Preventive Antibiotic Treatment Increases Susceptibility of Neonatal chicks to Salmonella Infection via Disrupting Gut Microbiota and Linoleic Acid Metabolis

Abstract Background: Antibiotics are widely employed in animal husbandry to prevent and treat diseases. Increasing evidence suggests they may alter the animals’ natural microbiota and increase their susceptibility to pathogen. However, the mechanisms linking the gut microbiota and pathogen colonization in poultry have not yet been full elucidated. Herein, we used metagenomic and metabonomic approaches to investigate the effects of florfenicol (FFC) pre-treatment on Salmonella enterica serovar Enteritidis (S. Enteritidis) colonization in the intestines of neonatal chicks in terms of host response, microbiota composition and metabolism. Results: We determined that FFC pre-treatment significantly alters the cecal microbiota and metabolome, and also increases the intestinal permeability and promotes a pro-inflammatory gene expression profile in the host. Host physiological changes were concordant with significantly increased susceptibility to S. Enteritidis infection in chicks with FFC pre-treatment relative to without pre-treatment chicks. Prior to Salmonella infection, FFC pre-treatment significantly reduced the abundance of Lactobacillus, and significantly affected linoleic acid metabolism, including significantly reducing the levels of conjugated linoleic acid (CLA), and significantly elevating the abundance of 12,13-EpOME and 12,13-diHOME in cecum. After infection with S. Enteritidis, the abundance of Proteobacteria were significantly increased and host inflammatory responses and intestinal permeability were significantly aggravated relative to without FFC pre-treatment chicks, suggestive of a profound exacerbating of the host response influenced by infection in the context of FFC pre-treatment. The linoleic acid metabolism was still significantly different pathway after Salmonella infection, and we screened CLA and 12,13-diHOME as the target metabolites using a multi-omics technique. Supplementation with CLA maintained intestinal integrity, reduced intestinal inflammation, and accelerated Salmonella clearance from the gut and remission of enteropathy. Whereas, treatment with 12,13-diHOME promoted intestinal inflammation and disrupted the intestinal barrier function to sustain Salmonella infection. Therefore, florfenicol reduces production of CLA by inhibiting Lactobacillus growth, increases 12,13-diHOME level of intestine, thereby reducing colonization resistance of neonatal chicks to Salmonella infection.Conclusion: This study reveals the potential health impact of antibiotics on gut microbiota and linoleic acid metabolism and contributing factors influencing Salmonella colonization in neonatal chicks, and provides mechanistic understanding into the role of the antibiotics promote the colonization of pathogens.