Polymeric immunoglobulin receptor deficiency exacerbates autoimmune hepatitis by inducing intestinal dysbiosis and barrier dysfunction

Abstract

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.

The significance of gut microbiota in the etiology of autoimmune hepatitis: a narrative review

“…Functional intestinal barrier integrity is required to prevent bacterial transfer (Kronsten et al, 2022). The integrity of the intestinal barrier is closely related to intestinal villi, tight junctions between cells, normal intestinal microbiota, and related cytokine proteins (Lin et al, 2023). In addition, the tightness and integrity of transmembrane and cytoplasmic protein junctions are also critical for maintaining the normal function of the intestinal barrier (Alizadeh et al, 2022).…”

“…Polymeric immunoglobulin receptor (pIgR) is a single transmembrane protein and a key regulator of AIH. Its extracellular secretory components can be released in the form of secretory immunoglobulin A (sIgA), but the deficiency of pIgR will reduce the intestinal sIgA level and increase the intestinal barrier dysfunction, leading to more severe intestinal microbiota imbalance, increased bacterial migration, and accelerated development of AIH (Lin et al, 2023). sIgA possesses antimicrobial properties that inhibit aberrant immune responses triggered by intestinal microorganisms and prevent autoimmune reactions (Lin et al, 2023).…”

“…Its extracellular secretory components can be released in the form of secretory immunoglobulin A (sIgA), but the deficiency of pIgR will reduce the intestinal sIgA level and increase the intestinal barrier dysfunction, leading to more severe intestinal microbiota imbalance, increased bacterial migration, and accelerated development of AIH (Lin et al, 2023). sIgA possesses antimicrobial properties that inhibit aberrant immune responses triggered by intestinal microorganisms and prevent autoimmune reactions (Lin et al, 2023). In addition, intestinal epithelial pIgR is closely associated with intestinal barrier destruction and subsequent liver injury in experimental AIH mice (Lin et al, 2023).…”

“…sIgA possesses antimicrobial properties that inhibit aberrant immune responses triggered by intestinal microorganisms and prevent autoimmune reactions (Lin et al, 2023). In addition, intestinal epithelial pIgR is closely associated with intestinal barrier destruction and subsequent liver injury in experimental AIH mice (Lin et al, 2023).…”

“…IgA is a significant component of the intestinal mucosa and plays a key role in maintaining intestinal immune homeostasis by regulating intestinal microbiota translocation and growth and even inhibiting or killing bacteria (Hapfelmeier et al, 2010;Gutzeit et al, 2014;Nakajima et al, 2018). IgA-mediated transport by pIgR is involved in mucosal immunity and plays an important role in regulating the development of AIH (Kaetzel, 2005;Lin et al, 2023). IgA binds to various bacteria to induce distinct IgA-type immune responses.…”