Ferric citrate-induced colonic mucosal damage associated with oxidative stress, inflammation responses, apoptosis, and the changes of gut microbial composition

• Published in: Ecotoxicology and environmental safety Vol. 249; p. 114364
• Main Authors: Xia, Yu, Luo, Qihui, Huang, Chao, Shi, Liangqin, Jahangir, Asad, Pan, Ting, Wei, Xiaoli, He, Junbo, Liu, Wentao, Shi, Riyi, Geng, Yi, Fang, Jing, Tang, Li, Guo, Hongrui, Ouyang, Ping, Chen, Zhengli
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.01.2023; Elsevier
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Colon; Colon - drug effects; Colon - metabolism; Ferric citrate; Ferric Compounds - toxicity; Food, Fortified - toxicity; Gastrointestinal Microbiome - drug effects; Glutathione - metabolism; Gut microbes; Inflammation; Inflammation - chemically induced; Inflammation - metabolism; Intestinal Mucosa - drug effects; Iron - metabolism; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Rats; Superoxide Dismutase - metabolism; PCoA; Oxidative stress; LefSe; IHC; SPF; PFA; MDA; LPS; Ferric citrate; 4-HNE; Colon; GSH; Gut microbes; BCA; GSH-Px; DAB; SOD; T-AOC; Inflammation; PVDF; ECL; SDS-PAGE; AB-PAS; CAT; FC; HE; TJPs; Apoptosis
• ISSN: 0147-6513; 1090-2414; 1090-2414
• DOI: 10.1016/j.ecoenv.2022.114364

Ferric citrate (FC) has been used as an iron fortifier and nutritional supplement, which is reported to induce colitis in rats, however the underlying mechanism remains to be elucidated. We performed a 16-week study of FC in male healthy C57BL/6 mice (nine-month-old) with oral administration of Ctr (0.9 % NaCl), 1.25 % FC (71 mg/kg/bw), 2.5 % FC (143 mg/kg/bw) and 5 % FC (286 mg/kg/bw). FC-exposure resulted in colon iron accumulation, histological alteration and reduce antioxidant enzyme activities, such as glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and total antioxidant capacity (T-AOC), together with enhanced lipid peroxidation level, including malondialdehyde (MDA) level and 4-Hydroxynonenal (4-HNE) protein expression. Exposure to FC was associated with upregulated levels of the interleukin (IL)− 6, IL-1β, IL-18, IL-8 and tumor necrosis factor α (TNF-α), while down-regulated levels of IL-4 and IL-10. Exposure to FC was positively associated with the mRNA and protein expressions of cysteine-aspartic proteases (Caspase)− 9, Caspase-3, Bcl-2-associated X protein (Bax), while negatively associated with B-cell lymphoma 2 (Bcl2) in mitochondrial apoptosis signaling pathway. FC-exposure changed the diversity and composition of gut microbes. Additionally, the serum lipopolysaccharide (LPS) contents increased in FC-exposed groups when compared with the control group, while the expression of colonic tight junction proteins (TJPs), such as Claudin-1 and Occludin were decreased. These findings indicate that the colonic mucosal injury induced by FC-exposure are associated with oxidative stress generation, inflammation response and cell apoptosis, as well as the changes in gut microbes diversity and composition. •FC-exposure induces iron accumulation in the colon and causes colon histopathological lesions.•FC-exposure induces oxidative stress in the colon by weakening the activities of antioxidant system and enhancing the lipid peroxidation levels.•FC-exposure induces inflammation activation by increasing the pro-inflammatory cytokines while decreasing the anti-inflammatory cytokines.•FC-exposure promotes the apoptosis via activating pro-apoptosis related gene, and inhibiting the anti-apoptosis related gene.•FC-exposure changes the diversity and composition of gut microbiome.