I-Corps: Development of a gut bacterial strain to stimulate mucus-secreting cells of the colon to treat leaky-gut

I-Corps项目更广泛的影响/商业潜力是解决肠道渗漏和改善微生物群。漏肠，或肠道通透性增加，是一种不健康的肠道粘膜，可能会导致部分消化的食物、毒素和微生物被释放出来。这可能会引发炎症，改变正常的肠道菌群，从而导致消化道出现问题。目前，市场上还没有产品有临床证据表明能够解决肠道渗漏问题。这项提议的技术可以缓解肠道渗漏及其相关的炎症，并改善宿主的微生物群。所提出的技术通过使肠道成为更适合益生菌生存的地方，从而增加了有益细菌的存在，因此不会降低微生物组的多样性。这个I-Corps项目是基于一种被称为副干酪乳杆菌D3.5的菌株的开发，这种菌株是通过筛选数百种人类分离的细菌菌株来治疗肠道渗漏而发现的。选择这种菌株是因为它具有刺激结肠粘液分泌细胞的独特能力，这种细胞被称为杯状细胞。由于产生这些效果的细菌成分在加热杀死细菌后变得更具生物可利用性，因此称为后生物LPD3.5的热处理版本被用于随后的临床前研究。在这项研究中，发现该制剂可以恢复衰老小鼠结肠粘膜层的厚度，从而导致肠道上皮细胞之间连接的紧密性恢复。这两种作用都可以防止细菌和毒素通过消化道渗漏到血液中，并缓解相关的炎症，这种情况被称为肠漏。此外，生物后LPD3.5还被证明可以增强宿主的细菌群落，减少焦虑，改善胰岛素敏感性，肌肉功能和记忆。为了测试LPD3.5是否能够刺激人体内粘液的产生，我们对人杯状细胞进行了体外处理。在人类杯状细胞中观察到的效果与在小鼠杯状细胞中观察到的效果相同。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this I-Corps project is to address leaky gut and improve the microbiome. Leaky gut, or increased intestinal permeability, is an unhealthy gut lining that may allow partially digested food, toxins, and microbes to be released. This may trigger inflammation and changes in the normal gut flora that could lead to problems within the digestive tract. Currently, there are no products on the market with clinical evidence of ability to address leaky gut. The proposed technology may relieve leaky gut and its associated inflammation, as well as improve the host’s microbiome. The proposed technology increases the presence of beneficial bacteria indiscriminately by making the gut a more suitable place for probiotics to live and thus does not decrease microbiome diversity. This I-Corps project is based on the development of a bacterial strain called Lactobacillus paracasei D3.5 that was discovered by screening hundreds of human-isolated bacterial strains to treat leaky gut. The bacterial strain was selected for its unique ability to stimulate mucus-secreting cells of the colon called goblet cells. Because the components of the bacteria responsible for these effects become more bioavailable after killing the bacteria with heat, the heat-treated version called Postbiotic LPD3.5 was used for a subsequent preclinical study. In this study, the preparation was found to restore the thickness of the colonic mucosal layer in aging mice, which then led to the recovery in tightness of the connections between epithelial cells lining the gut. Both of these effects prevented bacteria and toxins from leaking through the digestive tract into the blood stream, and relieved the associated inflammation, a condition referred to as leaky gut. Moreover, Postbiotic LPD3.5 also was shown to strengthen the host’s bacterial community, decrease anxiety, and improve insulin sensitivity, muscle function, and memory. In order to test whether Postbiotic LPD3.5 is able to stimulate the mucus production in humans, human goblet cells were treated in vitro. The effects seen in human goblet cells were the same as those observed in goblet cells of mice.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.