Metabolic syndrome, a group of several disturbances including obesity, insulin resistance, and non-alcoholic fatty liver disease that pose as risk factors for diabetes and heart disease, has been previously associated with vitamin D insufficiency/deficiency in epidemiological studies. In addition, gut microbiota dysbiosis is involved in metabolic disorders with underlying chronic systemic inflammation. However, the causal role of vitamin D deficiency in metabolic disorders and whether gut microbiota has a mechanistic role is still unknown.
A recent study, led by Dr. Yuan-Ping Han from the Centre for Growth, Metabolism and Aging and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry at College of Life Sciences at Sichuan University in Chengdu (China), has found that vitamin D deficiency is involved in metabolic syndrome progression through intestinal integrity disruption and gut microbiota dysbiosis in mice.
First, mice were fed for 18-20 weeks with four types of diet (n = 20 for each condition): 1) Control chow with vitamin D3 (VD3) at 1000 international units (IU)/kg; 2) Vitamin D depleted control chow; 3) High-fat chow (60% of calories from fat) with VD3 supplement at 1000 IU/kg; and 4) High-fat chow without vitamin D supplement. In the presence of sufficient vitamin D (control), the mice were tolerant of the high-fat diet and showed relatively less insulin resistance and hepatic steatosis. In contrast, mice that were vitamin D-deficient and also consumed a high-fat diet developed insulin resistance and signs of fatty liver. These results emphasize that in mice, high-fat feeding is not sufficient to induce robust hepatic steatosis and metabolic disorders, but additional vitamin D deficiency is needed. High-fat diet feeding initiated fatty liver and insulin resistance in mice and dietary vitamin D deficiency exacerbated them. Dietary vitamin D deficiency also aggravated the high-fat diet-exerted systemic and local inflammation.
Besides this, both a high-fat diet and vitamin D deficiency suppressed Paneth cell-specific defensins and tight junction genes in the ileum, leading to the gut dysbiosis, increased gut permeability, endotoxemia, and systemic inflammation that underlie insulin resistance and fatty liver.
The high-fat diet feeding and insufficient supply of vitamin D led to gut dysbiosis with increased Helicobacter hepaticus, a murine hepatic pathogen, and decreased Akkermansia muciniphila, a beneficial bacterium. Vitamin D receptor knockout mice exhibited impaired mucosa and ileal dysbiosis (characterized by down regulation of defensins and their converting enzyme in the ileum and increased H. hepaticus and decreased A. muciniphila) and hepatic steatosis. In addition, an oral supply of a synthetic defensin recovered gut bacterial dysbiosis, decreased blood sugar levels and improved hepatic steatosis. These results show that vitamin D signalling may influence gut microbiota composition through regulating intestinal barrier homeostasis, in which vitamin D receptors highly expressed in the ileum of the small intestine take part.
In conclusion, vitamin D (through vitamin D receptor signalling) may influence the expression of defensins and tight junction genes that maintain intestinal homeostasis to suppress hepatic steatosis and metabolic disorders in mice. Further research in humans is needed to confirm the role of vitamin D deficiency and gut dysbiosis in metabolic syndrome.
Su D, Nie Y, Zhu A, et al. Vitamin D signaling through induction of paneth cell defensins maintains gut microbiota and improves metabolic disorders and hepatic steatosis in animal models. Front Physiol. 2016; 7:498. doi: 10.3389/fphys.2016.00498.
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