The immune response as a therapeutic target in non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a complex and heterogeneous disorder considered a liver-damaging manifestation of metabolic syndrome. Its prevalence has increased in the last decades due to modern-day lifestyle factors associated with overweight and obesity, making it a relevant public health problem worldwide. The clinical progression of NAFLD is associated with advanced forms of liver injury such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). As such, diverse pharmacological strategies have been implemented over the last few years, principally focused on metabolic pathways involved in NAFLD progression. However, a variable response rate has been observed in NAFLD patients, which is explained by the interindividual heterogeneity of susceptibility to liver damage. In this scenario, it is necessary to search for different therapeutic approaches. It is worth noting that chronic low-grade inflammation constitutes a central mechanism in the pathogenesis and progression of NAFLD, associated with abnormal composition of the intestinal microbiota, increased lymphocyte activation in the intestine and immune effector mechanisms in liver. This review aims to discuss the current knowledge about the role of the immune response in NAFLD development. We have focused mainly on the impact of altered gut-liver-microbiota axis communication on immune cell activation in the intestinal mucosa and the role of subsequent lymphocyte homing to the liver in NAFLD development. We further discuss novel clinical trials that addressed the control of the liver and intestinal immune response to complement current NAFLD therapies.

Fibrocytes enhance mammary gland fibrosis in obesity

“…Obesity is associated with multiple fibrotic conditions in patients, including pulmonary and liver fibrosis. 116,117 Fibrocytes have been studied more extensively in the lungs for their role in pulmonary fibrosis and asthma. 118,119 Obesity increases the risk for development of asthma and leads to worsened response to therapy.…”

“…Increased myeloid progenitor cells within the bone marrow may also enhance fibrosis in other organs in obesity. Obesity is associated with multiple fibrotic conditions in patients, including pulmonary and liver fibrosis 116,117 . Fibrocytes have been studied more extensively in the lungs for their role in pulmonary fibrosis and asthma 118,119 .…”

Characterization of gut dominant microbiota in obese patients with nonalcoholic fatty liver disease

“…A key factor in the pathogenesis of NAFLD is chronic low-grade inflammation, which is linked to altered gut microbiota and elevated lymphocyte activation (Ortiz-López et al, 2022). Lymphocyte accumulation is seen in the liver of NAFLD patients, and lymphocytes can trigger oxidative stress leading to NAFLD (Bruzzì et al, 2018;Sutti and Albano, 2020;Ortiz-Loṕez et al, 2022). Through the release of interleukin 17, lymphocytes may alter the gut microbiota, which both causes and worsens NAFLD (Gomes et al, 2016;Douzandeh-Mobarrez and Kariminik, 2019).…”

“…Another possibility is that gut gram-negative bacterial cell wall LPS may reach the liver through an improperly functioning gut barrier, triggering an inflammatory reaction in the liver ( Brandl and Schnabl, 2017 ). In addition, bile acids and gut microbial metabolites may play possible roles in NAFLD ( Jiao et al., 2018 ; Canfora et al., 2019 ; Chu et al., 2019 ; Aron-Wisnewsky et al., 2020a ; Ortiz-López et al., 2022 ). Lymphocytes may be a risk factor for obesity with NAFLD, yet F. prausnitzii may act as a barrier against NAFLD in obese patients in our research.…”

“…A key factor in the pathogenesis of NAFLD is chronic low-grade inflammation, which is linked to altered gut microbiota and elevated lymphocyte activation ( Ortiz-López et al., 2022 ). Lymphocyte accumulation is seen in the liver of NAFLD patients, and lymphocytes can trigger oxidative stress leading to NAFLD ( Bruzzì et al., 2018 ; Sutti and Albano, 2020 ; Ortiz-López et al., 2022 ). Through the release of interleukin 17, lymphocytes may alter the gut microbiota, which both causes and worsens NAFLD ( Gomes et al., 2016 ; Douzandeh-Mobarrez and Kariminik, 2019 ).…”