The shaping of gut immunity in cirrhosis

Abstract

Cirrhosis is the common end-stage of chronic liver diseases of different etiology. The altered bile acids metabolism in the cirrhotic liver and the increase in the blood-brain barrier permeability, along with the progressive dysbiosis of intestinal microbiota, contribute to gut immunity changes, from compromised antimicrobial host defense to pro-inflammatory adaptive responses. In turn, these changes elicit a disruption in the epithelial and gut vascular barriers, promoting the increased access of potential pathogenic microbial antigens to portal circulation, further aggravating liver disease. After summarizing the key aspects of gut immunity during homeostasis, this review is intended to update the contribution of liver and brain metabolites in shaping the intestinal immune status and, in turn, to understand how the loss of homeostasis in the gut-associated lymphoid tissue, as present in cirrhosis, cooperates in the advanced chronic liver disease progression. Finally, several therapeutic approaches targeting the intestinal homeostasis in cirrhosis are discussed.

Single nuclear RNA sequencing of terminal ileum in patients with cirrhosis demonstrates multi-faceted alterations in the intestinal barrier

“…Immune exhaustion due to constant immune activation and exposure to antigens characterized by increased expression of inhibitor receptors on T cells could be contributory and result in upregulation of ITGAE (integrin alph E, also known as CD103) in exhausted T cells. While not studied here, the gut microbial changes in cirrhosis could also play a role in this altered immune activation and cirrhosis-related dysregulation of immune checkpoints and immune regulatory mechanisms [ 30 ]. Immune checkpoints, such as programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) could affect this immune profile.…”

“…Immune checkpoints, such as programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) could affect this immune profile. Finally, portal hypertension can influence immune cell trafficking and localization within the gut associated lymphoid tissue, which can affect the proportions of various immune cell subsets [ 30 ]. To explore the inflammatory genes further, in concordance with prior studies, there was a significant upregulation of inflammatory genes (IL1, IL6 and TNF) in patients with cirrhosis [ 31 ].…”

Exploring the Relationship between Liver Disease, Bacterial Translocation, and Dysbiosis: Unveiling the Gut-Liver Axis

“…1). Consequently, intestinal innate and adaptive immune cells are chronically activated and release proinflammatory and vasodilatory mediators, including cytokines IL-6, IL-17, or TNF-⍺, nitric oxide (NO), or chemokines (i.e., CCL2), and reactive oxygen species [21]. Common proinflammatory immune signatures are duodenal macrophages that produce inducible NO synthase (iNOS) and NO [22], activation of dendritic cells with capacity to produce TNF-⍺ [23], a relative increase in the duodenal CD8+/CD4+ lymphocyte population, and augmented T helper (Th) 1 differentiation [24].…”

“…PAMPs will activate immune cells to secrete proinflammatory soluble factors and NO. This intestinal inflammation will further contribute to gut permeability by hampering the expression of TJ proteins and inducing splanchnic vasodilation characteristic of portal hypertension linked to cirrhosis [21]. Sustained BT of bacteria and PAMPs in cirrhosis bursts systemic inflammation, key in development of acute decompensation episodes associated with multiorgan failure and progression from compensated to decompensated cirrhosis [59].…”

Which Comes First, Nonalcoholic Fatty Liver Disease or Arterial Hypertension?

“…These data were further supported by another meta-analysis showing that impaired intestinal permeability in patients with NAFLD was associated with the grade of hepatic steatosis [ 137 ]. Similarly to patients with AH, it was assumed that patients with NAFLD (and especially with cirrhosis associated with NASH) had qualitative and quantitative changes in tight junction proteins [ 138 , 139 ]. Increased translocation of bacterial products was believed to lead to inflammation and fibrogenesis in the liver through toll-like receptor 4 stimulation.…”