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The "Direct Structural Disruption" Hypothesis: Bacteroides fragilis Toxin as a Potentiating Cofactor in MASH
Ju-Eun Hong1, Soonjae Hwang2,3
1Department of Biomedical Laboratory Science, College of Software Digital Healthcare Convergence, Yonsei University MIRAE Campus, Wonju 26493, Republic of Korea.
Abstract:
Metabolic dysfunction-associated steatohepatitis (MASH) is a complex, multifactorial disease heavily influenced by the gut-liver axis. While enterotoxigenic Bacteroides fragilis (ETBF) and its principal virulence factor, B. fragilis toxin (BFT)-a zinc-dependent metalloprotease-are well-known for disrupting intestinal barriers, their potential systemic impact on distant organs remains an emerging area of interest. Although various gut-derived factors contribute to hepatic inflammation, the precise molecular triggers that exacerbate the transition from simple steatosis to progressive fibrosis remain incompletely understood. This review proposes the "Direct Structural Disruption" hypothesis, examining the biological activity of BFT and its proposed role in MASH pathogenesis. We postulate that under permissive conditions, systemic BFT may target hepatic structural proteins (e.g., cadherins). This hypothesized architectural impairment amplifies canonical fibrogenic signaling and hepatic stellate cell (HSC) activation. In addition, we discuss current challenges in the detection and characterization of systemic BFT, particularly the technical limitations in clinical diagnostics stemming from its profound structural homology with host metalloproteinases. Future research integrating advanced diagnostic methodologies and liver-specific in vivo models is essential to elucidate these pathophysiological mechanisms and evaluate the ETBF-BFT axis as a complementary target in progressive MASH.
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