BiomEdit, LLC, 2710 Innovation Way, Greenfield, IN, 46140, USA.
Department of Medicine, LSU Health Sciences Center, New Orleans, LA, 70112, USA.
Sci Rep. 2024 Aug 23;14(1):19584. doi: 10.1038/s41598-024-70549-6.
Intestinal barrier is a first line of defense that prevents entry of various harmful substances from the lumen into the systemic environment. Impaired barrier function with consequent translocation of harmful substances into systemic circulation ("leaky gut") is a central theme in many gastrointestinal, autoimmune, mental, and metabolic diseases. Probiotics have emerged as a promising strategy to maintain intestinal integrity and address "leaky gut". Using in silico, in vitro and avian in vivo analyses, we previously showed that two novel L. reuteri strains, PTA-126787 (L. reuteri 3630) and PTA-126788 (L. reuteri 3632), isolated from broiler chickens possess favorable safety profiles. Consistent with a recent study, here we show that L. reuteri 3630 and 3632 are phylogenetically similar to human L. reuteri strains. Daily administration of high doses of L. reuteri 3630 and 3632 to Sprague Dawley rats for 28 days was found to be safe with no adverse effects. More importantly, administration of L. reuteri 3630 and 3632 significantly reduced markers associated with alcohol-induced leaky gut, by downregulating inflammatory cytokines and upregulating anti-inflammatory cytokines in an alcohol model of leaky gut in mice. While L. reuteri 3630 cells and supernatant showed no activation, L. reuteri 3632 cells but not supernatant showed activation of AhR, a key transcription factor that regulates gut and immune homeostasis. L. reuteri 3630 is creamish white in morphology typical of Lactobacillus species and L. reuteri 3632 displays a unique orange pigmentation, which was stable even after passaging for 480 generations. We identified a rare polyketide biosynthetic gene cluster in L. reuteri 3632 that likely encodes for the orange-pigmented secondary metabolite. Similar to L. reuteri 3632 cells, the purified orange metabolite activated AhR. All together, these data provide evidence on the phylogenetic relatedness, safety, efficacy, and one of the likely mechanisms of action of L. reuteri 3630 and 3632 for potential probiotic applications to address "leaky gut" and associated pathologies in humans.
肠道屏障是防止各种有害物质从腔道进入全身环境的第一道防线。屏障功能受损导致有害物质易位进入全身循环（“肠漏”）是许多胃肠道、自身免疫、精神和代谢疾病的中心主题。益生菌已成为维持肠道完整性和解决“肠漏”的有前途的策略。通过计算机模拟、体外和禽类体内分析，我们之前表明，两种新型的 L. reuteri 菌株 PTA-126787（L. reuteri 3630）和 PTA-126788（L. reuteri 3632），从肉鸡中分离出来，具有良好的安全性。与最近的一项研究一致，在这里我们表明 L. reuteri 3630 和 3632 在系统发育上与人类 L. reuteri 菌株相似。每天给 Sprague Dawley 大鼠高剂量的 L. reuteri 3630 和 3632 进行 28 天的治疗被发现是安全的，没有不良反应。更重要的是，在酒精诱导的肠漏模型中，给予 L. reuteri 3630 和 3632 可显著降低与酒精相关的肠漏的标志物，通过下调炎症细胞因子和上调抗炎细胞因子。虽然 L. reuteri 3630 细胞和上清液没有激活，但 L. reuteri 3632 细胞而不是上清液显示 AhR 激活，AhR 是调节肠道和免疫稳态的关键转录因子。L. reuteri 3630 的形态呈乳白色，典型的乳杆菌属，而 L. reuteri 3632 呈现独特的橙色色素沉着，即使经过 480 代传代后仍保持稳定。我们在 L. reuteri 3632 中鉴定出一个罕见的聚酮生物合成基因簇，该基因簇可能编码橙色色素的次级代谢物。与 L. reuteri 3632 细胞类似，纯化的橙色代谢物激活了 AhR。所有这些数据提供了关于 L. reuteri 3630 和 3632 的系统发育关系、安全性、功效以及其作用机制之一的证据，为益生菌应用于解决人类“肠漏”及其相关病理提供了依据。
