Birabaharan Morgan, Kaelber David C, Nizet Victor, Zarrinpar Amir
Division of Infectious Diseases and Global Public Health, University of California, San Diego, La Jolla, California, USA.
Departments of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
medRxiv. 2024 Dec 15:2024.09.24.24313682. doi: 10.1101/2024.09.24.24313682.
The ongoing antimicrobial resistant crisis heralds the need for new therapeutics against enteric infection. In mouse models, colon epithelial peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling limits oxygen and nitrate luminal bioavailability, thereby preventing bacterial pathogen colonization. However, whether this mechanism operates similarly in humans remains uncertain.
To investigate, we used the cloud-based TriNetX Analytics Platform which aggregates health records from 117 million patients across 66 US healthcare organizations, to assess the risk of bacterial enteric infection among diabetic patients prescribed thiazolidinediones, a class of PPAR-γ agonists, to other anti-diabetes medications.
Among 85,117 thiazolidinedione users, we observed a 22-49% lower risk of bacterial enteric infections compared to users of other anti-diabetes medications. This reduction in risk was consistent across high-risk individuals, regardless of sex or age. Similar results were replicated in high-risk patients when thiazolidinedione users were directly compared to those on DPP-4 inhibitors.
These findings support the potential protective role of PPAR-γ signaling against bacterial enteric infection and call for further clinical investigation.
持续的抗菌药物耐药危机预示着需要针对肠道感染开发新的治疗方法。在小鼠模型中，结肠上皮过氧化物酶体增殖物激活受体γ（PPAR-γ）信号传导限制了氧气和硝酸盐在管腔中的生物利用度，从而防止细菌病原体定植。然而，这种机制在人类中是否同样起作用仍不确定。
为了进行研究，我们使用了基于云的TriNetX分析平台，该平台汇总了美国66个医疗保健机构中1.17亿患者的健康记录，以评估开具噻唑烷二酮类药物（一类PPAR-γ激动剂）的糖尿病患者与使用其他抗糖尿病药物的患者相比发生细菌性肠道感染的风险。
在85117名噻唑烷二酮类药物使用者中，我们观察到与使用其他抗糖尿病药物的患者相比，细菌性肠道感染风险降低了22%-49%。在高危个体中，无论性别或年龄，这种风险降低都是一致的。当将噻唑烷二酮类药物使用者与使用二肽基肽酶-4（DPP-4）抑制剂的患者直接比较时，高危患者也得到了类似的结果。
这些发现支持了PPAR-γ信号传导对细菌性肠道感染的潜在保护作用，并呼吁进行进一步的临床研究。
