From Mycobiome Remodeling to Therapeutic Candidate: Aspergillus ruber and 3-methyldioxyindole, Acknowledged as a Novel Modulator Via BPIS Treatment and Alleviating MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading significant public health concern, affecting 25-30% of the population globally. Recent advances in gut microbiome research are increasingly recognized. Studies exploring the gut-liver axis have mostly focused on bacteriomes. There are limited studies about commensal fungi. Our earlier research on the anti-inflammatory properties of bound polyphenols of the inner shell (BPIS) extracted from Foxtail millet in the mouse colitis model revealed that BPIS significantly increased the abundance of Aspergillus ruber (A. ruber) and remodeled the gut mycobiome. The present study demonstrated that BPIS mitigated MASLD caused by a high-fat diet (HFD), significantly enhancing A. ruber fungi in the gut microbiome. Further investigation exhibited that the administration of A. ruber and its metabolite 3-methyldioxyindole alleviated disordered lipid metabolism, abnormal weight gain, oxidative stress, low ATP synthesis, and histological complications in HFD-fed mice. A. ruber and 3-methyldioxyindole also improved HFD-induced breakage of the intestinal barrier by enhancing the expression of tight junction proteins (Occludin, ZO-1, and claudin) in the colon. The study suggests that the metabolite 3-methyldioxyindole demonstrates more promising effects in lipid metabolism homeostasis. A. ruber or 3-methyldioxyindole has great potential to be developed as an effective probiotic agent for treating MASLD.