Sexual Dimorphism in the gut microbiome of NAFLD: analysis of downstream tissue-specific bacterial colonization of jejunum and descending colon

PIROLA, CARLOS JOSE; LANDA, MARIA SILVINA; SALATINO ADRIAN; GARCÍA SILVIA INES; SOOKOIAN SILVIA,

Boston

Congreso; The liver meeting - AASLD; 2023

AASLD American Association for the Study of the liver disease

SEXUAL DIMORPHISM IN THE GUT MICROBIOME OF NAFLD: ANALYSIS OF DOWNSTREAM TISSUE-SPECIFIC BACTERIAL COLONIZATION OF JEJUNUM AND DESCENDING COLON Carlos Jose Pirola1,2,3, Maria Silvina Landa4, Adrian Salatino5, Silvia Ines Garcia4and Silvia C. Sookoian1,6, (1)Consejo Nacional De Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina, (2)Systems Biology of Complex Diseases. Centro De Altos Estudios En Ciencias Humanas y De La Salud (CAECIHS), Universidad Abierta Interamericana, (3)Center for Traslational Research in Health, Universidad Maimonides, (4)Idim Conicet, (5)Max Planck Institute for Immunobiology and Epigenetics. Bioinformatics Facility, (6)Universidad Maimonides Background: Evidence suggests that the gastrointestinal microbiome exerts a crucial role in the biology of NAFLD. Likewise, NAFLD pathophysiology is modified by gender differences that affect complex regulatory pathways. However, whether sexual dimorphism in the gut microbiome can contribute to the pathogenesis of NAFLD remains unknown. Methods: We performed sex-specific analyses of microbiome composition (high throughput 16S sequencing) in two structurally and functionally distinct anatomical gut regions, the small intestine and colon, in an experimental model of NAFLD and metabolic syndrome. We developed a high-fat diet (HFD)-induced NAFLD in the SHR (spontaneously hypertensive rat) and its control WKY (Wistar-Kyoto) rat strain. Eighteen-weeks old male and female SHR and WKY rats were divided into two experimental groups: standard chow diet and HFD (12 weeks, (n=6/group). HFD-fed rats, irrespective of the strain, developed NAFLD. Tissues were snap frozen and stored at −80 °C. High-quality sequences were assigned to operational taxonomic units using the QIIME pipeline. Results are expressed at the genus level. Results: The overall microbiome composition of females and males with NAFLD differed significantly, including differences between topographical gut regions (Figure shows a hierarchical tree with abundance ratio in NAFLD vs. controls indicated by colors; a: distal jejunum; b: descending colon). Compared to males, female rats showed higher jejunal (F-value: 15; R-squared: 0.15, PC2 21%, PC3 13.2%) and colon microbiome beta diversity (F-value: 14; R-squared: 0.14; PC2 26.3%, PC3 12.9%); Bray-Curtis index [PERMANOVA] p=0.001. Sex-specific analysis of relative bacterial abundances shows differences, including significant features in the jejunum (n=35) and colon (n=30). Identification of differentially abundant features by linear discriminant analysis effect size (LEfSe) showed distinctive differences between females and males with NAFLD (Figures c and d; top 15 significant features). Conclusion: This study demonstrates that there is sexual dimorphism in the gut microbiome of NAFLD, with microbial heterogeneity within different intestinal compartments. Gaining insight into the sex-specific differences in the microbiome composition between gut anatomical and functional regions, including the small intestine -the primary site for absorption of all nutrient-derived components, and the distal colon, may be used to tailor treatment strategies.♦