Mucosa-associated invariant T cells link intestinal immunity with antibacterial immune defects in alcoholic liver disease

Abstract

Background/aimsIntestinal permeability with systemic distribution of bacterial products are central in the immunopathogenesis of alcoholic liver disease (ALD), yet links with intestinal immunity remain elusive. Mucosa-associated invariant T cells (MAIT) are found in liver, blood and intestinal mucosa and are a key component of antibacterial host defences. Their role in ALD is unknown.Methods/designWe analysed frequency, phenotype, transcriptional regulation and function of blood MAIT cells in severe alcoholic hepatitis (SAH), alcohol-related cirrhosis (ARC) and healthy controls (HC). We also examined direct impact of ethanol, bacterial products from faecal extracts and antigenic hyperstimulation on MAIT cell functionality. Presence of MAIT cells in colon and liver was assessed by quantitative PCR and immunohistochemistry/gene expression respectively.ResultsIn ARC and SAH, blood MAIT cells were dramatically depleted, hyperactivated and displayed defective antibacterial cytokine/cytotoxic responses. These correlated with suppression of lineage-specific transcription factors and hyperexpression of homing receptors in the liver with intrahepatic preservation of MAIT cells in ALD. These alterations were stronger in SAH, where surrogate markers of bacterial infection and microbial translocation were higher than ARC. Ethanol exposure in vitro, in vivo alcohol withdrawal and treatment with Escherichia coli had no effect on MAIT cell frequencies, whereas exposure to faecal bacteria/antigens induced functional impairments comparable with blood MAIT cells from ALD and significant MAIT cell depletion, which was not observed in other T cell compartments.ConclusionsIn ALD, the antibacterial potency of MAIT cells is compromised as a consequence of contact with microbial products and microbiota, suggesting that the ‘leaky’ gut observed in ALD drives MAIT cell dysfunction and susceptibility to infection in these patients.

MAIT cells: a novel therapeutic target for alcoholic liver disease?

“…Because patients with ALD are associated with significant bacterial translocation from the gut to the liver,14 it is plausible to speculate that intrahepatic MAIT cells are exposed to these bacteria/bacterial products and are subsequently depleted in these patients. Surprisingly, by performing immunohistochemistry analysis, the authors found that the number of intrahepatic MAIT cells was comparable in patients with alcoholic cirrhosis compared with healthy controls 5. However, these studies were carried out in only a small number of patients with alcoholic cirrhosis without flow cytometric analysis and were not investigated in patients with SAH.…”

“…Although many types of immune cells have been found dysregulated and such dysregulation likely contributes to the increased bacterial infection in patients with SAH, the exact underlying mechanisms are not fully understood. In this issue of Gut , the study from Riva et al 5 added another type of immune cells called mucosa-associated invariant T cells (MAIT) that are also altered in patients with SAH, and such alteration probably plays a role in promoting bacterial infection in these patients.…”

“…Despite of an important antibacterial function of MAIT cells,13 their roles in the pathogenesis of severe ALD, which is often associated with bacterial infection, have not been investigated until this study by Riva et al 5. In this paper, the authors found that circulating MAIT cells were depleted and displayed defective antibacterial cytokine/cytotoxic response in alcoholic cirrhosis and SAH, which is probably an important mechanism contributing to the increased risk of bacterial infection in these patients (figure 1).…”

“…In this paper, the authors found that circulating MAIT cells were depleted and displayed defective antibacterial cytokine/cytotoxic response in alcoholic cirrhosis and SAH, which is probably an important mechanism contributing to the increased risk of bacterial infection in these patients (figure 1). Furthermore, Riva et al 5 demonstrated that intestinal bacterial antigens and metabolites but not ethanol itself selectively depleted MAIT cells without affecting CD8/CD3 T cells in vitro, suggesting that selective MAIT cell depletion and dysfunction are likely caused by chronic exposure to bacteria in patients with SAH. Because patients with ALD are associated with significant bacterial translocation from the gut to the liver,14 it is plausible to speculate that intrahepatic MAIT cells are exposed to these bacteria/bacterial products and are subsequently depleted in these patients.…”

“…The study from Riva et al 5 opened a new direction but just began to divulge this field; the exact roles of MAIT cells in the pathogenesis of SAH still remain largely unknown. Many questions remain unanswered (figure 1).…”