Changes in intestinal microbiome and barrier function are critical in the development of alcohol-related liver disease (ALD). Here, we determined the effects of a one-week alcohol withdrawal on parameters of intestinal barrier function in heavy drinkers with ALD in comparison to healthy non-drinkers (controls). In serum samples of 17 controls (m = 10/f = 7) and 37 age-matched ALD patients (m = 26/f = 11) undergoing a one-week alcohol withdrawal, markers of liver health and intestinal barrier function were assessed. Liver damage, e.g., fibrosis and hepatic steatosis, were assessed using FibroScan. Before alcohol withdrawal, markers of liver damage, lipopolysaccharide binding protein (LBP) and overall TLR4/TLR2 ligands in serum were significantly higher in ALD patients than in controls, whereas intestinal fatty acid binding protein (I-FABP) and zonulin protein concentrations in serum were lower. All parameters, with the exception of LBP, were significantly improved after alcohol withdrawal; however, not to the level of controls. Our data suggest that one-week of abstinence improves markers of intestinal barrier function and liver health in ALD patients.

Emerging evidence implicate the ‘microbiota–gut–brain axis’ in cognitive aging and neuroinflammation; however, underlying mechanisms still remain to be elucidated. Here, we assessed if potential alterations in intestinal barrier function and microbiota composition as well as levels of two key pattern-recognition receptors namely Toll-like receptor (TLR) 2 and TLR4, in blood and different brain regions, and depending signaling cascades are paralleling aging associated alterations of cognition in healthy aging mice. Cognitive function was assessed in the Y-maze and intestinal and brain tissue and blood were collected in young (4 months old) and old (24 months old) male C57BL/6 mice to determine intestinal microbiota composition by Illumina amplicon sequencing, the concentration of TLR2 and TLR4 ligands in plasma and brain tissue as well as to determine markers of intestinal barrier function, senescence and TLR2 and TLR4 signaling. Cognitive function was significantly impaired in old mice. Also, in old mice, intestinal microbiota composition was significantly altered, while the relative abundance of Gram-negative or Gram-positive bacteria in the small and large intestines at different ages was not altered. Moreover, intestinal barrier function was impaired in small intestine of old mice, and the levels of TLR2 and TLR4 ligands were also significantly higher in both portal and peripheral blood. Furthermore, levels of TLR2 and TLR4 ligands, and downstream markers of TLR signaling were higher in the hippocampal and prefrontal cortex of old mice compared to young animals. Taken together, our results suggest that even in ‘healthy’ aging, cognitive function is impaired in mice going along with an increased intestinal translocation of TLR ligands and alterations of TLR signaling in several brain regions.

Infections with Gram-negative bacteria are still among the leading causes of infection-related deaths. Several studies suggest that the chalcone xanthohumol (XN) found in hop (Humulus lupulus) possesses anti-inflammatory effects. In a single-blinded, placebo controlled randomized cross-over design study we assessed if the oral intake of a single low dose of 0.125 mg of a XN derived through a XN-rich hop extract (75% XN) affects lipopolysaccharide (LPS)-induced immune responses in peripheral blood mononuclear cells (PBMCs) ex vivo in normal weight healthy women (n = 9) (clinicaltrials.gov: NCT04847193) and determined associated molecular mechanisms. LPS-stimulation of PBMCs isolated from participants 1 h after the intake of the placebo for 2 h resulted in a significant induction of pro-inflammatory cytokine release which was significantly attenuated when participants had consumed XN. The XN-dependent attenuation of proinflammatory cytokine release was less pronounced 6 h after the LPS stimulation while the release of sCD14 was significantly reduced at this timepoint. The LPS-dependent activation of hTLR4 transfected HEK293 cells was significantly and dose-dependently suppressed by the XN-rich hop extract which was attenuated when cells were co-challenged with sCD14. Taken together, our results suggest even a one-time intake of low doses of XN consumed in a XN-rich hop extract can suppress LPS-dependent stimulation of PBMCs and that this is related to the interaction of the hop compound with the CD14/TLR4 signaling cascade.

