Oral iron supplementation exacerbates dextran sulfate sodium (DSS)-induced colitis in mice

Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterized by diarrhea, abdominal pain, and bloody, mucous-laden stools. In one-third of UC patients, severity of blood loss is sufficient to cause iron deficiency anemia, making it the most common extra-intestinal manifestation of UC. Oral iron supplementation is the first line treatment for IDA. However, there is a debate concerning the safety of orally administered iron, as some studies have reported an exacerbation of disease, whereas others report the treatment is well tolerated and effective. Aim: The purpose of this study was to determine the effect of oral iron administration on disease activity in dextran sulfate sodium (DSS)-induced colitis in mice, a model that effectively recapitulates ulcerative colitis. Hypothesis: We hypothesize that iron-supplemented chow will increase disease activity and lead to pathogenic changes in mice with DSS-induced colitis. Methods: Experimental acute colitis (UC) was produced in BALBc/AnNCrl (male and female; 7 weeks old) mice by administration of 3% DSS dissolved in drinking water for 7 days. Control mice received standard water. Normal control (NC) and UC (UC) animals were fed standard chow contained 200 parts per million (ppm) ferrous sulfate (2018 Teklad Global 18% Protein Rodent Diet, Huntingdon, UK), while normal (NCFe) and UC (UCFe) experimental animals were fed an iron-supplemented diet containing 600 ppm ferrous sulfate (2018 Teklad Global 18% Protein Rodent Custom Diet, Huntingdon, UK). Food and water were provided ad libitum. Daily scores for weight loss, stool consistency, and fecal blood content were averaged to produce a disease activity index as previously described by Friedman and co-workers (DAI, 2009). On day-8 post-treatment, mice were euthanized with 5% isoflurane. Length of colon was measured from cecum to rectum, and epithelial cells were isolated from distal colon by EDTA chelation technique. Histopathology, RNA isolation, and qRT-PCR analyses were performed using standard techniques. Results: Food and water consumption were not significantly altered among the 4 groups of mice. Additional iron supplementation significantly: 1) increased DAI; 2) decreased fecal dry weight; and 3) increased blood inflammatory cytokine levels in UCFe as compared to UC group. Colon length was shortened one-third in UC as compared to NC, but was not further significantly altered by iron supplementation. Loss of crypt architecture and increased influx of inflammatory cells identified in UC colon was not significantly altered in colons from the UCFe group. Expression of apical iron importer DMT1 was increased in UC as compared to NC, but not in the UCFe group. In total, there were no differences due to iron supplementation, and no differences were present due to gender. Conclusion: We conclude that iron supplementation increases the severity of colitis by stimulating water secretion. This study was supported by the National Institute of Health NIDDK DK104791 and DK112085 grants This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.