Niu Xinying, Lu Dongmei, Jaleel Sana, Palmer Suzette N, Mahendroo Mala, Zhan Xiaowei, Mirpuri Julie
Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Texas Southwestern, Dallas, TX, United States.
Department of Biomedical Engineering, University of Texas Southwestern, Dallas, TX, United States.
Front Immunol. 2024 Nov 18;15:1439804. doi: 10.3389/fimmu.2024.1439804. eCollection 2024.
Maternal high fat diet (mHFD) exposure expands IL-17 producing group 3 innate lymphoid cells (IL17 ILC3) in the small intestine of neonatal murine offspring and increases their susceptibility to intestinal inflammation. How mHFD modulates innate immunity in the fetal offspring remains unclear.
Dams were exposed to 60% high fat diet or maintained on regular diet (RD) prior to and during mating. Amniotic fluid (AF) was collected during mid-pregnancy and metabolites examined by global non-targeted mass spectrometry in conventional wild-type (WT) and germ-free pregnant dams. Offspring were delivered by C-section or vaginally and fecal contents examined for major bacterial phyla and small intestinal lamina propria cells (LP) by flow cytometry. Susceptibility to intestinal inflammation was determined using a lipopolysaccharide and platelet-activating factor model (LPS/PAF) in WT, germ-free and MyD88 deficient offspring. Neonatal germ-free pups were exposed to HFD or RD AF by gavage and LP examined by flow cytometry.
We identified differentially produced metabolites in mHFD AF when compared to RD AF in conventionally raised mice, with no difference seen in germ-free mice. C-section delivery maintained the mHFD phenotype of expansion of IL17 ILC3 and increased susceptibility to inflammation in neonatal offspring. In addition, mHFD offspring had expansion of IL17 ILC3 at birth and 2 weeks of life, which was not seen in germ-free and MyD88 KO mice exposed to mHFD. Germ-free and MyD88 KO mice were protected from mHFD induced LPS/PAF injury and IL17 ILC3 expansion, demonstrating that the maternal microbiome and MyD88 are prenatally necessary for the expansion of IL17 ILC3 in mHFD offspring. Furthermore, introduction of mHFD AF to neonatal germ-free pups by gavage was sufficient to expand IL17 ILC3 in the small intestine.
Our findings indicate that mHFD interacts with the maternal microbiome to modify AF metabolites and signal via MyD88 to expand IL17 ILC3 in murine neonatal offspring.
母体高脂饮食（mHFD）会使新生鼠后代小肠中产生白细胞介素-17的3型固有淋巴细胞（IL17 ILC3）增多，并增加其肠道炎症易感性。mHFD如何调节胎儿后代的固有免疫尚不清楚。
在交配前及交配期间，将母鼠暴露于60%高脂饮食或维持常规饮食（RD）。在妊娠中期收集羊水（AF），并通过全非靶向质谱分析常规野生型（WT）和无菌妊娠母鼠的代谢产物。通过剖宫产或阴道分娩后代，通过流式细胞术检测粪便中的主要细菌门类和小肠固有层细胞（LP）。使用脂多糖和血小板活化因子模型（LPS/PAF）在WT、无菌和MyD88缺陷后代中测定肠道炎症易感性。通过灌胃将新生无菌幼崽暴露于HFD或RD AF中，并通过流式细胞术检测LP。
与常规饲养小鼠的RD AF相比，我们在mHFD AF中鉴定出差异产生的代谢产物，在无菌小鼠中未观察到差异。剖宫产维持了IL17 ILC3扩增的mHFD表型，并增加了新生后代对炎症的易感性。此外，mHFD后代在出生时和出生后2周IL17 ILC3扩增，在暴露于mHFD的无菌和MyD88基因敲除小鼠中未观察到这种情况。无菌和MyD88基因敲除小鼠免受mHFD诱导的LPS/PAF损伤和IL17 ILC3扩增，表明母体微生物群和MyD88对mHFD后代中IL17 ILC3的扩增在产前是必需的。此外，通过灌胃将mHFD AF引入新生无菌幼崽足以在小肠中扩增IL17 ILC3。
我们的研究结果表明，mHFD与母体微生物群相互作用，改变AF代谢产物，并通过MyD88发出信号，以扩增小鼠新生后代中的IL17 ILC3。
