Maternal gut microbiome-induced IgG regulates neonatal gut microbiome and immunity: IgG-/- vs WT neonates. Mouse fecal pellets

The gut microbiome elicits antigen-specific IgG at steady state that cross-reacts to pathogens to confer protection against systemic infection. The role of gut microbiome-specific IgG antibodies in the development of gut microbiome and immunity against enteric pathogens in early life, however, remains largely undefined. In this study, we show that gut microbiome-induced maternal IgG is transferred to the neonatal intestine through maternal milk via the neonatal Fc receptor and directly inhibit C. rodentium colonization and attachment to the mucosa. Enhanced neonatal immunity against oral C. rodentium infection was observed following maternal immunization with a gut microbiome-derived IgG antigen, outer-membrane protein A (OMP-A), or induction of protective IgG antibodies by IgG-inducing gut bacteria. Furthermore, by generating a novel mouse model with complete IgG deficiency, we demonstrate that IgG KO neonates are more susceptible to C. rodentium infection, and exhibit alterations of the gut microbiome that promotes IL-17A- producing gd T cells in intestine, which persist into adulthood and contribute to increased disease severity in a DSS-induced colitis model. Taken together, our studies have defined a critical role for maternal gut microbiome-specific IgG antibodies in promoting immunity against enteric pathogens and shaping the development of the gut microbiome and immune cells in early life. 16S sequencing was performed on colon and small intestine luminal contents from two-week-old littermate IgG WT (n=5) and IgG-/- (n=7) pups.

生理稳态下，肠道微生物组可诱导产生抗原特异性免疫球蛋白G（IgG），该抗体可与病原体发生交叉反应，从而提供针对全身感染的保护作用。然而，肠道微生物组特异性IgG抗体在生命早期肠道微生物组发育以及抗肠道病原体免疫过程中所发挥的作用，目前仍未得到明确阐释。本研究发现，肠道微生物组诱导产生的母体IgG可通过新生Fc受体（neonatal Fc receptor）经母乳传递至新生小鼠肠道，并直接抑制鼠柠檬酸杆菌（C. rodentium）的定植与黏膜黏附。当母体以肠道微生物组来源的IgG抗原——外膜蛋白A（OMP-A）进行免疫，或通过诱导IgG的肠道细菌产生保护性IgG抗体后，新生小鼠对经口感染鼠柠檬酸杆菌的免疫力得到增强。此外，本研究通过构建完全IgG缺陷的新型小鼠模型，证实IgG敲除（IgG KO）新生小鼠更易感染鼠柠檬酸杆菌，且其肠道微生物组发生改变，可促进肠道内产生IL-17A的γδ T细胞增殖，该改变可持续至成年阶段，并在葡聚糖硫酸钠（DSS）诱导的结肠炎模型中加重疾病严重程度。综上，本研究明确了母体肠道微生物组特异性IgG抗体在促进抗肠道病原体免疫、塑造生命早期肠道微生物组与免疫细胞发育过程中的关键作用。本研究对2周龄同窝野生型IgG（IgG WT，n=5）与IgG敲除（IgG-/-，n=7）幼鼠的结肠及小肠腔内容物进行了16S测序。