The Gut Microbiota: A Novel Player in Autoimmune Hepatitis

Abstract

Autoimmune hepatitis (AIH) is a chronic immune-mediated liver disease distributed globally in all ethnicities with increasing prevalence. If left untreated, the disease will lead to cirrhosis, liver failure, or death. The intestinal microbiota is a complex ecosystem located in the human intestine, which extensively affects the human physiological and pathological processes. With more and more in-depth understandings of intestinal microbiota, a substantial body of studies have verified that the intestinal microbiota plays a crucial role in a variety of digestive system diseases, including alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). However, only a few studies have paid attention to evaluate the relationship between AIH and the intestinal microbiota. While AIH pathogenesis is not fully elucidated yet, some studies have indicated that intestinal microbiota putatively made significant contributions to the occurrence and the development of AIH by triggering several specific signaling pathways, altering the metabolism of intestinal microbiota, as well as modulating the immune response in the intestine and liver. By collecting the latest related literatures, this review summarized the increasing trend of the aerobic bacteria abundance in both AIH patients and AIH mice models. Moreover, the combination of specific bacteria species was found distinct to AIH patients, which could be a promising tool for diagnosing AIH. In addition, there were alterations of luminal metabolites and immune responses, including decreased short-chain fatty acids (SCFAs), increased pathogen associated molecular patterns (PAMPs), imbalanced regulatory T (Treg)/Th17 cells, follicular regulatory T (TFR)/follicular helper T (TFH) cells, and activated natural killer T (NKT) cells. These alterations participate in the onset and the progression of AIH via multiple mechanisms. Therefore, some therapeutic methods based on restoration of intestinal microbiota composition, including probiotics and fecal microbiota transplantation (FMT), as well as targeted intestinal microbiota-associated signaling pathways, confer novel insights into the treatment for AIH patients.

Brain-gut-liver axis: Chronic psychological stress promotes liver injury and fibrosis via gut in rats

“…This complex then enters the liver through the circulation of the portal vein, triggering a cascade of intracellular signals in liver through TLR4, which eventually leads to exacerbated liver fibrosis ( Seki et al., 2007 ), cirrhosis ( Milosevic et al., 2019 ; Wang et al., 2022 ) and even liver cancer ( Meng et al., 2018 ). This interaction effect between the gut microbiota and the liver mediated by the LPS-TLR4 signaling pathway is called the gut-liver axis ( Seki et al., 2007 ; Chassaing et al., 2014 ; Cheng et al., 2022 ).…”

Research Progress of Fecal Microbiota Transplantation in Liver Diseases

“…This study showed that FMT could modulate imbalance of T follicular regulatory (TFR) and T follicular helper (TH) cells and gut microbiota composition by immune pathways in vivo. Furthermore, metabolite pathways (e.g., short-chain fatty acid, amino acid, and bile acid) and receptor pathways (e.g., Toll-like receptor 4 (TLR4), and G protein-coupled receptors (GRP41/GPR43, GPR109a) in the intestine, while nucleotide-binding and oligomerization domain NOD-like receptors (NLRs), TLR4, TLR9, and GPBAR1 in liver) were found as the influential mechanisms of altered gut microbiota in AIH [ 79 ]. The above-mentioned evidence verified the underlying therapeutic value of FMT for AIH.…”

Incorporating the Molecular Mimicry of Environmental Antigens into the Causality of Autoimmune Hepatitis

“…Molecular mimicry may also be a mechanism that accelerates or sustains autoimmune hepatitis [ 44 , 73 , 125 ] (Table 2 ). The release of neo-antigens from damaged liver tissue [ 126 , 127 ] or the translocation of bacterial products from a permeable intestine [ 44 , 47 , 128 – 135 ] could promote molecular mimicry and affect the severity and course of autoimmune hepatitis. Furthermore, molecular mimicry could contribute to the ongoing inflammatory process by expanding the number of targeted epitopes (epitope spread) [ 136 – 139 ] and the population of memory CD4 + and CD8 + T cells (bystander activation) [ 140 , 141 ].…”

“…Diet [ 25 , 134 ], supplements [ 24 ], antibiotics [ 23 ], alcohol [ 23 ], pollutants [ 23 ], and toxins [ 26 ] have been associated with the risk of autoimmune hepatitis, and this risk may reflect changes in the intestinal microbiome induced by these diverse environmental factors [ 25 , 26 , 42 – 47 ] (Table 2 ). Findings in experimental models of autoimmune hepatitis [ 129 , 184 ] and other autoimmune diseases [ 185 – 188 ] have supported this premise, albeit there are many other factors outside of molecular mimicry that may be contributory [ 45 – 47 , 135 , 189 ].…”

“…Immune tolerances to commensal bacteria within the intestine may be lost by environmentally-induced dysbiosis [ 190 ], and toll-like receptors in the intestine may generate pathogenic T and B lymphocytes that are capable of systemic translocation and reactivity against homologous tissue antigens [ 188 , 191 ] (Table 2 ). Intestinal dysbiosis has been demonstrated in an experimental model [ 128 ] and in patients with autoimmune hepatitis [ 132 – 135 ]. The key distinguishing features from healthy individuals have been reduced biodiversity of the intestinal microbiome [ 128 , 132 – 134 , 192 ], increased aerobic and facultative anaerobic bacteria [ 134 ], increased Veillonella species [ 132 , 134 ], and decreased Bifidobacterium species [ 129 , 134 ] (Fig.…”