Microbiota encroachment and a gut-adipose-liver axis in metabolic dysfunction-associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects ∼40% of adults, but causal mechanisms remain elusive. Preclinical models implicate the gut microbiota in MASLD pathogenesis, yet translation to humans is hampered by variability in microbial composition. We addressed this gap by investigating whether stable, quantitative gut phenotypes, including microbiota encroachment, are pathological features of MASLD. Sigmoid colon biopsies were collected from participants with and without imaging-defined MASLD. Mucus immunostaining was paired with fluorescent in situ hybridization to image and quantify the distance separating bacteria from the colonic epithelium (i.e., encroachment). Secondary outcomes included intestinal permeability, colon histopathology, and insulin resistance. RNA sequencing was combined with weighted gene network correlation analysis to explore correlations between colonic gene expression and clinical endpoints. Microbiota encroachment did not differentiate participants with MASLD (<i>n</i> = 13 with simple steatosis, <i>n</i> = 13 with fibrosis stage <4) from controls (<i>n</i> = 12; <i>P</i> = 0.20). Circulating lipopolysaccharide and flagellin-specific immunoglobulins (intestinal permeability), and colon histopathology were similar across cohorts (<i>P</i> = 0.23, <i>P</i> = 0.11, and <i>P</i> = 0.73, respectively). Microbiota encroachment and adipose tissue insulin resistance (Adipo-IR) were correlated with a colonic gene network regulating insulin and lipid metabolism (Pearson's <i>r</i> = -0.33, <i>P</i> = 0.04 and <i>r</i> = 0.47, <i>P</i> = 0.003, respectively). Pathway analysis of this network revealed genes involved in hepatic steatosis (<i>P</i> = 3.95E-06) and liver cell proliferation (<i>P</i> = 0.0003), suggesting a gut-adipose-liver cross talk. Microbiota encroachment and related gut phenotypes do not correlate with MASLD severity. However, colonic expression of genes related to insulin signaling and lipid metabolism links microbiota encroachment to Adipo-IR and MASLD. Future research should investigate how colonic gene products interact with microbiota-focused MASLD mechanisms.<b>NEW & NOTEWORTHY</b> In a first-in-human study, we observed that colonic expression of insulin and lipid-related genes may bridge the pathophysiology of colonic microbiota encroachment with adipose tissue insulin resistance and metabolic dysfunction-associated steatotic liver disease.