Terkeltaub Robert, Dodd Dylan
University of California San Diego, La Jolla, California.
Stanford University, Stanford, California.
Arthritis Rheumatol. 2025 Jan 19. doi: 10.1002/art.43118.
Humans develop hyperuricemia via decreased urate elimination and excess urate production, consequently promoting monosodium urate crystal deposition and incident gout. Normally, approximately two-thirds of urate elimination is renal. However, chronic kidney disease (CKD) and other causes of decreased renal urate elimination drive hyperuricemia in most with gout. This places more demand on elimination of urate via the gut, where diet, purine metabolism, and microbiota intersect. Heritable impairment of urate transport into the gut is common and promotes hyperuricemia, renal urate overload, and early-onset and palpable tophaceous gout phenotypes. Lactobacilli, by sequestering and modifying ambient purines, are being studied for the potential to suppress diet-induced urate generation and associated gout flares. Landmark preclinical studies recently revealed much higher-capacity urate-lowering effects of diverse, obligate, and facultative anaerobic human and mouse gut microbiota (predominantly of the Bacillota phylum) termed purine-degrading bacteria (PDB). A conserved gene cluster in PDB drives urate conversion to lactate or anti-inflammatory short-chain fatty acids. When mice are rendered deficient in hepatic uricase to mimic human uricase absence, microbiota depletion rapidly elevates both cecal and serum urate, which is reversible by PDB administration. In healthy human volunteers with normal renal function, antibiotic-induced gut microbiota depletion decreases the urate-lowering gene cluster unique to PDB and elevates fecal urate. Also, prior exposure to antibiotics with anaerobic coverage has been linked to heightened incident gout risk. Notably, intestinal dysbiosis that includes Bacillota depletion has been observed in gout cohorts. Therefore, the capacity of diverse gut bacterial strains to biochemically compensate for human limits in urate disposition suggests novel probiotic treatment approaches for gout with inadequate pharmacologic control of both flares and hyperuricemia. This is particularly so for severe CKD, which limits the options and maximal doses for use of conventional oral urate-lowering drugs.
人类通过尿酸排泄减少和尿酸生成过多而发生高尿酸血症，进而促进尿酸钠晶体沉积并引发痛风。正常情况下，约三分之二的尿酸通过肾脏排泄。然而，慢性肾脏病（CKD）和其他导致肾脏尿酸排泄减少的原因在大多数痛风患者中引发了高尿酸血症。这就增加了通过肠道排泄尿酸的需求，而饮食、嘌呤代谢和微生物群在肠道中相互关联。尿酸转运至肠道的遗传性损伤很常见，会促进高尿酸血症、肾脏尿酸过载以及早发性和明显的痛风石性痛风表型。乳酸菌通过隔离和修饰周围的嘌呤，其抑制饮食诱导的尿酸生成及相关痛风发作的潜力正在研究中。近期具有里程碑意义的临床前研究表明，多种专性和兼性厌氧的人类及小鼠肠道微生物群（主要属于芽孢杆菌门）具有更高的降尿酸能力，这些微生物群被称为嘌呤降解菌（PDB）。PDB中一个保守的基因簇可驱动尿酸转化为乳酸或抗炎性短链脂肪酸。当使小鼠缺乏肝脏尿酸酶以模拟人类缺乏尿酸酶的情况时，微生物群耗竭会迅速升高盲肠和血清尿酸水平，而给予PDB可使其逆转。在肾功能正常的健康人类志愿者中，抗生素诱导的肠道微生物群耗竭会减少PDB特有的降尿酸基因簇，并升高粪便尿酸水平。此外，先前接触过覆盖厌氧菌的抗生素与痛风发病风险增加有关。值得注意的是，在痛风患者队列中已观察到包括芽孢杆菌门耗竭在内的肠道生态失调。因此，多种肠道细菌菌株在生化方面补偿人类尿酸排泄能力限制的能力，提示了针对痛风发作和高尿酸血症药物控制不足的新型益生菌治疗方法。对于严重的CKD尤其如此，因为它限制了传统口服降尿酸药物的使用选择和最大剂量。
