Protocatechuic Acid Alleviates Dextran-Sulfate-Sodium-Induced Ulcerative Colitis in Mice via the Regulation of Intestinal Flora and Ferroptosis

Abstract

Protocatechuic acid (PCA) is a natural component with multiple biological activities. However, the underlying mechanisms of the effects of PCA on anti-ulcerative colitis (UC) are unclear. A UC mouse model was established by allowing the mice to freely drink a dextran sulfate sodium solution. The mice were administered PCA intragastrically for 7 days. Histological pathology, intestinal flora, and ferroptosis regulators were determined in vivo. Additionally, ferroptotic Caco-2 cells were modeled to investigate the role of PCA in ferroptosis. Our results showed that PCA reduced the levels of the disease activity index, inflammatory factors, and histological damage in UC mice. We also found that the regulation of intestinal flora, especially Bacteroidetes, was one of the potential mechanisms underlying the protective effects of PCA anti-UC. Moreover, PCA downregulated the level of ferroptosis in the colon tissue, as evidenced by a reduced iron overload, decreased glutathione depletion, and a lower level of malondialdehyde production compared with the model group. Similar effects of PCA on ferroptosis were observed in Erastin-treated Caco-2 cells. The results obtained using reactive oxygen species assays and the changes in mitochondrial structure observed via scanning electron microscopy also support these results. Our findings suggested that PCA protected against UC by regulating intestinal flora and ferroptosis.

Unbiased serum metabolomic analysis in cats with naturally occurring chronic enteropathies before and after medical intervention

“…3,4-dihydroxybenzoic acid (protocatechuic acid) is another plant-derived xenobiotic with antioxidant and anti-inflammatory properties. Both supplementation with pinitol and protocatechuic acid have been shown to alleviate inflammation and clinical signs in rodent models of ulcerative colitis 86 , 90 . Results are consistent with previous studies, which have found several phytosterols, including campesterol, fucosterol, and stigmasterol to be altered in fecal samples of dogs and cats with CE 24 , 82 , 91 .…”

Therapeutic Implications of Phenolic Acids for Ameliorating Inflammatory Bowel Disease

“…Oral administration of protocatechuic acid at doses of 5, 10, and 20 mg/kg suppressed the DSS-induced increase in inflammatory factors, including IL-6, IL-12, and TNF-α, in mice treated with 3.5% DSS [17]. Furthermore, protocatechuic acid-treated mice exhibited a reduction in the expression of proinflammatory cytokines (IL-6, IL-1β, TNF-α, and cyclooxygenase 2 (COX-2)) in TNBS-induced colitis, achieved by modulating the sphingosine kinase (SphK)/S1P and related signaling pathways [18].…”

“…Similarly, treatment with 4-hydroxybenzoic acid (at concentrations of 3, 10, and 30 µM) resulted in an increased expression of tight junction proteins in mice and Caco-2 cells exposed to TNF-α (10 ng/mL) [15]. Protocatechuic acid, administered at doses of 5, 10, and 20 mg/kg, effectively alleviated the dextran sulfate sodium salt (DSS)-induced reduction in occludin protein expression in mice treated with 3.5% DSS [17]. Furthermore, intraperitoneal administration of protocatechuic acid at doses of 10, 30, or 60 mg/kg per day prevented both the macroscopic and microscopic damage to the colonic mucosa, as well as the decline in body weight gain in mice treated with 2,4,6-trinitrobenzene sulfonic acid (TNBS) and rats treated with DSS [18,19].…”

Research advancements and perspectives of inflammatory bowel disease: A comprehensive review

“… 242 Protocatechuic acid, existing in many edible vegetables, fruits, and nuts, protect against DSS-induced UC through regulating gut microbiota and inhibiting ferroptosis. 243 …”