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Background  Obesity is associated with many comorbidities including inflammatory bowel disease (IBD). We investigated prophylactic effects of an herbal extract (HE) on the DSS-induced colitis mice challenged with high AGEs-fat diet 60% (HFD).    Methods  Six-week-old C57BL/6 male mice were fed with either HFD (8 groups, 6 mice in each group), or normal diet (ND) (8 groups, 6 mice in each group). After 6 weeks, animals received HE (combination of turmeric, ginger, boswellia and cat’s claw extract) for 7 weeks in three doses (high dose (0.6 mg/g); low dose (0.15 mg/g) and mid dose (0.3 mg/g)). Next, mice were subjected to 2.5% DSS in drinking water. Control mice received ND and instead of HE and DSS they received distilled water. Obesity index markers were determined, H&E staining and TUNEL assay evaluated apoptosis. Colonic expressions of  IL-6 ,  RAGE ,  AGER1 ,  Sirt1 ,  Bax, Bcl2, ZO-1  and  P53  were determined.Results  HE ameliorated colitis in HFD mice by reducing colonic myeloperoxidase activity (by 2.3-fold), macrophage accumulation (by 2.6-fold) and mRNA expression of  IL-6  (by 2.3-fold) in HFD mice. Moreover, HE restored  ZO-1  (by 2.7-fold), prevented apoptosis and maintained immune homeostasis. HE reduced activation of NF-κB protein (by 1.3-fold) through decreasing  RAGE  (by 1.93-fold) and up-regulation of  Sirt1  (by 7.71-fold) and prevented down-regulation of  DDOST  (by 6.6-fold) in HFD mice.    Conclusions  HE ameliorated colitis in prophylactic in HFD mice and it was, at least partly, due to the restoration of the gut integrity, suppression of inflammation and apoptosis via modulation of colonic  Sirt1 ,  RAGE  and  DDOST  signaling.    Graphic abstractSupplementary Information  The online version contains supplementary material available at 10.1186/s12986-021-00603-x.

Anti-inflammatory and -apoptotic effects of a long-term herbal extract treatment on DSS-induced colitis in mice fed with high AGEs-fat diet