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

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.

Oxidative Stress, Inflammation, Gut Dysbiosis: What Can Polyphenols Do in Inflammatory Bowel Disease?

“…Interestingly, in another study, a novel strategy of combining resveratrol and Ligilactobacillus salivarius Li01 (Li01), a probiotic strain capable of promoting the recovery of the gut microbiota and gut barrier, showed favorable synergetic effects in treating colitis mice. Resveratrol promotes the growth of Li01 in vivo, which in turn affects the turnover of resveratrol into more bioactive metabolites, such as dihydroresveratrol, which can facilitate the suppression of inflammation by activating the environmental sensor mammalian aryl hydrocarbon receptor (AHR) and affecting the serotonin pathway [ 194 ]. In another approach, the combination of polysaccharides (TPS) with tea polyphenols (TPP) decreased the relative abundance of intestinal probiotics, including Lactobacillaceae and Lactobacillus , and thus improved the intestinal barrier function, thereby alleviating colitis [ 195 ].…”

Prevention of Loperamide-Induced Constipation in Mice and Alteration of 5-Hydroxytryotamine Signaling by Ligilactobacillus salivarius Li01

“…In addition, Li01 has also been reported to be able to decrease the serum level of inflammatory cytokines and prevent bacterial translocations [ 17 ]. Our recent study found that Li01 was related to the regulation of the 5-HT signaling pathway and promoted 5-HT synthesis [ 18 ]. Since several studies have shown the potential of Li01 in preventing GI diseases, it can be inferred and suspected that the probiotic could be a promising agent for constipation therapy.…”

An Engineered Butyrate-Derived Polymer Nanoplatform as a Mucosa-Healing Enhancer Potentiates the Therapeutic Effect of Magnolol in Inflammatory Bowel Disease

“…Another useful strategy is that we can utilize some natural anti-inflammatory biomolecules to manage IBD. Naturally plant-derived small molecular bioactive polyphenols, including epigallocatechin gallate, 12 resveratrol, 13 and berberine, 14 have been widely used in the colitis mouse models owing to the great anti-inflammatory activity. Intriguingly, these compounds could act as antioxidants to scavenge reactive oxygen species (ROS), which are of great abundance at inflamed colons and exacerbates the immune response.…”

“…Naturally plant-derived small molecular bioactive polyphenols, including epigallocatechin gallate, resveratrol, and berberine, have been widely used in the colitis mouse models owing to the great anti-inflammatory activity. Intriguingly, these compounds could act as antioxidants to scavenge reactive oxygen species (ROS), which are of great abundance at inflamed colons and exacerbates the immune response. − Magnolol (Mag) is the main bioactive ingredient of traditional Chinese medicine Magnolia, which exhibited good antibacterial, antioxidant and anti-inflammatory effects. , Mag exerts anti-inflammatory effects mainly by regulating the NF-κB, MAPK and PPAR-γ signaling pathways. , In addition to these bioactive polyphenols, some metabolites of gut microbiota, such as short chain fatty acids (SCFAs) and ketone (like beta-hydroxybutyrate), are gradually recognized as pivotal modulators of gut homeostasis for their multiple biological functions including anti-inflammation and microbiota regulation. , Butyrate, a four-carbon SCFA, can enhance intestinal epithelial barrier, , mitigates inflammatory responses, and regulates gut microbiota, showing a great potential in colitis remission .…”