Human gut commensals are increasingly suggested to impact non-communicable diseases, such as inflammatory bowel diseases (IBD), yet their targeted suppression remains a daunting unmet challenge. In four geographically distinct IBD cohorts (n = 537), we identify a clade of Klebsiella pneumoniae (Kp) strains, featuring a unique antibiotics resistance and mobilome signature, to be strongly associated with disease exacerbation and severity. Transfer of clinical IBD-associated Kp strains into colitis-prone, germ-free, and colonized mice enhances intestinal inflammation. Stepwise generation of a lytic five-phage combination, targeting sensitive and resistant IBD-associated Kp clade members through distinct mechanisms, enables effective Kp suppression in colitis-prone mice, driving an attenuated inflammation and disease severity. Proof-of-concept assessment of Kp-targeting phages in an artificial human gut and in healthy volunteers demonstrates gastric acid-dependent phage resilience, safety, and viability in the lower gut. Collectively, we demonstrate the feasibility of orally administered combination phage therapy in avoiding resistance, while effectively inhibiting non-communicable disease-contributing pathobionts.

越来越多的人认为人类肠道共生体会影响非传染性疾病，例如炎症性肠病 (IBD)，但它们的靶向抑制仍然是一项尚未解决的艰巨挑战。在四个地理上不同的 IBD 队列 (n = 537) 中，我们确定了肺炎克雷伯菌的一个进化枝(Kp) 菌株具有独特的抗生素耐药性和移动组特征，与疾病恶化和严重程度密切相关。将临床 IBD 相关 Kp 菌株转移到易患结肠炎、无菌和定植的小鼠体内会增强肠道炎症。逐步生成裂解​​性五噬菌体组合，通过不同的机制靶向敏感和耐药的 IBD 相关 Kp 进化枝成员，从而在易患结肠炎的小鼠中实现有效的 Kp 抑制，从而减轻炎症和疾病的严重程度。对人造人类肠道和健康志愿者中 Kp 靶向噬菌体的概念验证评估证明了胃酸依赖性噬菌体在下肠道中的恢复力、安全性和生存能力。总的来说，我们证明了口服联合噬菌体疗法在避免耐药性方面的可行性，