Vancomycin-induced gut microbial dysbiosis alters enteric neuron-macrophage interactions during a critical period of postnatal development.
Vancomycin-induced gut microbial dysbiosis alters enteric neuron-macrophage interactions during a critical period of postnatal development.
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DOI：
10.3389/fimmu.2023.1268909
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发表时间：
2023
影响因子：
7.3
通讯作者：
Newberry, Rodney D.
中科院分区：
文献类型：
--
作者：
Schill, Ellen Merrick;Joyce, Elisabeth L.;Floyd, Alexandria N.;Udayan, Sreeram;Rusconi, Brigida;Gaddipati, Shreya;Barrios, Bibiana E.;John, Vini;Kaye, Mitchell E.;Kulkarni, Devesha H.;Pauta, Jocelyn T.;McDonald, Keely G.;Newberry, Rodney D.
关键词：
万古霉素是一种广谱抗生素，广泛用于早产儿疑似败血症的病例。虽然在这种情况下适当且可能挽救生命，但早期抗生素暴露会改变发育中的微生物组，并与致命并发症的风险增加有关，包括迟发性败血症（LOS）和坏死性小肠结肠炎（NEC）。最近的研究表明，新生儿万古霉素治疗破坏了出生后肠神经系统（ENS）的发展，在小鼠幼崽，这是部分依赖于神经免疫相互作用。这表明早期抗生素暴露可能会破坏新生儿肠道中的这些相互作用。值得注意的是，一个子集的组织驻留肠道巨噬细胞，肌层巨噬细胞，已被确定为重要的贡献者的发展，出生后ENS。我们假设，万古霉素诱导的新生儿生态失调的影响出生后ENS的发展，通过其对巨噬细胞的影响。使用小鼠模型，我们发现在生命的前10天暴露于万古霉素，但在成年小鼠中没有，通过增加骨髓源性巨噬细胞的募集导致促炎性结肠巨噬细胞的扩增。新生儿结肠巨噬细胞的单细胞RNA测序显示，生命早期的万古霉素暴露与未成熟和炎性巨噬细胞的增加有关，与分化为巨噬细胞的循环单核细胞的流入一致。谱系追踪证实，万古霉素显着增加非卵黄囊来源的巨噬细胞群体。与这些结果一致，早期生活万古霉素暴露没有扩大结肠巨噬细胞群体，也没有减少CCR 2缺陷小鼠的肠神经元密度。总的来说，这些发现表明，与成年小鼠中的万古霉素暴露相比，早期生活万古霉素暴露以不同的方式改变巨噬细胞数量和表型，并导致ENS发育改变。
Vancomycin is a broad-spectrum antibiotic widely used in cases of suspected sepsis in premature neonates. While appropriate and potentially lifesaving in this setting, early-life antibiotic exposure alters the developing microbiome and is associated with an increased risk of deadly complications, including late-onset sepsis (LOS) and necrotizing enterocolitis (NEC). Recent studies show that neonatal vancomycin treatment disrupts postnatal enteric nervous system (ENS) development in mouse pups, which is in part dependent upon neuroimmune interactions. This suggests that early-life antibiotic exposure could disrupt these interactions in the neonatal gut. Notably, a subset of tissue-resident intestinal macrophages, muscularis macrophages, has been identified as important contributors to the development of postnatal ENS. We hypothesized that vancomycin-induced neonatal dysbiosis impacts postnatal ENS development through its effects on macrophages. Using a mouse model, we found that exposure to vancomycin in the first 10 days of life, but not in adult mice, resulted in an expansion of pro-inflammatory colonic macrophages by increasing the recruitment of bone-marrow-derived macrophages. Single-cell RNA sequencing of neonatal colonic macrophages revealed that early-life vancomycin exposure was associated with an increase in immature and inflammatory macrophages, consistent with an influx of circulating monocytes differentiating into macrophages. Lineage tracing confirmed that vancomycin significantly increased the non-yolk-sac-derived macrophage population. Consistent with these results, early-life vancomycin exposure did not expand the colonic macrophage population nor decrease enteric neuron density in CCR2-deficient mice. Collectively, these findings demonstrate that early-life vancomycin exposure alters macrophage number and phenotypes in distinct ways compared with vancomycin exposure in adult mice and results in altered ENS development.
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影响因子：
9.8
作者：
通讯作者：
--
影响因子：
48
作者：
Callahan BJ;McMurdie PJ;Rosen MJ;Han AW;Johnson AJ;Holmes SP
通讯作者：
Holmes SP
影响因子：
30.5
作者：
Gensollen T;Lin X;Zhang T;Pyzik M;See P;Glickman JN;Ginhoux F;Waldor M;Salmi M;Rantakari P;Blumberg RS
通讯作者：
Blumberg RS
影响因子：
4.4
作者：
Gonzalez-Perez, Gabriela;Hicks, Allison L.;Lamouse-Smith, Esi S. N.
通讯作者：
Lamouse-Smith, Esi S. N.
影响因子：
32.4
作者：
Gerlach, Carmen;Moseman, E. Ashley;Loughhead, Scott M.;Alvarez, David;Zwijnenburg, Anthonie J.;Waanders, Lisette;Garg, Rohit;de la Torre, Juan C.;von Andrian, Ulrich H.
通讯作者：
von Andrian, Ulrich H.