The analysis of the gut microbiome during liver disease progression led to the identification of biomarkers for related mild cognitive impairment

Lola Giner Pérez¹Juan-José Gallego²Carla Gimenez-Garzó³Daniela Batallas⁴Víctor H. Jarquín-Díaz⁵Franc Casanova-Ferrer²Alessandra Fiorillo²Amparo Urios²Jennifer Nazat Martinez Medina⁵Adrià López-Gramaje²Yaiza Mª Arenas Ortiz²Desamparados Escudero-García⁶Salvador Benlloch⁷Alicia Salvador⁴Vicente Felipo³Sofia Forslund⁵Gaspar Perez Martinez^1*Carmina Montoliu^2*

• ¹Instituto de Agroquimica y Tecnologia de Alimentos, Paterna, Spain
• ²Fundacion para la Investigacion del Hospital Clinico de la Comunitat Valenciana, Valencia, Spain
• ³Fundacion de la Comunidad Valenciana Centro de Investigacion Principe Felipe, Valencia, Spain
• ⁴Universitat de Valencia Institut d'Investigacio en Psicologia del RRHH del Desenvolupament Organitzacional i de la Qualitat de Vida Laboral, Valencia, Spain
• ⁵Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft Experimental and Clinical Research Center, Berlin, Germany
• ⁶Universitat de Valencia Departament de Medicina, Valencia, Spain
• ⁷Hospital Arnau de Vilanova, Valencia, Spain

Introduction: Although it is well established that liver disease is associated with alterations in the gut microbiome (GM), the mechanisms linking these microbial changes to the progression of liver disease—and more critically, to its related cognitive impairment—remain poorly understood. Therefore, to define biomarkers for the early and advanced phases of these conditions, it is necessary to gain insight into changes in the GM throughout the evolution of the disease, particularly regarding the early onset of cognitive decline. Methods: The GM taxonomy and function profiles were defined, data were collected for dietary intake, fecal short-chain fatty acids (SCFA), cognitive status, quality of life and biochemical and immunological blood parameters of patients belonging to different stages of liver disease (MASLD and cirrhosis) and cognitive function. Results: This study showed: 1) the fibrosis stage severity (F1 to F4) in liver disease was associated with reduced GM diversity independently of cognitive status and with a decline in beneficial autochthonous bacteria; 2) Streptococcus mutans and Allisonella histaminiformans could serve as potential biomarkers for MCI; 3) bacterial metabolic functions involved in sugar degradation and the breakdown of tryptophan and glutamate were downregulated and linked to CXCL13 plasma levels and neuroinflammation; 4) in this context, maintaining a balanced production of fecal SCFA is more important than individual concentrations, since correlations between SCFA concentrations disappeared with liver disease and cognitive impairmentSCFA correlations are altered with liver disease and cognitive impairment progressions. Conclusions: In this context, maintaining a balanced production of fecal SCFA is more important than individual concentrations. The downregulation of specific microbial metabolic pathways, along with the presence of certain bacterial species, holds promise as early-stage biomarkers and highlights the potential of microbiome-targeted strategies for monitoring and managing liver-related cognitive impairment.