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

项目概要/摘要 在美国，泌尿系结石病（USD）的发病率正在迅速增加，影响8.8%的 在2010年的人口中，有一半的患者表现出复发性发作，从1968年的2.6%上升。草酸钙 结石约占USD病例的80%，草酸盐代谢完全由肠道提供 细菌USD发病率增加的典型假设是，单一的降解琥珀酸盐的物种， 草酸钙，足以减少尿草酸排泄，足以防止草酸钙 结石形成，并由于口服抗生素的使用而丢失。然而，在一系列范式转变的研究中，我们发现， 发现1）O.产甲酸杆菌既不必要也不足以减少尿草酸排泄或预防 2）口服抗生素可增加USD的风险，无论其对O.产甲酸菌; 3）功能上 不同的草酸盐降解微生物网络（ODMN）负责草酸盐代谢，而不是单一的 4）ODMN防止外源草酸盐对宿主和微生物组的毒性作用;以及5） 在两种动物模型和USD临床队列中，ODMN与口服抗生素呈负相关 患者鉴于这些新的数据，进一步了解ODMN如何维持体内平衡至关重要。 与草酸盐相关的环境，有助于预防USD。本提案的目标 是建立宿主微生物机制，通过该机制ODMN促进持久的草酸盐代谢 在体内预防肠高尿症。草酸盐可以刺激或抑制肠道微生物多样性， 在基线成分上。我们的初步工作表明，当实验室啮齿动物与减少ODMN， 暴露于外源性草酸，尿草酸排泄量随着时间的推移逐渐增加， 微生物多样性，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 强大的ODMN草酸盐代谢的副产物是甲酸盐和CO2。甲酸盐已知有毒 对人类和细菌的影响。然而，产乙酸、产甲烷和硫酸盐还原细菌 (AMS)可以使用甲酸盐和CO2作为碳源和能源，始终存在于ODMN中。 因此，我们提出，降解琥珀酸盐和AMS细菌表现出协同的代谢相互作用， 促进宿主肠上皮细胞的持续定植并减少炎症，从而减少草酸盐 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 调节肠道高尿酸的相互作用，确定AMS细菌在预防高尿酸中的作用， 并研究在临床患者队列中导致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.