Targeting gut microbiota in liver disease: A pharmacological approach for hepatic encephalopathy and beyond

Figure 1 Dysbiosis and its role in hepatic encephalopathy. During chronic liver disease gut dysbiosis and disruption of the intestinal barrier lead to bacterial overgrowth and a reduction in beneficial commensal organisms. This imbalance results in the release of pathogen-associated molecular patterns such as lipopolysaccharide, flagellin, and peptidoglycan. These molecules along with bacteria translocate across the compromised intestinal barrier, triggering immune cell activation and the production of proinflammatory cytokines. These cytokines travel through the portal vein to the liver. In the context of liver dysfunction, toxins like ammonia are not properly metabolized and can reach the brain, contributing to blood-brain barrier disruption. The combination of systemic inflammation and elevated ammonia levels leads to astrocyte swelling, a hallmark of hepatic encephalopathy. Astrocyte swelling results from ammonia-induced glutamine accumulation within these brain cells, leading to osmotic imbalance and cerebral edema, which contribute to neuroinflammation and the cognitive impairments characteristic of hepatic encephalopathy. PAMPs: Pathogen-associated molecular patterns; sBA: Secondary bile acids; SCFA: Short-chain fatty acids; LPS: Lipopolysaccharide; IL: Interleukin; TNF-α: Tumor necrosis factor-alpha; TLR-4: Toll-like receptor 4.