During resolution, CD8 + Trm cells attracted hepatic stellate cells (HSCs) in a CCR5-dependent manner, and predisposed activated HSCs to FasL-Fas-mediated apoptosis. Histological assessment of patients with NASH revealed CD69 + CD8 + Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8 + Trm in fibrosis resolution. The cellular and molecular mechanisms underlying the resolution of non-alcoholic steatohepatitis remain incompletely understood. Here the authors report a single cell-based analysis that identified CD8 + tissue-resident memory T cells, which contribute to resolution of liver fibrosis potentially via elimination of hepatic stellate cells through Fas-mediated cytotoxicity.

Liver has a unique vascular system receiving the majority of the blood supply from the gastrointestinal tract through the portal vein and faces continuous exposure to foreign pathogens and commensal bacterial products. These gut-derived antigens stimulate liver cells and result in a distinctive immune response via a family of pattern recognition receptors, the Toll-like receptors (TLRs). TLRs are expressed on Kupffer cells, dendritic cells, hepatic stellate cells, endothelial cells, and hepatocytes in the liver. The crosstalk between gut-derived antigens and TLRs on immune cells trigger a distinctive set of mechanisms to induce immunity, contributing to various acute and chronic liver diseases including liver cirrhosis and hepatocellular carcinoma. Accumulating evidence has shown that TLRs stimulation by foreign antigens induces the production of immunoactivating and immunoregulatory cytokines. Furthermore, the immunoregulatory arm of TLR stimulation can also control excessive tissue damage. With this knowledge at hand, it is important to clarify the dual role of disease-specific TLRs as activators and regulators, especially in the liver. We will review the current understanding of TLR signaling and subsequent immune activation and tolerance by the innate immune system in the liver.

Recent clinical and experimental evidence has evoked the concept of the gut–brain axis to explain mutual interactions between the central nervous system and gut microbiota that are closely associated with the bidirectional effects of inflammatory bowel disease and central nervous system disorders 1 – 4 . Despite recent advances in our understanding of neuroimmune interactions, it remains unclear how the gut and brain communicate to maintain gut immune homeostasis, including in the induction and maintenance of peripheral regulatory T cells (pT reg cells), and what environmental cues prompt the host to protect itself from development of inflammatory bowel diseases. Here we report a liver–brain–gut neural arc that ensures the proper differentiation and maintenance of pT reg cells in the gut. The hepatic vagal sensory afferent nerves are responsible for indirectly sensing the gut microenvironment and relaying the sensory inputs to the nucleus tractus solitarius of the brainstem, and ultimately to the vagal parasympathetic nerves and enteric neurons. Surgical and chemical perturbation of the vagal sensory afferents at the hepatic afferent level reduced the abundance of colonic pT reg cells; this was attributed to decreased aldehyde dehydrogenase (ALDH) expression and retinoic acid synthesis by intestinal antigen-presenting cells. Activation of muscarinic acetylcholine receptors directly induced ALDH gene expression in both human and mouse colonic antigen-presenting cells, whereas genetic ablation of these receptors abolished the stimulation of antigen-presenting cells in vitro. Disruption of left vagal sensory afferents from the liver to the brainstem in mouse models of colitis reduced the colonic pT reg cell pool, resulting in increased susceptibility to colitis. These results demonstrate that the novel vago-vagal liver–brain–gut reflex arc controls the number of pT reg cells and maintains gut homeostasis. Intervention in this autonomic feedback feedforward system could help in the development of therapeutic strategies to treat or prevent immunological disorders of the gut. A liver–brain–gut neural circuit responds to the gut microenvironment and regulates the activity of peripheral regulatory T cells in the colon by controlling intestinal antigen-presenting cells in a muscarinic signalling-dependent manner.

Fibrosis is an organ dysfunction caused by excessive deposition of fibrous components produced by parenchymal cells. Effective treatments are lacking for this progressive pathological condition that manifests in various organs and can lead to mortality. The involvement of the immune system in various aspects of fibrosis development, including chronic organ damage induced by macrophages and T cells, wound healing by macrophages and growth factors such as TGF-β, and polarization toward the type II cytokine phenotype, has been widely reported. Recently, immune cells were also reported to contribute to the resolution phase of fibrotic conditions, highlighting the relevance of immune cell analysis in the understanding of both progression and recovery of fibrotic pathologies. However, owing to the complexity and diversity of disease progression, conventional pathological analyses that focus on individual cells and factors have limitations. Technological advancements, such as next-generation sequencing and spatial transcriptome analysis, have enabled pathological analysis at the single-cell level rendering positional information on cells within organs. These advancements have allowed for the redefinition of heterogeneous cells present in organs and a precise understanding of individual cell phenotypes from small human patient samples. Furthermore, integration of transcriptome, proteome, and epigenome data from each cell has begun to reveal important cell-cell interactions under various fibrotic conditions. This review comprehensively discusses the involvement of the immune system and fibrosis, as well as the key interactions between immune and parenchymal cells unraveled via recent advancements in single-cell analysis of fibrotic pathologies in various organs. It also introduces novel strategies leveraging the latest single-cell analyses for fibrosis treatment.

