Microbiota-associated tryptophan catabolism induces autoimmune activation in a lupus murine model

The mechanisms involved in systemic lupus erythematosus (SLE) manifestations and progression remain elusive. Gut dysbiosis affects both humans and mice with SLE. Here, we demonstrate the inherent dysbiotic microbiota of lupus-prone mice, and how autoimmune phenotypes are induced if it is transferred into germfree mice. By elucidating the fecal metabolites, we focused on tryptophan (Trp) that presents an altered metabolism in SLE patients, potentially affecting the murine lupus. We found that high level of kynurenine (Kyn) in both the serum and fecal samples of lupus-prone mice, which was profoundly decreased after antibiotic treatment, potentially highlighting the relevance of gut commensals in Trp catabolism. Notably, low dietary Trp prevented autoimmune pathology, while high dietary Trp exacerbated the disease in mice. Further, modifying the levels of dietary Trp reprogrammed microbial taxa in lupus-prone mice and the congenic normal controls. Conclusively, the interplay among gut dysbiosis, Trp metabolism, and the genetic susceptibility suggest that Trp metabolism altered by microbial dysbiosis in lupus susceptible mice may be one of the mechanisms contributing to autoimmune activation. Thus, our findings may serve as a potential target for developing therapeutic interventions to perhaps mitigate lupus progression.

系统性红斑狼疮（systemic lupus erythematosus, SLE）的临床表现及疾病进展的相关机制仍未被完全阐明。肠道菌群失调在SLE患者与狼疮易感小鼠中均存在。本研究证实，狼疮易感小鼠体内存在固有菌群失调，且将其菌群移植至无菌小鼠体内后可诱发自身免疫表型。通过解析粪便代谢组，本研究聚焦于在SLE患者体内代谢模式发生改变的色氨酸（tryptophan, Trp）——该代谢物可能对小鼠狼疮模型产生影响。我们发现，狼疮易感小鼠的血清与粪便样本中犬尿氨酸（kynurenine, Kyn）水平均显著升高，且该水平经抗生素处理后大幅下降，这一结果凸显了肠道共生菌在色氨酸分解代谢中的关键作用。值得注意的是，低膳食色氨酸摄入可抑制小鼠自身免疫病理损伤，而高膳食色氨酸摄入则会加重疾病进程。此外，调整膳食色氨酸水平可重塑狼疮易感小鼠及同基因正常对照小鼠的菌群类群组成。综上，肠道菌群失调、色氨酸代谢与遗传易感性之间的相互作用表明，狼疮易感小鼠中菌群失调所介导的色氨酸代谢异常，可能是促进自身免疫激活的潜在机制之一。因此，本研究结果可为开发缓解狼疮进展的治疗干预手段提供潜在靶点。