Probiotics and Gut Health: Unlocking the Mystery of How Lacticaseibacillus rhamnosus Heals the Gut Barrier

Inflammatory Bowel Diseases (IBDs), such as Crohn’s disease and ulcerative colitis, affect millions worldwide, often characterized by a compromised intestinal barrier. This barrier, crucial for nutrient absorption and protection against toxins, becomes more permeable in IBD, sometimes years before clinical symptoms appear. While probiotics, particularly Lacticaseibacillus rhamnosus GG (LGG), have shown promise in improving symptoms and enhancing gut barrier function, the exact mechanisms behind their benefits have remained unclear.

            A new Rutgers study from the Gao and Ferraris Labs sheds light on these mechanisms, revealing a novel interaction between LGG, dietary tryptophan, and host arginine metabolism that significantly enhances gut barrier protection.

         The research highlights that LGG boosts gut barrier functions partly by stimulating the intestinal arginine metabolic pathway. Arginine is vital for gut homeostasis, serving as a precursor for crucial molecules like nitric oxide (NO), polyamines, and urea, all essential for immune modulation and epithelial integrity. In IBD, arginine metabolism is often dysregulated, with elevated serum dimethylarginines linked to barrier impairment.

            Their core discovery centers on argininosuccinate lyase (ASL), an enzyme that converts argininosuccinate into arginine. The study found that LGG markedly upregulates ASL. Conversely, ASL expression is significantly reduced during experimental colitis, leading to an accumulation of serum argininosuccinate (ASA).

         Their findings show that high levels of serum ASA inversely correlate with tight junction gene expression, impair barrier function, and worsen colitis. Tight junctions are critical protein structures that seal epithelial cells together, forming the gut barrier. The study revealed that ASA treatment in isolated intestinal organoids significantly increased permeability and reduced levels of occludin, a key tight junction protein. Furthermore, in mice, supplemental ASA exacerbated mucosal damage and delayed recovery from chemically induced colitis, coinciding with reduced occludin levels.

            In human IBD patients, there's an observed increase in argininosuccinate synthase 1 (ASS1) and a decrease in ASL expression, suggesting a metabolic bottleneck that drives ASA accumulation. This means that while the body might be making the precursor (ASA), it struggles to convert it into beneficial arginine due to reduced ASL activity. Importantly, ASL expression positively correlates with tight junction gene expression in IBD patients, underscoring its role in maintaining barrier integrity.

         So, how does LGG intervene in this complex process?

• LGG colonization in mice significantly increased intestinal and colonic expression of ASL, thereby reducing serum ASA levels. This direct effect of LGG on ASL helps normalize arginine metabolism.

• LGG also enhanced the expression of nitric oxide synthase (NOS2), linking microbial metabolism to nitric oxide production and epithelial homeostasis. In epithelial cells, NO plays a protective role by enhancing barrier function.

• Sufficient dietary tryptophan in the host produces LGG-derived indoles (tryptophan metabolites), such as indole-3-acetamide and indole-3-lactic acid, as well as arginine metabolites, were found to enhance both ASL and NOS2 expression. These indoles are known to strengthen the intestinal barrier and are often depleted in colitis.

• In experimental models of colitis, LGG supplementation significantly dampened weight loss, improved histological colitis scores, and restored the expression of key epithelial junction proteins like occludin and E-cadherin in both the ileum and colon. It also reduced inflammatory markers like interleukin-6.

         This study suggests that LGG's benefits stem from its ability to remodel host arginine metabolism, particularly by upregulating ASL and NOS2, which leads to reduced ASA accumulation and increased NO production, ultimately strengthening the gut barrier. The findings propose that targeting the signaling pathways underlying LGG and tryptophan-mediated ASL upregulation could be a useful therapeutic strategy to normalize arginine metabolism in select IBD patients.

            By uncovering these intricate host-microbe interactions, this research paves the way for more precise probiotic strategies and targeted therapies to restore intestinal homeostasis and mitigate the effects of inflammatory bowel diseases.

Antonio JM, Liu Y, Suntornsaratoon P, Jones A, Ambat J, Bala A, Kanattu JJ, Flores J, Bandyopadhyay S, Upadhyay R, Bhupana JN, Su X, Li WV, Gao N, Ferraris RP. Lacticaseibacillus rhamnosus GG-driven remodeling of arginine metabolism mitigates gut barrier dysfunction. Am J Physiol Gastrointest Liver Physiol. 2025 Jul 1;329(1):G162-G185. doi: 10.1152/ajpgi.00366.2024. Epub 2025 May 26. PMID: 40418622; PMCID: PMC12282327.

https://journals.physiology.org/doi/full/10.1152/ajpgi.00366.2024