Dietary Oxalate and Intestinal Inflammation: Evidence From Experimental Colitis and Inflammatory Bowel Disease Patient Cohorts

BACKGROUND & AIMS: The role of diet in the pathogenesis of inflammatory bowel diseases remains unclear. Most dietary interventions for inflammatory bowel disease improve symptoms without consistent mucosal healing; exceptions include exclusive enteral nutrition and exclusion diets in patients with Crohn's disease. Oxalate, a naturally occurring compound found in all plant foods, is absorbed through the gut and has been shown to activate systemic and renal proinflammatory immune responses. However, the impact of intestinal oxalate on innate immune response in the context of inflammatory bowel disease is unknown. METHODS: We measured gene expression, stool oxalate content, and dietary intake in people with inflammatory bowel diseases and controls. Complementary studies were conducted in mouse models of chemically induced colitis, spontaneous colitis, and ex vivo cell culture systems to evaluate the relationships observed between oxalate transporter expression, stool oxalate content, and mucosal inflammation. RESULTS: Intestinal oxalate transporters, SLC26A2 and SLC26A3 are consistently downregulated across inflammatory bowel disease subtypes (Crohn's disease, ulcerative colitis), inflammatory bowel disease tissues (colon, ileum), and in mouse models of experimental colitis irrespective to experimental diet assignment. In patients with Crohn's disease, we observed higher stool oxalate content despite variable dietary oxalate intake. Altered expression of SLC26A6 corresponded to stricturing behavior of disease in patients with Crohn's disease. Altered expression corresponded more directly to higher stool oxalate content and increased disease activity in mice fed an oxalate supplemented diet. CONCLUSIONS: Dietary oxalate may exacerbate innate immune responses in susceptible individuals. Expression of oxalate transporters may be a disease-associated biological signal of both sensitivity to dietary oxalate and possibly, pathogenesis and clinical trajectory of patients with inflammatory bowel disease. This warrants future exploration of the role of dietary oxalate in mucosal inflammation in inflammatory bowel diseases.