Dehydrodiisoeugenol attenuates ulcerative colitis via regulating Anaerostipes caccae-mediated uric acid metabolism

The gut microbiota plays a crucial role in the pathogenesis of ulcerative colitis (UC). Dehydrodiisoeugenol (DEH) is a major benzofuran-type neolignane isolated from Myristica fragrans Houtt., a plant whose fruit has been incorporated into traditional Chinese medicine (TCM) formulations for clinical treatment of gastrointestinal disorders. However, the pharmacological mechanisms underlying the anti-colitic efficacy of DEH remain to be elucidated.

The present study aimed to investigate the anti-colitic efficacy of DEH and its therapeutic mechanism, with a specific focus on the role of gut microbiota regulation.

A dextran sulfate sodium (DSS)-induced murine model of UC was utilized to assess the effects of DEH on UC progression. Co-housing experiments and fecal microbiota transplantation (FMT) were conducted to verify whether DEH's anti-colitic effects depend on the gut microbiota. 16S rRNA gene sequencing and quantitative PCR (qPCR) were performed to identify gut bacterial taxa altered by DEH. Bacterial colonization was carried out to evaluate the effects of differential species on symptoms of UC. Metabolomic analyses and in vitro incubations were conducted to identify key metabolites.

First, DEH exerted potent anti-colitic efficacy in DSS-induced UC mice by alleviating colonic inflammation and enhancing intestinal epithelial integrity. Administration of DEH at 50 mg/kg significantly prolonged the colon length to 6.27 ± 0.19 cm, which was longer than that of the vehicle group (4.85 ± 0.18 cm) and the positive control drug SASP group (200 mg/kg, 5.83 ± 0.18 cm). Co-housing and FMT validated that DEH's efficacy is dependent on the gut microbiota. Subsequently, we found that DEH significantly upregulated the abundance of Anaerostipes caccae, the colonization with which could alleviate symptoms of UC. Furthermore, we identified A. caccae as a uric acid (UA)-metabolizing microbe, and its colonization in UC mice obviously reduced UA levels. Blocking UA synthesis with allopurinol (Allo) completely abolished A. caccae's anti-colitic effects, verifying its therapeutic effects rely on the UA-lowering capacity. Finally, we found the pathologically elevated UA exacerbated UC via activating the p38 mitogen-activated protein kinase (MAPK) signaling pathway.

Our study highlights that the A. caccae-mediated maintenance of UA metabolic homeostasis restrains UC pathogenesis, a process that is the core mechanism through which DEH exerts its anti-colitic efficacy.