NK Cell Subtypes as Regulators of Autoimmune Liver Disease

As major components of innate immunity, NK cells not only exert cell-mediated cytotoxicity to destroy tumors or infected cells, but also act to regulate the functions of other cells in the immune system by secreting cytokines and chemokines. Thus, NK cells provide surveillance in the early defense against viruses, intracellular bacteria, and cancer cells. However, the effecter function of NK cells must be exquisitely controlled to prevent inadvertent attack against normal “self” cells. In an organ such as the liver, where the distinction between immunotolerance and immune defense against routinely processed pathogens is critical, the plethora of NK cells has a unique role in the maintenance of homeostasis. Once self-tolerance is broken, autoimmune liver disease resulted. NK cells act as a “two-edged weapon” and even play opposite roles with both regulatory and inducer activities in the hepatic environment. That is, NK cells act not only to produce inflammatory cytokines and chemokines, but also to alter the proliferation and activation of associated lymphocytes. However, the precise regulatory mechanisms at work in autoimmune liver diseases remain to be identified. In this review, we focus on recent research with NK cells and their potential role in the development of autoimmune liver disease

Predicting Liver Disease Risk Using a Combination of Common Clinical Markers:A Screening Model from Routine Health Check-Up

Background. Early detection is crucial for the prognosis of patients with autoimmune liver disease (AILD). Due to the relatively low incidence, developing screening tools for AILD remain a challenge.Aims. To analyze clinical characteristics of AILD patients at initial presentation and identify clinical markers, which could be useful for disease screening and early detection.Methods. We performed observational retrospective study and analyzed 581 AILD patients who were hospitalized in the gastroenterology department and 1000 healthy controls who were collected from health management center. Baseline characteristics at initial presentation were used to build regression models. The model was validated on an independent cohort of 56 patients with AILD and 100 patients with other liver disorders.Results. Asymptomatic AILD individuals identified by the health check-up are increased yearly (from 31.6% to 68.0%,

Extrahepatic Autoimmune Diseases in Patients with Autoimmune Liver Diseases: A Phenomenon Neglected by Gastroenterologists

Autoimmune liver diseases (AILDs) often coexist with other extrahepatic autoimmune diseases (EHAIDs). The spectrum of EHAIDs in patients with AILDs is similar, whereas the incidence is different. Notably, autoimmune thyroid disease and Sjogren’s syndrome are the most common EHAIDs. Associated extrahepatic diseases may predate the appearance of AILDs or coincide with their onset. More frequently, they may appear during the course and even occur years after the diagnosis of AILDs. Importantly, associated EHAIDs may influence the natural course and prognosis of AILDs. To date, a definite pathophysiological pathway which contributes to the coexistence of AILDs and EHAIDs is still lacking. The current view of autoimmunity clustering involves a common susceptibility genetic background which applies to related pathologies. Herein, we review the current published researches regarding EHAIDs in patients with AILDs, particularly in relation to their clinical impact and pathophysiology. In managing patients with AILDs, gastroenterologists should be aware of the possibly associated EHAIDs to ensure a prompt diagnosis and better outcome

Novel HLA-DRB1 alleles contribute risk for disease susceptibility in primary biliary cholangitis

Background: Primary biliary cholangitis (PBC) is a complex disease with high heritability. We investigated the association between human leukocyte antigen (HLA)-DRB1 alleles and PBC in families and sporadic cases to evaluate the genetic components of the disease. Methods: We performed whole exome sequencing in three PBC families. We genotyped HLA-DRB1 and calculated the association between HLA-DRB1 alleles and the encoding amino acid sequences with the clinical features. Results: Ten variants harboured the HLA-DRB1 gene associated with PBC. DRB1 x07:01, 14:01 and 14:05 were highly increased in PBC. Ten coding region polymorphisms were associated with PBC that encode the amino acid variants of HLA-DR beta 54, beta 59 and beta 66 located in the peptide-binding site of the MHC molecule. Glutamine at position 54 was confirmed as a risk amino acid, verifying the results of familial aggregation analysis of PBC families. Discussion: Familial aggregation analysis indicated that HLA-DRB1 is a candidate gene for the risk of disease course. Considering that amino acid variations are critical to peptide-binding properties, they underlie the major component of MHC association with PBC. (c) 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved

