Microbiome alterations in liver disease and their impact on cognitive function

Despite the well-established association between liver disease and alterations in the gut microbiome (GM), the mechanisms by which these changes contribute to disease progression and associated cognitive impairment remain incompletely understood. Identifying biomarkers for early and advanced disease stages therefore requires a deeper understanding of GM dynamics throughout disease evolution, particularly in relation to early cognitive decline and hyperammonemia (HA). Hepatic encephalopathy (HE) exemplifies the central role of the gut-liver-brain axis, presenting as a neuropsychiatric syndrome with a broad spectrum of severity. Although rifaximin has been shown to improve cognitive function and reduce HE risk in a subset of patients, the underlying mechanisms of response remain unclear. In this regard, the main aim of this thesis is to elucidate the role of the GM in liver disease and its associated mild cognitive impairment. Specifically, this work examines GM alterations, both taxonomic and functional, related to hyperammonemia (HA), as well as changes occurring across different stages of liver disease and the corresponding spectrum of cognitive impairment. Within this framework, it also aimed to decipher the GM involvement in the response to rifaximin treatment. This thesis integrates evidence from animal models and clinical studies, including analysis of fecal 16S rRNA sequencing and metagenomic sequencing, to provide a comprehensive view of the role of the GM in liver disease and its associated cognitive impairment. This approach allowed the identification of the following global conclusions: 1) HA emerges as a central driver of GM alterations at both compositional and functional levels, supporting a mechanistic link between microbial dysregulation and the peripheral and neuroinflammatory processes in HE. 2) The functional metabolic capacity of the GM is a critical element in the context of cognitive impairment in liver disease, underscoring the relevance of microbial metabolism beyond taxonomic composition alone. 3) The balance among SCFA provides more informative insight than the isolated analysis of their individual concentrations, highlighting the importance of functional balance as a feature of a resilient ecosystem. 4) Taxonomic and functional signatures associate with mild cognitive impairment in MASLD and with differential response to rifaximin treatment, highlighting the potential of microbiome‑based biomarkers for patient stratification and therefore further therapeutic optimization. In summary, the GM in liver disease must be approached from an integrative perspective that considers not only compositional changes but also functional interactions, the host’s pathophysiological context, and interindividual variability in response to treatments. This lays the groundwork for future, more personalized and effective approaches in this field.