Sugar-rich diets, but also the use of intense sweeteners, may alter intestinal barrier function. Here, we assessed the effect of sucrose and sucralose on post-prandial endotoxemia in a randomized placebo-controlled single-blinded crossover-designed study. Following a 2-day standardization of their diet, healthy men and women received a beverage containing either sucrose, sucralose (iso-sweet) or an isocaloric combination of sucralose + maltodextrin. Plasma endotoxin levels were measured after consumption of the respective beverages. Moreover, the effect of sucrose and sucralose on intestinal permeability was assessed in Caco-2 cells and ex vivo in an everted gut sac model. The nutritional standardization recommended by nutrition societies was associated with a significant decrease in plasma endotoxin levels. The intake of the sucrose-sweetened beverage resulted in a significant increase in plasma endotoxin levels while being unchanged after the intake of sucralose-sweetened beverages. In Caco-2 cells, the challenge with sucrose but not with sucralose significantly increased the permeation of the bacterial endotoxin across the cell monolayer. Xylose permeation in small intestinal everted tissue sacs was significantly higher upon the challenge with sucrose while remaining unchanged in sucralose-challenged sacs. Our data suggest that an acute intake of physiologically relevant amounts of sucrose but not of sucralose can result in post-prandial endotoxemia.

Background: Exercise and the consumption of sugars result in a dysfunction of the intestinal barrier (IB). Here, we determined the effect of sugar in a natural matrix on the intestinal barrier after moderate (A) and intensive endurance exercise (B). Method: The IB function was determined before (pre) and after running (post), and 120 and 180 min after consuming the drink by measuring serum endotoxin concentrations (lipopolysaccharides—LPS), IL-6, CD14, and i-FABP. In study A, nonspecifically trained participants (n = 24, males and females, age 26 ± 4) ran for one hour at 80% of their individual anaerobic threshold (IAT). After finishing, the runners consumed, in a crossover setup, either 500 mL of water, diluted cloudy apple juice (test drink), or an identical drink (placebo) without the fruit juice matrix (FJM). In study B, the participants (n = 30, males and females, age 50 ± 9) completed an ultra-marathon run, were divided into groups, and consumed one of the above-mentioned drinks. Results: Study A: Exercise resulted in a significant increase in serum LPS, i-FABP, and IL-6, which decreased fast after finishing. No impact of the different drinks on LPS i-FABP, or IL-6 could be observed, but there was an impact on CD14. Study B: The ultra-marathon resulted in a strong increase in serum LPS, which decreased fast after finishing in the water and test drink groups, but not in the placebo group. Conclusions: The consumed drinks did not affect the kinetics of IB regeneration after moderate exercise, but impacted CD14 serum concentrations, indicating possible beneficial effects of the FJM on the immune system. After an ultra-marathon, IB function regenerates very fast. The intake of sugar (placebo) seems to have had a negative impact on IB regeneration, which was diminished by the presence of the FJM.

L-Citrulline (L-Cit) is discussed to possess a protective effect on intestinal barrier dysfunction but also to diminish aging-associated degenerative processes. Here, the effects of L-Cit on lifespan were assessed in C. elegans, while the effects of L-Cit on aging-associated decline were determined in C57BL/6J mice. For lifespan analysis, C. elegans were treated with ±5 mM L-Cit. Twelve-month-old male C57BL/6J mice (n = 8–10/group) fed a standard chow diet received drinking water ± 2.5 g/kg/d L-Cit or 5 g/kg/d hydrolyzed soy protein (Iso-N-control) for 16 or 32 weeks. Additionally, 4-month-old C57BL/6J mice were treated accordingly for 8 weeks. Markers of senescence, glucose tolerance, intestinal barrier function, and intestinal microbiota composition were analyzed in mice. L-Cit treatment significantly extended the lifespan of C. elegans. The significant increase in markers of senescence and signs of impaired glucose tolerance found in 16- and 20-month-old control mice was attenuated in L-Cit-fed mice, which was associated with protection from intestinal barrier dysfunction and a decrease in NO₂⁻ levels in the small intestine, while no marked differences in intestinal microbiota composition were found when comparing age-matched groups. Our results suggest that pharmacological doses of L-Cit may have beneficial effects on lifespan in C. elegans and aging-associated decline in mice.