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• SMCS was able to reduce blood glucose from the diabetic rats. • SMCS mitigated morphological alterations caused by DM1 by preventing duodenal changes in volume and villus length. • The beneficial effects of SMCS administration in the duodenal morphology were at least partially attributed to NF-kB modulation. Diabetes mellitus (DM) is a metabolic disease associated with several intestinal disorders. S-methyl cysteine sulfoxide (SMCS) ​​is an amino acid present in Allium cepa L with hypoglycemic effects. However, the effects of SMCS on diabetic intestinal changes are unknown. Thus, we aimed to investigate the effects of SMCS on duodenal morphology and immunomodulatory markers in diabetic rats. Twenty-six rats were divided into three groups: control (C), diabetic (D) and diabetic +200 mg/kg SMCS (DSM). DM was induced by intraperitoneal injection of streptozotocin (50 mg/kg). After 30 days, duodenum samples were processed to assess histopathological and stereological alterations in volume, villus length, and immunohistochemical expression of NF-kB, IL-10, BCL-2, and caspase-3. SMCS reduced hyperglycemia and mitigated the increase in total reference volume of the duodenum, the absolute volume of the mucosa, and the length of the intestinal crypts in the DMS group when compared to D. IL-10 immunostaining was reduced in D when compared to C, while NF-kB was increased in D in comparison to the other groups. SMCS ​​supplementation could decrease the NF-kB immunostaining observed in D. Positive staining for BCL-2 and caspase-3 were not statistically different between groups. In summary, SMCS decreased hyperglycemia and mitigated the morphological changes of the duodenum in diabetic animals, and these beneficial effects can be partially explained by NF-kB modulation. [ABSTRACT FROM AUTHOR]