Vitamin D mitigates diabetes-associated metabolic and cognitive dysfunction by modulating gut microbiota and colonic cannabinoid receptor 1

Eur J Pharm Sci. 2022 Mar 1:170:106105. doi: 10.1016/j.ejps.2021.106105. Epub 2021 Dec 20.


Introduction: Obesity is associated with elevated endocannabinoid tone, gut dysbiosis, and inflammation predisposing to diabetes. The endocannabinoid system mediates the effects of gut microbiota and regulates the gut barrier integrity. We examined the effects of vitamin D (VD) on colonic cannabinoid receptor 1(CB1R), tight junction proteins, gut dysbiosis, metabolic and cognitive dysfunction in a model of type 2 diabetes compared with metformin.

Methods: Rats received high-fat, high-sucrose diet (HFSD) and either VD (500 IU/kg/day; p.o.), or metformin (200 mg/kg/day; p.o.) for 8 weeks. After 6 weeks, streptozotocin (STZ) (40 mg/kg; i.p) was injected. Behavioral, cognitive, and metabolic assessments were carried out. Finally, fecal, blood, and tissue samples were collected to examine Bacteroidetes/Firmicutes ratio, colonic CB1R, zonula occludens-1 (ZO-1), occludin, and Toll-like receptor 4 (TLR4); serum lipopolysaccharides (LPS), peptidoglycan (PGN), tumor necrosis factor-alpha (TNF-ɑ), glucagon-like peptide-1 (GLP-1), lipids, and VD; hippocampal brain-derived neurotrophic factor (BDNF) and inflammatory markers.

Results: VD ameliorated HFSD/STZ-induced dysbiosis/gut barrier dysfunction as indicated by lower circulating LPS, PGN and TNF-ɑ levels, likely by downregulating colonic CB1R and upregulating ZO-1 and occludin expressions. Additionally, VD suppressed HFSD/STZ-induced hyperglycemia, hyperinsulinemia, dyslipidemia, and hippocampal neuroinflammation. These changes culminated in improved glycemic control and cognitive function. VD was more effective than metformin in decreasing serum LPS and TNF-ɑ levels; whereas metformin resulted in better glycemic control.

Conclusion: Targeting gut microbiota by VD could be a successful strategy in the treatment of diabetes and associated cognitive deficit. The crosstalk between VD axis and the endocannabinoid system needs further exploration.

Keywords: CB1R; Cognitive function; Diabetes; Gut microbiota; Obesity; Vitamin D.

MeSH terms

  • Animals
  • Cognitive Dysfunction*
  • Diabetes Mellitus, Type 2*
  • Diet, High-Fat
  • Gastrointestinal Microbiome*
  • Mice
  • Mice, Inbred C57BL
  • Neuroinflammatory Diseases
  • Rats
  • Receptor, Cannabinoid, CB1*
  • Receptors, Cannabinoid
  • Vitamin D


  • Receptor, Cannabinoid, CB1
  • Receptors, Cannabinoid
  • Vitamin D