The liver is the main gateway from the gut, and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zones, including the periportal vein (PV) and the pericentral vein zones^1,2,3,4,5. However, functional differences in the immune system in each zone remain poorly understood. Here intravital imaging revealed that inflammatory responses are suppressed in PV zones. Zone-specific single-cell transcriptomics detected a subset of immunosuppressive macrophages enriched in PV zones that express high levels of interleukin-10 and Marco, a scavenger receptor that sequesters pro-inflammatory pathogen-associated molecular patterns and damage-associated molecular patterns, and consequently suppress immune responses. Induction of Marco⁺ immunosuppressive macrophages depended on gut microbiota. In particular, a specific bacterial family, Odoribacteraceae, was identified to induce this macrophage subset through its postbiotic isoallolithocholic acid. Intestinal barrier leakage resulted in inflammation in PV zones, which was markedly augmented in Marco-deficient conditions. Chronic liver inflammatory diseases such as primary sclerosing cholangitis (PSC) and non-alcoholic steatohepatitis (NASH) showed decreased numbers of Marco⁺ macrophages. Functional ablation of Marco⁺ macrophages led to PSC-like inflammatory phenotypes related to colitis and exacerbated steatosis in NASH in animal experimental models. Collectively, commensal bacteria induce Marco⁺ immunosuppressive macrophages, which consequently limit excessive inflammation at the gateway of the liver. Failure of this self-limiting system promotes hepatic inflammatory disorders such as PSC and NASH.

肝脏是肠道的主要门户，从门静脉到中央静脉的单向正弦血流构成了异质区，包括门静脉周围静脉（PV）和中央静脉周围区域^1,2,3,4,5。然而，人们对每个区域免疫系统的功能差异仍知之甚少。活体成像显示 PV 区的炎症反应受到抑制。区域特异性单细胞转录组学检测到PV区域中富集的免疫抑制巨噬细胞子集，这些细胞表达高水平的白细胞介素10和Marco，Marco是一种清道夫受体，可隔离促炎病原体相关分子模式和损伤相关分子模式，因此抑制免疫反应。 Marco ⁺免疫抑制巨噬细胞的诱导取决于肠道微生物群。特别是，一个特定的细菌家族，Odoribacteraceae，被鉴定为通过其后生异别石胆酸诱导这种巨噬细胞亚群。肠屏障渗漏导致 PV 区炎症，在 Marco 缺乏的情况下炎症明显加剧。慢性肝脏炎症性疾病如原发性硬化性胆管炎（PSC）和非酒精性脂肪性肝炎（NASH）显示Marco ⁺巨噬细胞数量减少。 Marco ⁺巨噬细胞的功能性消融导致与结肠炎相关的 PSC 样炎症表型，并在动物实验模型中加剧 NASH 中的脂肪变性。总的来说，共生细菌诱导 Marco ⁺免疫抑制巨噬细胞，从而限制肝脏入口处的过度炎症。这种自限系统的失败会促进 PSC 和 NASH 等肝脏炎症性疾病。