Study On The Effect And Mechanism Of Early Antibiotic Administration On Necrotizing Enterocolitis

Background and ObjectiveNecrotizing Enterocolitis(NEC)is a serious gastrointestinal disease that can lead to intestinal perforation,multi-organ failure and even death in severe cases.The pathogenesis of NEC is still unclear and effective therapeutic drugs are lacking.Clinical antibiotics are used to treat newborns suspected of being at risk of infection,but irrational antibiotic therapy can lead to adverse outcomes,including NEC,which may be associated with immature intestinal defenses and disturbed intestinal flora.However,existing animal models of NEC do not represent the actual pathogenesis of NEC in children with early clinical antibiotic use,while few studies have focused on the effects of different antibiotics on NEC compared to early prophylactic use.The aim of this study was to investigate the effects of preventive use of clinically used antibiotics cephalosporins and carbapenems on the development of NEC,including the structure and function of the intestinal tract and microbial characteristics,and also to provide a basis for the subsequent exploration of the pathogenesis and prevention of NEC.MethodsExperiment 1:Newborn littermates received antibiotic intervention.Intestinal tissues from each group were collected and the expression levels of barrier and inflammation-related indicators were detected by qPCR to compare the effects of two antibiotics alone on the intestine of the littermates.Experiment 2:Newborn littermates received antibiotic intervention,and NEC was modeled by hypoxia and other methods.Intestinal tissues and contents were collected from each group,and the expression levels of tight junction proteins and inflammation-related indicators were detected by qPCR,and intestinal flora were analyzed by 16S sequencing to compare the severity of NEC in littermates with the use of two antibiotics.Experiment 3:Analysis of antibiotic use and incidence of NEC in a prospective observational cohort,with emphasis on a case-control study of NEC occurring with and without antibiotics,and stool samples subjected to 16S sequencing to further compare the differences in intestinal flora between the two groups.ResultsResult 1:When antibiotic interventions were given to neonatal pups alone,both antibiotics slowed the rate of pup weight gain,with the effect of meropenem being more pronounced.There were no significant changes in intestinal barrier and immune inflammation in the cefmetazole group.In the meropenem group,the expression levels of ZO-1 and other tight junction proteins were reduced,the intestinal barrier was impaired,the expression levels of IL-1β and IL-6 were significantly upregulated,and the level of intestinal immune inflammation was increased.Result 2:Neonatal littermates were given antibiotic intervention and were modeled for NEC,and cefmetazole and meropenem had different effects on NEC.In the cefmetazole group,the intestinal tissues were less damaged and there were no significant changes in the expression of intestinal barrier-related proteins,immune inflammation and oxidative stress levels.The meropenem group showed severe intestinal tissue damage,significantly reduced expression of intestinal barrier-related proteins,increased intestinal permeability,elevated levels of intestinal immune inflammation and stress,and increased severity of NEC disease.Result 3:Post-modeling flora analysis revealed that the diversity and composition of the cefmetazole group was similar to that of the model group,while the diversity of the meropenem group was significantly reduced,where Lefse analysis confirmed a significant decrease in the relative abundance of Lactobacillus.Result 4:Cohort analysis revealed a higher incidence of NEC in children on meropenem,with significant changes in the diversity and composition of their intestinal flora,and Lefse analysis confirmed a significant reduction in the relative abundance of Lactobacillus,consistent with the results of animal studies.ConclusionThere may be differences in the effects of cefmetazole or meropenem on NEC in terms of intestinal structure,barrier function,and flora,with meropenem use exacerbating intestinal damage accompanied by elevated levels of intestinal inflammation and oxidative stress,which may be associated with dysbiosis and are important factors in the increased pathogenesis of NEC.In contrast,cefmetazole use did not exacerbate the severity of the NEC model.This experiment suggests that when antibiotics are used empirically in neonates in clinical practice,the effects of different antibiotics on the intestine should be taken into account and targeted antibiotics should be used rationally to reduce the risk of disease development.