At the 2026 Digestive Disease Week (DDW), the research team led by Professor Bai Feihu from the Department of Gastroenterology, the Second Affiliated Hospital of Hainan Medical University (SHHMU) had three oral presentations and one poster presentation selected for inclusion. Centering on the crosstalk between gut microbiota (bacteria and fungi) and metabolic-associated fatty liver disease (MASLD) as well as alcoholic liver disease (ALD), their series of systematic researches cover lipid deposition, hepatic inflammation, liver fibrosis and lipophagy regulation. Combining clinical cohort analysis, multi-omics profiling and causal mechanism verification, these findings provide solid novel evidence for functional food development and microecological intervention against liver diseases.

1 Spirulina Alleviates MASLD via Gut Microbiota-Derived Metabolite HMBA to Activate GPR81 and Induce Macrophage M2 Polarization

Hailed as an ideal superfood of the 21st century, the exact therapeutic mechanism of spirulina against MASLD remained poorly elucidated for long. Professor Bai's team has for the first time illustrated the complete regulatory pathway by which spirulina remotely modulates hepatic macrophages to reverse hepatic steatosis through reshaping gut microbiota and its metabolites.

In clinical practice, 8-week oral spirulina intervention significantly improved fatty liver lesions, liver enzyme levels and glycolipid metabolism among 25 MASLD patients, accompanied by elevated abundance of Clostridium leptum and its metabolite HMBA. Consistent therapeutic effects were observed in two murine MASLD models, while such benefits vanished in germ-free mice, confirming that the hepatoprotective efficacy of spirulina is strictly gut microbiota-dependent.

Further experiments including fecal microbiota transplantation, single-cell RNA sequencing and flow cytometry identified Clostridium leptum as the primary strain producing HMBA. Mechanistically, HMBA restructures hepatic macrophage phenotypes: it suppresses pro-inflammatory M1 macrophage signaling pathways (TNF/NF-κB) and boosts the reparative functions of hepatic macrophages. HMBA directly acts as an agonist of GPR81, and GPR81 knockdown abolishes HMBA-mediated M2 polarization and subsequent Lrp1 upregulation.

This study firstly establishes the spirulina-Clostridium leptum-HMBA-GPR81 signaling axis in MASLD prevention, paving a brand-new avenue for intervening metabolic liver diseases with functional foods and HMBA analogues.

2 Enterotoxigenic Bacteroides fragilis Aggravates ALD via Kynurenine-Mediated Dual Injury: AMPK Inhibition and Retinoic Acid Depletion

The gut microbiota-driven pathogenic mechanism underlying alcoholic liver disease (ALD) has long been unclear. Professor Bai’s team pinpointed enterotoxigenic Bacteroides fragilis (ETBF) as the core pathogenic bacterium in ALD patients, revealing its role in disrupting hepatic vitamin A metabolic homeostasis to trigger liver injury, steatosis and fibrosis.

Multi-omics analysis on 50 ALD patients and 25 healthy controls verified prominent ETBF enrichment in the intestinal tract of ALD cases. Fecal microbiota transplantation from ALD patients and pure ETBF gavage both exacerbated alcohol-induced liver damage, inflammation and fibrosis in mice, proving ETBF as a causal driver of ALD progression.

Mechanically, ETBF upregulates hepatic IDO1 expression via inflammatory factors to accelerate kynurenine synthesis. Excessive kynurenine exerts dual adverse effects: it inhibits AMPK activity to promote lipid accumulation, and upregulates CYP26A1 to accelerate retinoic acid (RA) degradation. RA deficiency relieves the inhibitory effect on PPARγ, thereby activating hepatic stellate cells and accelerating liver fibrosis, while RA supplementation can effectively mitigate fibrotic lesions.

This research clarifies the IDO1-kynurenine-CYP26A1-RA-PPARγ regulatory cascade disrupted by ETBF, offering multiple promising therapeutic targets including IDO1 inhibitors, kynurenine antagonists and retinoic acid supplements for ALD treatment.

3 Intestinal Fungal Dysbiosis Deteriorates MASLD: Rhizopus rhizopodiformis Derived 13(S)-HODE Activates Elane-PAR2-SREBP-1c Signaling

Most gut microbiota researches focus on bacteria, whereas the pathogenic role of intestinal fungi has long been overlooked. In his oral report, Dr. Zhang Daya firstly demonstrated that intestinal pathogenic fungus Rhizopus rhizopodiformis facilitates excessive hepatic lipogenesis via its metabolite 13(S)-HODE.

ITS sequencing analysis of fecal samples from 107 MASLD patients and 120 healthy controls revealed declined intestinal fungal diversity and sharply increased abundance of Rhizopus rhizopodiformis in MASLD patients, which was positively correlated with the severity of hepatic steatosis and BMI. Fecal microbiota transplantation from MASLD patients successfully induced typical MASLD phenotypes in mice, and antifungal treatment with amphotericin B effectively halted disease deterioration.

In high-fat diet-fed mice, Rhizopus rhizopodiformis colonization triggers intestinal flora imbalance and intestinal barrier dysfunction, activating the hepatic LPS-TLR4-NF-κB inflammatory pathway and promoting hepatic neutrophil infiltration. Fungal metabolite 13(S)-HODE induces neutrophils to secrete Elane, which further cleaves and activates SREBP-1c through the non-canonical PAR2 pathway, leading to uncontrolled de novo hepatic lipogenesis.

This study innovatively proposes the cross-talk mechanism among intestinal fungi, neutrophils and liver tissues, and the Elane-PAR2-SREBP-1c axis serves as a novel intervention target for MASLD.

4 Novel Lipophagy-Regulating Mechanism for Adolescent MASLD: Alistipes putredinis Alleviates Hepatic Lipid Accumulation via Acetate-GPR43 Axis

Effective microecological intervention targets for adolescent-onset MASLD remain scarce. In the poster research, Dr. Zhang Daya focused on the beneficial gut bacterium Alistipes putredinis (AP), confirming that AP-derived acetate activates hepatic lipophagy to eliminate excessive intrahepatic lipids efficiently.

Fecal metagenomic sequencing of 29 obese adolescents with MASLD and 17 healthy peers showed markedly reduced AP abundance in adolescent MASLD patients. Supplemental AP administration significantly relieved hepatic lipid deposition in high-fat diet-induced MASLD mouse models.

Acetate is identified as the core functional metabolite of AP. Acetate activates the hepatic GPR43/AMPK signaling pathway, inhibits excessive S385 phosphorylation of PTEN and restores PTEN biological activity, thereby suppressing the PI3K/Akt/mTOR pathway and lifting the blockade of lipophagy to accelerate hepatic lipid clearance.

This finding validates the therapeutic potential of the AP-acetate-GPR43-lipophagy axis in adolescent MASLD, providing scientific support for the development of AP-based probiotic preparations and acetate-related microecological regulators.

Summary

The four pioneering studies presented by Professor Bai Feihu’s team at 2026 DDW establish a complete research system covering etiology clarification, mechanism exploration and clinical intervention strategies for metabolic fatty liver diseases, involving beneficial microbes (Clostridium leptum, Alistipes putredinis), pathogenic bacteria (ETBF) and harmful intestinal fungi (Rhizopus rhizopodiformis).

A series of newly discovered signaling axes and druggable targets including HMBA-GPR81, kynurenine-retinoic acid, 13(S)-HODE-Elane and acetate-mediated lipophagy further highlight the outstanding original innovation strength and international leading academic influence of China in the field of digestive microecology and liver disease research.