Background Non-alcoholic liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and it can progress to non-alcoholic steatohepatitis (NASH). Alterations in the gut microbiome have been implicated in the development of NAFLD/NASH, although the underlying mechanisms remain unclear. Results We found that the consumption of the prebiotic inulin markedly ameliorated the phenotype of NAFLD/NASH, including hepatic steatosis and fibrosis, in mice. Inulin consumption resulted in global changes in the gut microbiome, including concomitant enrichment of the genera Bacteroides and Blautia , and increased concentrations of short-chain fatty acids, particularly acetate, in the gut lumen and portal blood. The consumption of acetate-releasing resistant starch protected against NAFLD development. Colonisation by Bacteroides acidifaciens and Blautia producta in germ-free mice resulted in synergetic effects on acetate production from inulin. Furthermore, the absence of free fatty acid receptor 2 (FFAR2), an acetate receptor, abolished the protective effect of inulin, as indicated by the more severe liver hypertrophy, hypercholesterolaemia and inflammation. These effects can be attributed to an exacerbation of insulin resistance in the liver, but not in muscle or adipose tissue. Conclusion These findings demonstrated that the commensal microbiome–acetate–FFAR2 molecular circuit improves insulin sensitivity in the liver and prevents the development of NAFLD/NASH. 1auxpva_RZCTQ5SP89UX9T Video abstract

Primary sclerosing cholangitis (PSC) is characterized by progressive biliary inflammation and fibrosis. Although gut commensals are associated with PSC, their causative roles and therapeutic strategies remain elusive. Here we detect abundant Klebsiella pneumoniae (Kp) and Enterococcus gallinarum in fecal samples from 45 PSC patients, regardless of intestinal complications. Carriers of both pathogens exhibit high disease activity and poor clinical outcomes. Colonization of PSC-derived Kp in specific pathogen-free (SPF) hepatobiliary injury-prone mice enhances hepatic Th17 cell responses and exacerbates liver injury through bacterial translocation to mesenteric lymph nodes. We developed a lytic phage cocktail that targets PSC-derived Kp with a sustained suppressive effect in vitro. Oral administration of the phage cocktail lowers Kp levels in Kp-colonized germ-free mice and SPF mice, without off-target dysbiosis. Furthermore, we demonstrate that oral and intravenous phage administration successfully suppresses Kp levels and attenuates liver inflammation and disease severity in hepatobiliary injury-prone SPF mice. These results collectively suggest that using a lytic phage cocktail shows promise for targeting Kp in PSC. Patients with primary sclerosing cholangitis (PSC) harboring Klebsiella pneumoniae (Kp) exhibit poor clinical outcomes. Here, the authors show that administration of a phage cocktail targeting PSC-derived Kp reduces bacterial burden in Kp-colonized mice and alleviates liver injury.

Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease and its frequent complication with ulcerative colitis highlights the pathogenic role of epithelial barrier dysfunction. Intestinal barrier dysfunction has been implicated in the pathogenesis of PSC, yet its underlying mechanism remains unknown. Here, we identify Klebsiella pneumonia in the microbiota of patients with PSC and demonstrate that K.   pneumoniae disrupts the epithelial barrier to initiate bacterial translocation and liver inflammatory responses. Gnotobiotic mice inoculated with PSC-derived microbiota exhibited T helper 17 (T H 17) cell responses in the liver and increased susceptibility to hepatobiliary injuries. Bacterial culture of mesenteric lymph nodes in these mice isolated K.   pneumoniae , Proteus mirabilis and Enterococcus gallinarum , which were prevalently detected in patients with PSC. A bacterial-organoid co-culture system visualized the epithelial-damaging effect of PSC-derived K.   pneumoniae that was associated with bacterial translocation and susceptibility to T H 17-mediated hepatobiliary injuries. We also show that antibiotic treatment ameliorated the T H 17 immune response induced by PSC-derived microbiota. These results highlight the role of pathobionts in intestinal barrier dysfunction and liver inflammation, providing insights into therapeutic strategies for PSC. Klebsiella pneumoniae from the gut microbiota of patients with primary sclerosing cholangitis (PSC) can damage the intestinal epithelial barrier, resulting in bacterial translocation and T helper 17 cell responses in the liver, indicating a role in PSC pathogenesis.

