Changes in Gut Microbiota by Drug Treatments and Possible Intermediate Effects on Metabolic Syndrome and Norovirus Infection: Metformin Treatment and Vitamin A Supplementation

Abstract

Gastrointestinal tract, especially the small and large intestine, is a prominent part of the digestion and absorption of nutrients and the immune system. Gut microbiota is the name given to the vast collection of symbiotic microorganisms living in the intestine. It contains tens of trillions of microorganisms, including up to 1,000 bacterial species. Recently, next generation sequencing (NGS) technique-based metagenomic analyses make it possible to reveal the total microbial communities including uncultured bacteria and understand the interaction between host and gut microbiota. Various health problems such as metabolic syndromes, autoimmune disease, and infection disease were implicated by microbial disorder. However, because of the complexity of microbial community, mechanical interactions between gut microbiota and metabolic disorder are not fully understood until now. In this study, we investigated the change of gut microbiota by metformin treatment and vitamin A administration from two different mouse models. First, the specific bacterial community by metformin treatment, first-line oral antidiabetic agent, was revealed using high-fat diet (HFD)-induced obese mouse model. The metformin treatment in HFD-induced obese mouse changed gut microbiota to have low diversity and unique microbiota in comparison to untreated obese mice. The composition of phylum Proteobacteria (2.1 ± 2.8%) and Verrucomicrobia (12.4 ± 5.3%) were significantly increased after metformin treatment during HFD (HF-Met), especially, the genome of Akkermansia muciniphila which was suggested as an intestinal mucin-degrading bacterium was highly increased during metformin treatment. In addition, abundance of Akkermansia muciniphila was showed in BHI medium supplemented with metformin in vitro test. In the analysis of metabolic functions, total 18 KEGG pathways were significantly predicted to be upregulated in HF-Met, among them, sphingolipid and fatty acid metabolism belong to lipid metabolism were most remarkable. These results demonstrated that gut microbiota significantly changed in the process of improvement of metabolic disorders by metformin treatment. Moreover, we could suggested that the change of gut microbiota composition by metformin treatment was strongly linked to improvement of metabolic syndrome. Second, we investigated the changes in gut microbiota by MNV inoculation during retinoic acid (RA) administration. RA, the metabolite of dietary vitamin A, plays essential roles in innate immune responses for virus infection. Recently, it has been reported that gut microbiota is highly related with both innate and adaptive immunity. But, the relation between RA administration and gut microbiota was not characterized until now. Here, mice were inoculated with murine norovrius (MNV) during RA administration (1 and 10 mg/kg/d), those gut microbiota was compared to MNV- or RA-negative controls. Bacterial diversity was most significantly changed in MNV-inoculated mice during RA administration, especially, Lactobacillus was significantly increased by 1 mg/kg/d RA administration. Moreover, abundance of Lactobacillus has a positive correlation with RIG-1, MDA-5, and F4/80, and was negatively correlated with MNV positive. Therefore, we could predict that the change of gut microbiota by RA administration is related with innate immunity for virus infection. In conclusion, gut microbiota was significantly changed by metformin treatment in improvement of metabolic disorders as well as incidence of metabolic syndrome. And, specific gut microbiota was characterized by MNV inoculation during RA administration. From those results, we could suggest that gut microbiota plays important role in improvement of metabolic syndrome and activation of innate immunity against virus infection, eventually, further studies should be required to verify the beneficial effects of gut microbiota in human health.