Hyperammonemia reduces the populations of beneficial lactobacilli and bifidobacteria, disrupting the metabolic balance of the gut microbiome in rats

Introduction The gut microbiome (GM) plays a critical role in metabolic and neurological health and is implicated in hepatic encephalopathy (HE). Chronic hyperammonemia (HA), a major contributor to cognitive and motor impairment in HE, may influence GM structure and function, yet its specific efects in GM remain unclear. Methods Here, it was investigated how chronic HA alters the GM using a rat model fed an ammonia-enriched diet for 4 weeks. Fecal microbiota profiles obtained by 16S rRNA gene sequencing revealed marked taxonomic shifts in HA rats, with beta-diversity showing clear separation from controls. Results Genera within the Lachnospiraceae family and Alistipes genus were enriched in HA rats, while lactic acid-producing and xylanolytic Firmicutes were reduced. Network analysis identified Alistipes as a central node in the HA microbiome. Predicted metabolic functions were significantly altered, showing negative associations between HA and pathways related to the pyruvate dehydrogenase complex, sucrose and urea degradation, and 4-aminobutyrate (GABA) degradation. Consistent with these predictions, fecal short-chain fatty acid (SCFA) analysis revealed reduced acetic and butyric acid, alongside increased valeric and isobutyric acid levels. The predicted GABA levels increasement by GM would activate GABA receptors in immune cells and would also contribute to peripheral inflammation and, eventually, neuroinflammation. Conclusions Together, these findings demonstrate that chronic HA reshapes GM composition, disrupts key metabolic pathways, and alters SCFA profiles, providing mechanistic insight into how HA- associated dysbiosis may contribute to the metabolic, immune, and neurological dysfunction characteristic of HE.