Farnesoid X receptor and bile acids regulate vitamin A storage

The nuclear receptor Farnesoid X Receptor (FXR) is activated by bile acids and controls multiple metabolic processes, including bile acid, lipid, carbohydrate, amino acid and energy metabolism. Vitamin A is needed for proper metabolic and immune control and requires bile acids for efficient intestinal absorption and storage in the liver. Here, we analyzed whether FXR regulates vitamin A metabolism. Compared to control animals, FXR-null mice showed strongly reduced (>90%) hepatic levels of retinol and retinyl palmitate and a significant reduction in lecithin retinol acyltransferase (LRAT), the enzyme responsible for hepatic vitamin A storage. Hepatic reintroduction of FXR in FXR-null mice induced vitamin A storage in the liver. Hepatic vitamin A levels were normal in intestine-specific FXR-null mice. Obeticholic acid (OCA, 3 weeks) treatment rapidly reduced (>60%) hepatic retinyl palmitate levels in mice, concurrent with strongly increased retinol levels (>5-fold). Similar, but milder effects were observed in cholic acid (12 weeks)-treated mice. OCA did not change hepatic LRAT protein levels, but strongly reduced all enzymes involved in hepatic retinyl ester hydrolysis, involving mostly post-transcriptional mechanisms. In conclusion, vitamin A metabolism in the mouse liver heavily depends on the FXR and FXR-targeted therapies may be prone to cause vitamin A-related pathologies

Berberine Inhibits Intestinal Polyps Growth in Apc (min/+) Mice via Regulation of Macrophage Polarization

Antitumor effect of berberine has been reported in a wide spectrum of cancer, however, the mechanisms of which are not fully understood. The aim of this study was to investigate the hypothesis that berberine suppresses tumorigenesis in the familial adenomatous polyposis (FAP) by regulating the macrophage polarization in Apc (min/+) mouse model. Berberine was given to Apc (min/+) mice for 12 weeks. Primary macrophages were isolated; after berberine treatment, the change in signaling cascade was determined. The total number and size of polyps were reduced remarkably in berberine group, compared with control group. A significant decrease in protein levels of F4/80, mannose receptor (MR), and COX-2 in stroma of intestinal polyps and an increase in the level of iNOS were observed after berberine treatment. The mRNA level of MR and Arg-1 in berberine group was significantly lower than those in IL-10 or IL-4 group, while no significant difference in mRNA levels of iNOS and CXCL10 was observed. The migration and invasiveness assays in vitro showed that berberine could reduce the capability of migration and invasiveness. These findings suggest that berberine attenuates intestinal tumorigenesis by inhibiting the migration and invasion of colorectal tumor cells via regulation of macrophage polarization

Maternal High Fat Diet Alters Gut Microbiota of Offspring and Exacerbates DSS-Induced Colitis in Adulthood

Background: Accumulating evidence shows that high fat diet is closely associated with inflammatory bowel disease. However, the effects and underlying mechanisms of maternal high fat diet (MHFD) on the susceptibility of offspring to colitis in adulthood lacks confirmation.Methods: C57BL/6 pregnant mice were given either a high fat (60 E% fat, MHFD group) or control diet [10 E% fat, maternal control diet (MCD) group] during gestation and lactation. The intestinal development, mucosal barrier function, microbiota, and mucosal inflammation of 3-week old offspring were assessed. After weaning all mice were fed a control diet until 8 weeks of age when the microbiota was analyzed. Offspring were also treated with 2% DSS solution for 5 days and the severity of colitis was assessed.Results: The offspring in MHFD group were significantly heavier than those in MCD group only at 2–4 weeks of age, while no differences were found in the body weight between two groups at other measured time points. Compared with MCD group, MHFD significantly inhibited intestinal development and disrupted barrier function in 3-week old offspring. Although H&E staining showed no obvious microscopic inflammation in both groups of 3-week old offspring, increased production of inflammatory cytokines indicated low-grade inflammation was induced in MHFD group. Moreover, fecal analysis of the 3-week old offspring indicated that the microbiota compositions and diversity were significantly changed in MHFD group. Interestingly after 5 weeks consumption of control diet in both groups, the microbiota composition of offspring in MHFD group was still different from that in MCD group, although the bacterial diversity was partly recovered at 8 weeks of age. Finally, after DSS treatment in 8-week old offspring, MHFD significantly exacerbated the severity of colitis and increased the production of proinflammatory cytokine.Conclusions: Our data reveal that MHFD in early life can inhibit intestinal development, induce dysbiosis and low-grade inflammation and lead to the disruption of intestinal mucosal barrier in offspring, and enhance DSS-induced colitis in adulthood

Role of Gut Barrier Function in the Pathogenesis of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease, and its incidence is increasing year by year. Many efforts have been made to investigate the pathogenesis of this disease. Since 1998 when Marshall proposed the conception of “gut-liver axis,” more and more researchers have paid close attention to the role of gut barrier function in the pathogenesis of NAFLD. The four aspects of gut barrier function, including physical, chemical, biological, and immunological barriers, are interrelated closely and related to NAFLD. In this paper, we present a summary of research findings on the relationship between gut barrier dysfunction and the development of NAFLD, aiming at illustrating the role of gut barrier function in the pathogenesis of this disease