Short-Chain Fatty Acids in the Gut-Brain-Liver Axis: Implications for Hepatic Encephalopathy

Abstract

Hepatic encephalopathy (HE) is one of the serious complications of liver cirrhosis, characterized by a broad spectrum of neuropsychiatric symptoms, ranging from subtle cognitive impairment to coma, due to brain dysfunction associated with acute or chronic liver failure and/or portosystemic shunting. Globally, the prevalence of hepatic encephalopathy (HE) is reported to range from 20% to 80% in patients with liver cirrhosis, depending on whether the assessment includes minimal (MHE) or overt (OHE) forms. In Indonesia, determining the true prevalence of HE is challenging due to diagnostic difficulties, with estimates ranging from 30% to 84%. At Cipto Mangunkusumo General Hospital, the prevalence of HE in 2009 was 63.2%. In recent years, evidence has highlighted the role of the gut microbiota in the pathogenesis of hepatic encephalopathy (HE), a concept now widely referred to as the “gut–liver–brain axis.”  Short-chain fatty acids (SCFAs) are gut microbial-derived metabolites that provide numerous health benefits. SCFA has been demonstrated to impact gut barrier function, immunomodulation, and glucose homeostasis.  In this issue, Ferdianto et al. conducted a cross-sectional observational study comparing the amount and composition of fecal SCFA in cirrhotic patients with and without HE. The study revealed no significant difference in SFA levels between HE and non-HE groups; however, the HE groups demonstrated higher levels of total SCFA, acetate, and butyrate compared to the non-HE groups. While this study contributes valuable early evidence from an Indonesian cohort, several important limitations should be acknowledged. First, the diagnostic approach for covert or minimal HE requires clarification. The authors did not explicitly state the neuropsychological tools and specific criteria used. Clear definitions are essential, as minimal and covert HE is susceptible to the choice of diagnostic method and can substantially influence group classification. Second, although SCFAs represent key microbial metabolites, the study did not explore the underlying microbiome composition. Without bacterial taxonomy or species-level data, it remains difficult to determine whether differences in SCFA levels truly reflect gut dysbiosis or altered microbial diversity. SCFA concentrations may be influenced by multiple factors, and therefore, inclusion of metagenomic or sequencing data would strengthen the mechanistic interpretation and allow linking specific bacterial taxa with cognitive impairment. Future studies that include larger and more heterogeneous cohorts, alongside integrated analyses of microbiome composition and validated neurocognitive testing, will be crucial to validate the role of SCFAs in HE development.