Leaky gut — a trendy diagnosis or the source of many diseases?

Aim of the study: Probiotics play a vital role in treating immune and inflammatory diseases by improving intestinal barrier function; however, a comprehensive evaluation is missing. The present study aimed to explore the impact of probiotics on the intestinal barrier and related immune function, inflammation, and microbiota composition. A systematic review and meta-analyses were conducted.

Results: Meta-analysis of data from a total of 26 RCTs (n = 1891) indicated that probiotics significantly improved gut barrier function measured by levels of TER (MD, 5.27, 95% CI, 3.82 to 6.72, P < 0.00001), serum zonulin (SMD, -1.58, 95% CI, -2.49 to -0.66, P = 0.0007), endotoxin (SMD, -3.20, 95% CI, -5.41 to -0.98, P = 0.005), and LPS (SMD, -0.47, 95% CI, -0.85 to -0.09, P = 0.02). Furthermore, probiotic groups demonstrated better efficacy over control groups in reducing inflammatory factors, including CRP, TNF-α, and IL-6. Probiotics can also modulate the gut microbiota structure by boosting the enrichment of Bifidobacterium and Lactobacillus. The present work revealed that probiotics could improve intestinal barrier function, and alleviate inflammation and microbial dysbiosis. Further high-quality RCTs are warranted to achieve a more definitive conclusion.

Aim of the study: Given the magnitude and variety of chronic metabolic disease linked to increased intestinal permeability, appropriate strategies to reinforce gut barrier function are urgently needed.

Results: The analysis on 24 trials (28 ES, n = 1603) revealed a significant reduction in lipopolysaccharide levels following pro- and synbiotics consumption with high heterogeneity and very low certainty of evidence (SMD (95 %CI) = -0.54 (-1.01, -0.07); I2 (%) = 94.4). Synthesis of 13 trials showed zonulin levels were significantly lowered after pro- and synbiotics consumption with high heterogeneity and moderate certainty of evidence (15 ES, n=778) (SMD (95 %CI) = -0.49 (-0.79, -0.18); I2 (%) = 74.9). Following prebiotics supplementation, a significant reduction in lipopolysaccharide levels was observed, with high heterogeneity identified from data including 16 RCTs (n = 792; SMD (95 %CI) = -0.88 (-1.28, -0.47); P < 0.001; high certainty of evidence; I2 (%) = 85.7; P-heterogeneity< 0.001). This meta-analysis revealed promising findings regarding the efficacy of pro- and synbiotic and prebiotic supplements in alleviating "leaky gut".

Aim of the study: Only 20%-30% of individuals with alcohol use disorder (AUD) develop alcoholic liver disease (ALD). While the development of gut-derived endotoxemia is understood to be a required cofactor, increased intestinal permeability in ALD is not completely understood.

Results: Five-hour urinary lactulose/mannitol ratio (primarily representing small intestinal permeability) was not statistically different in HC, ALC, ALD, and MASLD groups ( P = 0.40). Twenty-four-hour urinary sucralose (representing whole gut permeability) was increased in ALD ( F = 5.3, P < 0.01) and distinguished ALD from ALC; 24-hour sucralose/lactulose ratio (primarily representing colon permeability) separated the ALD group ( F = 10.2, P < 0.01) from the MASLD group. After aspirin challenge, intestinal permeability increased in all groups and ALD had the largest increase.

Aim of the study: Intestinal epithelial expression of the tight junction protein claudin-2, which forms paracellular cation and water channels, is precisely regulated during development and in disease. Here, we show that small intestinal epithelial claudin-2 expression is selectively upregulated in septic patients.

