Prophylactic Treatment of Probiotic and Metformin Mitigates Ethanol-Induced Intestinal Barrier Injury: In Vitro, In Vivo, and In Silico Approaches

Abstract

Ethanol depletes intestinal integrity and promotes gut dysbiosis. Studies have suggested the individual role of probiotics and metformin Met in protecting intestinal barrier function from injuries induced by ethanol. The objective of the current study is to investigate the potential mechanism by which coadministration of probiotic Visbiome® (V) and Met blocks the ethanol-induced intestinal barrier dysfunction/gut leakiness utilizing Caco-2 monolayers, a rat model with chronic ethanol injury, and in silico docking interaction models. In Caco-2 monolayers, exposure to ethanol significantly disrupted tight junction (TJ) localization, elevated monolayer permeability, and oxidative stress compared with controls. However, cotreatment with probiotic V and Met largely ameliorated the ethanol-induced mucosal barrier dysfunction, TJ disruption, and gut oxidative stress compared with ethanol-exposed monolayers and individual treatment of either agent. Rats fed with ethanol-containing Lieber-DeCarli liquid diet showed decreased expression of TJ proteins, and increased intestinal barrier injury resulting in pro-inflammatory response and oxidative stress in the colon. We found that co-administration of probiotic V and Met improved the expression of intestinal TJ proteins (ZO-1 and occludin) and upregulated the anti-inflammatory response, leading to reduced ER stress. Moreover, co-administration of probiotic V and Met inhibited the CYP2E1 and NOX gene expression, and increase the translocation of Nrf-2 as well as anti-oxidative genes (SOD, catalase, Gpx, and HO-1), leading to reduced colonic ROS content and malondialdehyde levels. The combined treatment of probiotic V and Met also improved their binding affinities towards HO-1, Nrf-2, SLC5A8, and GPR109A, which could be attributed to their synergistic effect. Our findings based on in-vitro, in-vivo, and in-silico analyses suggest that the combination of probiotic V and Met potentially acts in synergism, attributable to their property of inhibition of inflammation and oxidative stress against ethanol-induced intestinal barrier injury.

Flavonoid Extract from Seed Residues of Hippophae rhamnoides ssp. sinensis Protects against Alcohol-Induced Intestinal Barrier Dysfunction by Regulating the Nrf2 Pathway

“…Excessive generation of ROS induced lipid peroxidation, thus causing a large amount of MDA formation, which could react with protein and nucleic acid to make it lose its function [ 44 ]. In our results, the MDA production of Caco-2 cell treatment with alcohol was 3.6-fold compared with the control group ( Figure 4 B), which was in accordance with a previous report that alcohol could promote MDA accumulation [ 45 ]. Similar to the effect on ROS production, the MDA content of the HRSF pretreatment group decreased in a dose-dependent manner, reducing to 55.6% in the alcohol alone treatment group at the concentration of 20 μg/mL.…”

Bifidobacterium lactis TY-S01 protects against alcoholic liver injury in mice by regulating intestinal barrier function and gut microbiota

“…As previously reported, alcohol causes impairment of intestinal barrier function, an increase in intestinal permeability, and rapid proliferation of intestinal gram-negative bacteria, resulting in the transfer of endotoxin from the intestines to the liver and blood; thus, activated liver immune cells trigger a series of inflammatory reactions and ultimately cause liver injury [ 34 ]. Impaired intestinal barrier function is closely associated with the loss of TJ proteins, including ZO-1 , occludin , claudin-1 and claudin-3 [ 35 , 36 ].…”

Pediococcus acidilactici pA1c® Improves the Beneficial Effects of Metformin Treatment in Type 2 Diabetes by Controlling Glycaemia and Modulating Intestinal Microbiota

“…Other studies carried out on probiotics and the combination with metformin have been described in the literature, both in murine models [28,99] and in humans [58,100,101] in the context of T2D. In the same line, other studies tested this combination in different clinical contexts, such as ulcerative colitis [55], colorectal cancer [56], non-alcoholic steatohepati-tis [102] and polycystic ovarian syndrome [103].…”