Antonio Jayson M, Liu Yue, Suntornsaratoon Panan, Jones Abigail, Ambat Jayanth, Bala Ajitha, Kanattu Joshua Joby, Flores Juan, Bandyopadhyay Sheila, Upadhyay Ravij, Bhupana Jagannatham Naidu, Su Xiaoyang, Li Wei Vivian, Gao Nan, Ferraris Ronaldo P
Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, United States.
Department of Biological Sciences, Rutgers University, Newark, New Jersey, United States.
Am J Physiol Gastrointest Liver Physiol. 2025 Jul 1;329(1):G162-G185. doi: 10.1152/ajpgi.00366.2024. Epub 2025 May 26.
Inflammatory bowel diseases (IBDs) and gut barrier impairment are associated with changes in dietary tryptophan and arginine metabolism, but mechanisms of barrier perturbation and restoration are unclear. We show here that the widely consumed probiotic GG (LGG) enhances gut barrier functions in part through stimulating the intestinal arginine metabolic pathway, and this mechanism depends on the sufficiency of dietary tryptophan in the host. Specifically, LGG markedly upregulates argininosuccinate lyase (ASL), the enzyme that breaks down argininosuccinate into arginine. ASL expression is markedly reduced during experimental colitis with an accumulation of serum argininosuccinate. LGG colonization in mice reduces serum argininosuccinate, a metabolite that inversely correlates with tight junction gene expression, impairs barrier function, and exacerbates dextran sodium sulfate colitis. We show that LGG-derived indoles as well as arginine metabolites enhanced argininosuccinate lyase (ASL) and nitric oxide synthase (NOS2) expression, linking microbial metabolism to nitric oxide production and epithelial homeostasis. Patients with IBD have increased ASS1 and decreased ASL expression, suggesting a metabolic bottleneck driving ASA accumulation. We propose that signaling pathways underlying LGG and tryptophan-mediated ASL upregulation can be useful therapeutic targets to normalize arginine metabolism in select patients with IBD. This study identifies a novel probiotic-driven mechanism linking dietary tryptophan and host arginine metabolism. GG, in synergy with tryptophan, enhances gut barrier integrity by upregulating argininosuccinate lyase (ASL), a critical enzyme in arginine biosynthesis. Furthermore, we uncover ASL downregulation and serum argininosuccinate elevation in experimental colitis in mice, suggesting a target to guide precision probiotics.
炎症性肠病（IBD）与肠道屏障功能受损与饮食中色氨酸和精氨酸代谢的变化有关，但屏障扰动和恢复的机制尚不清楚。我们在此表明，广泛食用的益生菌GG（LGG）部分通过刺激肠道精氨酸代谢途径来增强肠道屏障功能，而这一机制取决于宿主饮食中色氨酸的充足程度。具体而言，LGG显著上调精氨琥珀酸裂解酶（ASL），该酶可将精氨琥珀酸分解为精氨酸。在实验性结肠炎期间，ASL表达显著降低，同时血清精氨琥珀酸积累。小鼠中LGG定殖可降低血清精氨琥珀酸水平，这种代谢物与紧密连接基因表达呈负相关，损害屏障功能，并加重葡聚糖硫酸钠诱导的结肠炎。我们表明，LGG衍生的吲哚以及精氨酸代谢物可增强精氨琥珀酸裂解酶（ASL）和一氧化氮合酶（NOS2）的表达，将微生物代谢与一氧化氮产生及上皮细胞稳态联系起来。IBD患者的ASS1增加而ASL表达降低，提示存在驱动精氨琥珀酸积累的代谢瓶颈。我们提出，LGG和色氨酸介导的ASL上调所涉及的信号通路可能是使特定IBD患者精氨酸代谢正常化的有用治疗靶点。本研究确定了一种将饮食色氨酸与宿主精氨酸代谢联系起来的新型益生菌驱动机制。LGG与色氨酸协同作用，通过上调精氨琥珀酸裂解酶（ASL）（精氨酸生物合成中的关键酶）来增强肠道屏障完整性。此外，我们发现小鼠实验性结肠炎中ASL下调和血清精氨琥珀酸升高，提示这是指导精准益生菌治疗的一个靶点。
