A curcumin derivative metalloprotease inhibitor (CMC2.24) mitigates Brachyspira spp.-induced swine dysentery

Swine dysentery, a mucohemorrhagic diarrheal disease affecting young pigs, is caused by infections in the colon with Brachyspira spp. and threatens the sustainability of the pork industry due to mortality, hindered animal growth, and increased treatment costs. Given that proteases play critical roles in the progression of colitis, this study evaluated the therapeutic potential of a novel curcumin derivative (CMC 2.24) with matrix metalloproteinase inhibitory properties, CMC2.24, in alleviating the clinical manifestations of swine dysentery. This study shows that weaned pigs challenged with B. hampsonii and treated with CMC2.24 from days 5 to 9 post-challenge exhibited reduced clinical signs, improved survival rates, and decreased B. hampsonii shedding compared to their untreated counterparts. The colons of B. hampsonii-infected pigs treated with CMC2.24 revealed reduced histologically mucosal thickening and a lesser proteomic pro-inflammatory profile. Fecal protease levels in CMC2.24-treated pigs were lower at the peak of colitis, with a specific reduction in metalloproteases. CMC2.24 also increased the synthesis of key short-chain fatty acids in pigs, including acetate, propionate, and butyrate. Mechanistically, CMC2.24 (1 mM) exhibited slightly dose-dependent in vitro microbicidal activity against B. hampsonii. In cultured murine primary macrophages exposed to B. hampsonii and related B. hyodysenteriae, CMC2.24 reduced the synthesis of reactive oxygen species (ROS) and pro-inflammatory Il-1β. Thus, metalloprotease inhibitor CMC2.24 exhibits direct antimicrobial activity alongside essential anti-inflammatory, anti-protease, and antioxidant effects in protecting pigs from swine dysentery.