Serum amyloid A in the gut-liver axis: Implications for alcohol-associated pathology

Alcohol-associated liver disease (ALD) remains a major global health concern, with alcohol consumption a leading cause of liver-related mortality. Gut-liver axis has been implicated in ALD development; however, the mechanisms of gut-liver crosstalk are not fully understood. Serum amyloid A (SAA) is a family of highly conserved acute-phase proteins, which is essential in immune-mediated inflammatory processes, like ALD. SAA can bind a diverse set of ligands and perform multiple functions in tissue specific ways. It has been shown that SAA has dual roles in the inflammatory process. It can stimulate inflammatory responses and induce the pathogenic differentiation of Th17 cells. On the other hand, it promotes healthy gut immune homeostasis via its retinol transport ability. It is involved in ECM remodeling, cancer development, cell proliferation and cholesterol recycling for tissue repair. In addition, SAA can remove toxic lipids produced during inflammatory responses, bacteria and membrane debris from dead cells. Some of the functions of SAA are tightly associated with its role in acute phase HDL. In ALD, SAA has important functions both in the liver, where it promotes inflammation and regeneration and repair after alcohol cessation, and in the intestine, where it induces T-cell differentiation, and promotes phagocytosis of Gram-negative bacteria. Circulating SAA and its cargo might be an important contributor to gut-liver axis in ALD.