The role of acetogenic, methanogenic, and sulfate-reducing bacteria in oxalate metabolism and hyperoxaluria

项目摘要/摘要 在美国，尿路结石病的发病率正在迅速增加，影响到8.8%的 人口从1968年的2.6%上升到2010年的2.6%，有一半的患者表现出反复发作。草酸钙 结石约占UU病例的80%，草酸代谢完全由肠道提供 细菌。关于美国发病率增加的典型假设是，单一的草酸降解物种， 草酸杆菌，足以减少尿草酸排泄，足以防止草酸钙 结石形成，由于口服抗生素使用而丢失。然而，在一系列改变范式的研究中，我们有 发现1)产甲氧菌既不必要也不足以减少尿草酸排泄或预防 2)无论口服抗生素对产甲氧西林杆菌有何影响，都会增加其发病风险；3)功能上 多种草酸降解微生物网络(ODMN)负责草酸代谢，而不是单一的 4)ODMN可防止外源草酸对寄主和微生物群的毒害作用；5) 在两种动物模型和美国临床队列中，ODMN与口服抗生素呈负相关 病人。鉴于这些新的数据，进一步了解ODMN如何维持内环境平衡是至关重要的 与草酸盐相关的环境，有助于预防美元兑美元。当前提案的目标是 是建立宿主-微生物机制，通过这些机制，ODMN促进持久的草酸代谢 体内预防肠源性高草酸尿。草酸盐可以刺激或抑制肠道微生物多样性，具体取决于 在基线组成上。我们的初步工作表明，当实验室啮齿动物的ODMN减少时 均暴露于外源性草酸后，尿草酸排泄量随时间逐渐增加，有一种损失 微生物多样性和肠道通透性增加的迹象是明显的。这些效应在动物身上是相反的。 拥有强大的ODMN。草酸代谢的副产物是甲酸盐和二氧化碳。甲酸盐已知有毒性 对人类和细菌都有影响。然而，产乙酸菌、产甲烷菌和硫酸盐还原细菌 可以利用甲酸盐和二氧化碳作为碳和能源的(AM)一直存在于ODMN中。 因此，我们认为降解草酸的细菌和AMS细菌表现出协同作用的代谢相互作用。 促进宿主肠道上皮的持续定植，减少炎症，从而减少草酸 吸收。为了验证这一假设，我们将研究微生物-微生物和宿主-微生物的机制 调节肠道高草酸尿的相互作用，决定了AMS细菌在预防高草酸尿中的作用， 并在一组临床队列患者中调查导致ODMN功能丧失的机制。

PROJECT SUMMARY/ABSTRACT In the United States, the incidence of urinary stone disease (USD) is rapidly increasing, affecting 8.8% of the population in 2010, up from 2.6% in 1968, with half of patients exhibiting recurrent episodes. Calcium oxalate stones comprise approximately 80% of USD cases and oxalate metabolism is provided exclusively by gut bacteria. The canonical hypothesis for the increase in USD incidence is that a single oxalate-degrading species, Oxalobacter formigenes, is sufficient to reduce urinary oxalate excretion enough to prevent calcium oxalate stone formation and is lost due to oral antibiotic use. However, in a paradigm-shifting series of studies, we have found that 1) O. formigenes is neither necessary nor sufficient to reduce urinary oxalate excretion or prevent USD; 2) Oral antibiotics increase the risk of USD regardless of their effect on O. formigenes; 3) A functionally diverse oxalate-degrading microbial network (ODMN) is responsible for oxalate metabolism rather than a single species; 4) The ODMN prevents the toxic effects of exogenous oxalate on the host and the microbiome; and 5) The ODMN is negatively associated with oral antibiotics in both animal models and in a clinical cohort of USD patients. Given these new data, it is critical to further understand how the ODMN maintains a homeostatic environment relative to oxalate and contributes to the prevention of USD. The objective of the current proposal is to establish the host-microbe mechanisms through which the ODMN facilitates persistent oxalate metabolism in vivo to prevent enteric hyperoxaluria. Oxalate can either stimulate or inhibit gut microbial diversity depending on the baseline composition. Our preliminary work shows that when laboratory rodents with a reduced ODMN are exposed to exogenous oxalate, urinary oxalate excretion gradually increases over time, there is a loss of microbial diversity, and signs increased gut permeability are apparent. These effects are reversed in animals with a robust ODMN. The by-products of oxalate metabolism are formate and CO2. Formate has known toxic effects for both humans and bacteria. However, acetogenic, methanogenic, and sulfate-reducing bacteria (AMS), which can use formate and CO2 as carbon and energy sources, are consistently present in the ODMN. Thus, we propose oxalate-degrading and AMS bacteria exhibit metabolic interactions that synergistically promote persistent colonization and reduce inflammation of host intestinal epithelium, thereby reducing oxalate absorption. To test this hypothesis, we will Investigate the mechanistic microbe-microbe and host-microbe interactions that modulate enteric hyperoxaluria, determine the role of AMS bacteria in preventing hyperoxaluria, and investigate the mechanisms that drive the loss of ODMN function in a clinical cohort of patients.