Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): the interplay of gut microbiome, insulin resistance, and diabetes

Abstract

The global prevalence of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has reached alarming levels, affecting nearly one-third of the world's population. This review analyzes current evidence on the intricate relationships between MASLD, insulin resistance, and type 2 diabetes mellitus (T2DM), with particular emphasis on gut microbiome interactions. As MASLD progresses from simple steatosis to Metabolic Dysfunction-Associated Steatohepatitis (MASH), it can lead to severe complications including fibrosis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of MASLD is multifactorial, involving hepatic lipid accumulation, oxidative stress, inflammation, and dysregulation of the gut-liver axis. Insulin resistance is a central driver of disease progression, closely linked to obesity and metabolic syndrome. Recent research highlights how gut microbiome dysbiosis exacerbates MASLD through mechanisms such as increased intestinal permeability, systemic inflammation, and altered metabolic signaling. Identification of microbial signatures offers promise for novel diagnostic and therapeutic strategies. By integrating metabolic, inflammatory, and microbial perspectives, this review provides a comprehensive overview of MASLD pathogenesis and its association with obesity, insulin resistance, and T2DM.

Keywords: MASH; MASLD; NAFLD; NASH; dysbiosis; metabolic syndrome; microbiome.

Figure 1

Progressive stages of MASLD and its complications. This diagram shows the progressive nature of MASLD, encompassing a spectrum of liver conditions ranging from simple steatosis to advanced stages such as MASH, cirrhosis, and hepatocellular carcinoma. In healthy individuals, fat content within hepatocytes typically remains low. In NAFL, fat accumulation increases, but the condition is often reversible with lifestyle modifications. MASH, however, involves not only fat accumulation but also inflammation, increasing degeneration of hepatocytes, and the formation of fibrosis. Cirrhosis, the most advanced stage, is characterized by extensive scarring that disrupts liver function, leading to serious complications like liver failure and increasing the risk of developing hepatocellular carcinoma. The diagram also depicts key pathological mechanisms contributing to MASH progression, including lipid accumulation due to increased uptake of free fatty acids and de novo lipogenesis (DNL), mitochondrial dysfunction, ER stress, oxidative stress, and inflammation mediated by immune cell activation and cytokine release.

Figure 2

Association of MASLD with metabolic syndrome. This diagram shows the complex interplay of factors contributing to the development and progression of MASLD/MASH. Key processes include increased lipolysis in obese individuals, leading to elevated FFA levels. Insulin resistance impairs hepatic insulin signaling, promoting DNL, reducing fatty acid oxidation, and increasing glucose production. Excessive FFA influx, coupled with impaired fatty acid oxidation and increased DNL, results in triglyceride accumulation within the liver. This lipid accumulation triggers ER stress, leading to the activation of inflammatory pathways. Activated Kupffer cells release pro-inflammatory cytokines such as TNF-α and IL-6, exacerbating inflammation and tissue damage. Furthermore, increased fatty acid oxidation generates ROS, contributing to oxidative stress and hepatocellular damage.

Figure 3

Pathogenic mechanisms linking gut dysbiosis to MASLD progression. Intestinal dysbiosis and SIBO lead to barrier dysfunction through disruption of tight junction proteins (ZO, Claudin, JAM-A). This results in increased intestinal permeability and translocation of bacterial endotoxins (LPS) via the portal vein. In the liver, LPS activates Kupffer and stellate cells, triggering inflammatory cascades (TNFα, IL1, IL18, CXCL) and oxidative stress (ROS). Concurrent metabolic alterations include increased ethanol production, altered SCFA metabolism, and choline deficiency due to enhanced bacterial conversion to trimethylamine. These pathways collectively promote hepatic steatosis, inflammation, and fibrosis characteristic of MASLD.