Altered enteric microorganisms in concert with host genetics shape inflammatory bowel disease (IBD) phenotypes. However, insight is limited to bacteria and fungi. We found that eukaryotic viruses and bacteriophages (collectively, the virome), enriched from non-IBD, noninflamed human colon resections, actively elicited atypical anti-inflammatory innate immune programs. Conversely, ulcerative colitis or Crohn’s disease colon resection viromes provoked inflammation, which was successfully dampened by non-IBD viromes. The IBD colon tissue virome was perturbed, including an increase in the enterovirus B species of eukaryotic picornaviruses, not previously detected in fecal virome studies. Mice humanized with non-IBD colon tissue viromes were protected from intestinal inflammation, whereas IBD virome mice exhibited exacerbated inflammation in a nucleic acid sensing–dependent fashion. Furthermore, there were detrimental consequences for IBD patient–derived intestinal epithelial cells bearing loss-of-function mutations within virus sensor MDA5 when exposed to viromes. Our results demonstrate that innate recognition of IBD or non-IBD human viromes autonomously influences intestinal homeostasis and disease phenotypes. Thus, perturbations in the intestinal virome, or an altered ability to sense the virome due to genetic variation, contribute to the induction of IBD. Harnessing the virome may offer therapeutic and biomarker potential.

中文翻译：

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人类肠道病毒通过不同的先天免疫调节自主塑造炎症性肠病表型


肠道微生物的改变与宿主遗传学共同塑造炎症性肠病（IBD）表型。然而，洞察力仅限于细菌和真菌。我们发现，从非 IBD、非炎症人类结肠切除物中富集的真核病毒和噬菌体（统称为病毒组）能够积极引发非典型抗炎先天免疫程序。相反，溃疡性结肠炎或克罗恩病结肠切除病毒组会引发炎症，而非IBD病毒组可以成功抑制炎症。 IBD 结肠组织病毒组受到干扰，包括真核小核糖核酸病毒的肠道病毒 B 种增加，这是以前在粪便病毒组研究中未检测到的。用非IBD结肠组织病毒体人源化的小鼠免受肠道炎症的影响，而IBD病毒体小鼠则以核酸传感依赖性方式表现出加剧的炎症。此外，当IBD患者来源的肠上皮细胞暴露于病毒体时，其病毒传感器MDA5内携带功能丧失突变，会产生有害后果。我们的结果表明，IBD 或非 IBD 人类病毒组的先天识别会自主影响肠道稳态和疾病表型。因此，肠道病毒组的扰动，或由于遗传变异而改变的感知病毒组的能力，都会导致 IBD 的诱发。利用病毒组可能提供治疗和生物标志物的潜力。