Kefiran, a polysaccharide from kefir grain, modulates gut microbiota and hepatic metabolism to mitigate metabolic dysfunction-associated steatotic liver disease.

To address the global burden of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), we investigated kefiran, an extracellular polysaccharide from kefir grains, as a potential intervention. Kefiran (K1A) was isolated, purified, and identified as a highly branched heteropolysaccharide, featuring a backbone of glucose and galactose (C4/C3 positions) with 2,6-galactose (C2/C6) as the primary branching point. In high fat diet (HFD)-induced MASLD mice, K1A supplementation ameliorated hepatic injury, lowered inflammation and insulin resistance, suppressed lipogenic protein expression, and thereby alleviated hepatic steatosis. Additionally, K1A also restored HFD-induced gut dysbiosis, significantly elevating Parabacteroides (p < 0.001), Alistipes (p < 0.05), and Alloprevotella (p < 0.01), while, reducing Lachnoclostridium (p < 0.001), Psychrobacter (p < 0.01), Allobaculum (p < 0.001), and Coriobacteriaceae_UCG-002 (p < 0.01). The K1A-modified gut microbiota plays a crucial role in ameliorating MASLD. Furthermore, K1A improved hepatic metabolism dysregulation, notably enhancing one‑carbon pool by folate (p = 0.0018, ER = 0.22), which correlated positively with gut Parabacteroides and Alistipes (both p < 0.001). These findings confirm the therapeutic potential of kefiran against MASLD, revealing a novel gut-liver axis-based intervention strategy.