Results: Most strikingly, claudin-2 deletion dramatically enhanced survival in sepsis. Finally, the microbial changes induced by sepsis were less pathogenic in claudin-2 KO mice as survival of healthy WT mice injected with cecal slurry collected from WT mice 24 h after sepsis was far worse than that of healthy WT mice injected with cecal slurry collected from claudin-2 KO mice 24 h after sepsis. Claudin-2 upregulation and increased pore pathway permeability are, therefore, key intermediates that contribute to development of dysbiosis, intestinal damage, inflammation, ineffective pathogen control, and increased mortality in sepsis. The striking impact of claudin-2 deletion on progression of the lethal cascade activated during sepsis suggests that claudin-2 may be an attractive therapeutic target in septic patients.

Aim of the study: Increased intestinal permeability exacerbates the development of metabolic dysfunction-associated steatohepatitis (MASH), but the underlying mechanisms remain unclear. Autophagy is important for maintaining normal intestinal permeability. Here, we investigated the impact of intestinal transcription factor EB (TFEB), a key regulator of autophagy, on intestinal permeability and MASH progression.

Results: TFEB expression was analyzed in the proximal colon of 45 individuals with metabolic dysfunction-associated steatotic liver disease and 23 healthy controls. We used immunoprecipitation-mass spectrometry to identify TFEB-interacting proteins. Intestine-specific Tfeb knockout mice were generated by mating Tfebfl/fl mice with Villin- Cre mice. The mice were fed a high-fat, high-sucrose diet, and assessments were performed to evaluate intestinal permeability and MASH progression. Intestinal TFEB levels were reduced in patients with MASH and negatively correlated with intestinal permeability and hepatic toxicity. Intestine-specific TFEB deficiency increased intestinal permeability and worsened MASH severity, whereas moderate TFEB overexpression conferred protective effects. Mechanistically, the E3 ligase TRIP12 promotes the ubiquitination and degradation of nuclear TFEB, thereby inhibiting autophagic flux to aggravate intestinal barrier impairment and subsequently promote MASH progression.

Aim of the study: Intestinal barrier dysfunction drives complications in advanced chronic liver disease (ACLD). Confocal laser endomicroscopy (CLE) enables direct visualization of transepithelial fluorescein leakage during endoscopy. This study evaluated the link between CLE-assessed intestinal permeability and disease severity in ACLD.

Results: Transepithelial fluorescein permeation into the gut lumen was absent in healthy controls but frequent in ACLD, and increased with disease severity (Vienna cohort: compensated vs. first decompensation vs. further decompensation: 24%, 57%, and 71%, p=0.019). The 3-line and 3-compartment methods robustly distinguished healthy controls from cirrhosis (3-line apex/base ratio: 0.42 ±0.12 vs. ACLD 0.83 ±0.18, p=0.001), and exhibited lowest inter-observer variability. In both cohorts, quantitative permeability measures - especially epithelial 3-line apex/base ratio and 3-line-slopes (all p<0.05) - increased across Child-Turcotte-Pugh stages, and correlated with HVPG (apex/base-ratio: r=0.575, p<0.001) and liver function parameters (e.g. albumin: r= -0.553, p<0.001). CLE-based barrier dysfunction was linked to higher LRE incidence during follow-up (Cox regression; apex/base ratio: HR 10.6, 95% CI 1.71-66.0, p=0.011).

Aim of the study: Primary infection by Epstein-Barr virus (EBV) often causes infectious mononucleosis (IM), which is frequently accompanied by acute hepatitis despite the absence of direct EBV infection of hepatocytes. Our previous studies using murine γ-herpesvirus 68 (MHV68), a murine model of EBV, demonstrated that intestinal bacteria contribute to hepatitis induced by MHV68 airway infection, although the underlying mechanism remains unclear.

Results: To gain insight into a possible mechanism underlying intestinal barrier dysfunction, we also evaluated circulating cytokine responses during MHV68 infection. Collectively, we found intestinal barrier dysfunction upon MHV68 airway infection, possibly through systemic cytokine responses and resulting in transient intestinal bacterial translocation to the liver. This process likely contributes to MHV68-induced hepatitis and further supports that targeting intestinal bacteria represents a potential therapeutic strategy for IM-associated hepatitis. (250/250 words).