The Role of Dihydroresveratrol in Enhancing the Synergistic Effect of Ligilactobacillus salivarius Li01 and Resveratrol in Ameliorating Colitis in Mice

Yiqiu Fei; Shuobo Zhang; Shengyi Han; Bo Qiu; Yanmeng Lu; Weixing Huang; Fang Li; Deying Chen; Björn Berglund; Hang Xiao; Lanjuan Li; Mingfei Yao

doi:10.34133/2022/9863845

The Role of Dihydroresveratrol in Enhancing the Synergistic Effect of Ligilactobacillus salivarius Li01 and Resveratrol in Ameliorating Colitis in Mice

Research (Wash D C). 2022 Jun 14:2022:9863845. doi: 10.34133/2022/9863845. eCollection 2022.

Authors

Yiqiu Fei¹, Shuobo Zhang¹, Shengyi Han¹, Bo Qiu¹, Yanmeng Lu¹, Weixing Huang^{2

3}, Fang Li^{4

5}, Deying Chen¹, Björn Berglund⁶, Hang Xiao^{5

7}, Lanjuan Li^{1

2}, Mingfei Yao¹

Affiliations

¹ State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
² Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250021, China.
³ Zhejiang Tongchuang Yuecheng Health Science and Technology Co., Ltd., Shaoxing, China.
⁴ Cardiometabolic Genomics Program, Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, 630 W 168th St, P&S10-401, New York, NY 10032, USA.
⁵ Department of Food Science, University of Massachusetts, Amherst, Massachusetts 01003, USA.
⁶ Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
⁷ Zhejiang University, Department of Food Science and Nutrition, Zhejiang Key Laboratory for Agro-Food Processing, Fuli Institute of Food Science, Zhejiang R & D Center for Food Technology and Equipment, Hangzhou 310058, China.

Abstract

Currently approved therapeutical strategies for inflammatory bowel diseases (IBD) suffer from variable efficacy and association with risk of serious side effects. Therefore, efforts have been made in searching for alternative therapeutics strategies utilizing gut microbiota manipulation. In this study, we show that the probiotic strain Ligilactobacillus salivarius Li01 (Li01) and the phytochemical prebiotic resveratrol (RSV) have synergistic effect in ameliorating colitis in mice. Oral coadministration of Li01 (10⁹ CFU/d) and RSV (1.5 g/kg/d) promoted restoration of various inflammatory injuries and gut microbiota composition, exhibiting a favorable anti-inflammatory effect in DSS-induced colitis mice. The combination treatment was associated with reductions in the levels of proinflammatory cytokines IL-1β and IL-6 and increases in the levels of the anti-inflammatory cytokine IL-17A in mouse serum. Moreover, the combination treatment was found to alter the composition and metabolism of the gut microbiota, especially influencing the production of short chain fatty acids and anti-inflammatory related molecules. The mechanism underlying the improved anti-inflammatory effect from the RSV and Li01 combination treatment was found to be associated with the environmental sensor mammalian aryl hydrocarbon receptor (AHR) and tryptophan metabolism pathway. Administration of RSV in combination with Li01 in different mouse model led to enhanced conversion of RSV into metabolites, including dihydroresveratrol (DHR), resveratrol-sulfate, and resveratrol-glucuronide. DHR was found to be the dominant metabolite of RSV in conventional and colitis mice. An increased DHR/RSV ratio was confirmed to activate AHR and contribute to an enhanced anti-inflammatory effect. DHR is considered as a potential AHR ligand. The DHR/RSV ratio also affected the serotonin pathway by controlling the expression of Tph1, SERT, and 5-HT₇R leading to amelioration of colitis in mice. Our data suggest that treatment with a combination of Li01 and RSV has potential as a therapeutic strategy for IBD; further investigation of this combination in clinical settings is warranted.