The Japanese diagnostic guidelines for autoimmune hepatitis (AIH) were proposed in 2014. This study aimed to determine the trends and characteristics of AIH based on a Japanese nationwide survey. Data for 796 patients who were newly diagnosed with AIH from 2014 to 2017 were collected from January to March, 2019 from 54 hospitals throughout Japan. Clinical characteristics, including treatment, were compared with those reported in a prior 2015 survey. The population had a median age of 63 years at diagnosis, and the male to female ratio was 1:5.3. The numbers of women was significantly lower in this survey than in the 2015 survey. Moreover, the incidence of AIH with histological acute hepatitis increased significantly from 11.0 to 21.7%. The changes in the laboratory findings, such as in transaminase and immunoglobulin G levels and antinuclear antibody titers, as well as in prednisolone treatment, reflected an increasing incidence of acute AIH. The clinical characteristics of AIH changed rapidly, in parallel with the increasing incidence of acute AIH. The elucidation and diagnosis of AIH with acute hepatitis are important in the management of AIH.

Cyp2a12 -/- Cyp2c70 -/- double knockout (DKO) mice have a human-like hydrophobic bile acid (BA) composition and show reduced fertility and liver injury. Ursodeoxycholic acid (UDCA) is a hydrophilic and cytoprotective BA used to treat various liver injuries in humans. This study investigated the effects of orally administered UDCA on fertility and liver injury in DKO mice. UDCA treatment prevented abnormal delivery (miscarriage and preterm birth) in pregnant DKO mice, presumably by increasing the hydrophilicity of serum BAs. UDCA also prevented liver damage in six-week-old DKO mice, however liver injury emerged in UDCA-treated 20-week-old female, but not male, DKO mice. In 20-week-old male UDCA-treated DKO mice, conjugated plus unconjugated UDCA proportions in serum, liver, and bile were 71, 64, and 71% of the total BAs, respectively. In contrast, conjugated plus unconjugated UDCA proportions in serum, liver, and bile of females were 56, 34, and 58% of the total BAs, respectively. The UDCA proportion was considerably low in female liver only and was compensated by highly hydrophobic lithocholic acid (LCA). Therefore, UDCA treatment markedly reduced the BA hydrophobicity index in the male liver but not in females. This appears to be why UDCA treatment causes liver injury in 20-week-old female mice. To explore the cause of LCA accumulation in the female liver, we evaluated the hepatic activity of CYP3A11 and SULT2A1, which metabolize LCAs to more hydrophilic BAs. However, there was no evidence to suggest that either enzyme activity was lower in females than in males. As female mice have a larger BA pool than males, excessive loading of LCAs on the hepatic bile salt export pump (BSEP) may be the reason for the hepatic accumulation of LCAs in female DKO mice with prolonged UDCA treatment. Our results suggest that the improvement of BA hydrophobicity in DKO mice by UDCA administration is sex-, age-, and organ-dependent.

Aims/hypothesisAccumulation of adipose tissue macrophages is considered pivotal in the development of obesity-associated inflammation and insulin resistance. In addition, recent studies suggest an involvement of the intestine as the primary organ in inducing hyperglycaemia and insulin resistance. We have reported that the C-C motif chemokine receptor (CCR) CCR9 is associated with intestinal immunity and has a pathogenic role in various liver diseases. However, its contribution to type 2 diabetes is unknown. In the current study, we aimed to clarify the involvement of CCR9 in the pathology of type 2 diabetes and the potential underlying mechanisms.MethodsTo elucidate how CCR9 affects the development of metabolic phenotypes, we examined the impact of CCR9 deficiency on the pathogenesis of type 2 diabetes using male C57BL/6J (wild-type [WT]) and CCR9-deficient (CCR9 knockout [KO]) mice fed a 60% high-fat diet (HFD) for 12 weeks.ResultsWT and Ccr9KO mice fed an HFD exhibited a comparable weight gain; however, glucose tolerance and insulin resistance were significantly improved in Ccr9KO mice. Moreover, visceral adipose tissue (VAT) and the liver of Ccr9KO mice presented with less inflammation and increased expression of glucose metabolism-related genes than WT mice. Ccr9 and Ccl25 expression were specifically higher in the small intestine but was not altered by HFD feeding and type 2 diabetes development. Accumulation of IFN-γ-producing CD4+ T lymphocytes and increased intestinal permeability in the small intestine was observed in WT mice following HFD feeding, but these changes were suppressed in HFD-fed Ccr9KO mice. Adoptive transfer of gut-tropic CCR9-expressing T lymphocytes partially reversed the favourable glucose tolerance found in Ccr9KO mice via exacerbated inflammation in the small intestine and VAT.Conclusions/interpretationCCR9 plays a central role in the pathogenesis of type 2 diabetes by inducing an inflammatory shift in the small intestine. Our findings support CCR9 as a new therapeutic target for type 2 diabetes via the gut–VAT–liver axis.