Early-life antibiotic exposure drives adult asthma through succinate/SUCNR1 signaling

DONG Bo; ZHANG Juan; LI Qiuhong; HUANG Jinli; ZHANG Wei; ZHANG Panpan; SUN Xin

doi:10.13276/j.issn.2097-1656.2025.11.020

Abstract：Objective To investigate the effects of early-life antibiotic exposure on inflammatory response in asthma and its relationship with succinate/SUCNR1 signaling.Methods In this study,3-week-old female BALB/c mice were used to establish models of early-life gut microbiota dysbiosis and early-life succinate accumulation by oral administration of antibiotic-drinking water and succinate-drinking water,respectively.Asthma models were induced by ovalbumin(OVA)sensitization(including normal control group,asthma model group,antibiotic group,antibiotic asthma group,succinate group and succinate asthma group).Mouse serum,feces,and bronchoalveolar lavage fluid(BALF)were collected.Airway hyperresponsiveness was assessed using a mouse pulmonary function tester.Leukocyte count and classification in BALF were performed with Wright-Giemsa staining.Inflammatory cytokines,eotaxin(EOT)in BALF,and serum OVA-specific IgE were measured using ELISA.Succinate levels in serum and cecal contents of mice were detected by colorimetric methods.The expression of SUCNR1 in the small intestine was analyzed by immunofluorescence at protein levels and qRT-PCR at gene levels.Gut microbiota composition and diversity were determined using 16S rRNA sequencing.Results Compared with asthmatic mice that did not receive oral antibiotics,asthmatic mice subjected to early-life antibiotic exposure exhibited significantly increased airway hyperresponsiveness,inflammatory cytokines,EOT,and OVA-specific IgE(P＜0.05),accompanied by reduced diversity of gut microbiota and an imbalance of succinate-producing and succinate-consuming bacteria(P＜0.05).The contents of the cecum and serum succinate increased(P＜0.01),and the expression of SUCNR1 in the small intestine was significantly elevated(P＜0.05).Additionally,compared with mice that did not receive early-life succinate-drinking water,asthmatic mice that received early-life succinate-drinking water showed significantly elevated airway hyperresponsiveness,inflammatory cytokines,EOT,and OVA-specific IgE(P＜0.05),accompanied by a significant upregulation of SUCNR1 expression in the small intestine(P＜0.05).Conclusion Early-life antibiotic exposure that exacerbates asthma inflammat ory responses is associated with succinate/SUCNR1 signaling,which may serve as a potential predictor of asthma inflammation.This study provides new insights and directions for the diagnosis and treatment of asthma.