Abstract
Necrotic enteritis (NE) caused by Clostridium perfringens infection has reemerged as a prevalent poultry disease worldwide due to reduced usage of prophylactic antibiotics under consumer preferences and regulatory pressures. The lack of alternative antimicrobial strategies to control this disease is mainly due to limited insight into the relationship between NE pathogenesis, microbiome, and host responses. Here we showed that the microbial metabolic byproduct of secondary bile acid deoxycholic acid (DCA), at as low as 50 µM, inhibited 82.8% of C. perfringens growth in Tryptic Soy Broth (P < 0.05). Sequential Eimeria maxima and C. perfringens challenges significantly induced NE, severe intestinal inflammation, and body weight (BW) loss in broiler chickens. These negative effects were diminished (P < 0.05) by 1.5 g/kg DCA diet. At the cellular level, DCA alleviated NE-associated ileal epithelial death and significantly reduced lamina propria cell apoptosis. Interestingly, DCA reduced C. perfringens invasion into ileum (P < 0.05) without altering the bacterial ileal luminal colonization. Molecular analysis showed that DCA significantly reduced inflammatory mediators of Infγ, Litaf, Il1β, and Mmp9 mRNA accumulation in ileal tissue. Mechanism studies revealed that C. perfringens induced (P < 0.05) elevated expression of inflammatory mediators of Infγ, Litaf, and Ptgs2 (Cyclooxygenases-2 (COX-2) gene) in chicken splenocytes. Inhibiting the COX signaling by aspirin significantly attenuated INFγ-induced inflammatory response in the splenocytes. Consistent with the in vitro assay, chickens fed 0.12 g/kg aspirin diet protected the birds against NE-induced BW loss, ileal inflammation, and intestinal cell apoptosis. In conclusion, microbial metabolic product DCA prevents NE-induced BW loss and ileal inflammation through attenuating inflammatory response. These novel findings of microbiome protecting birds against NE provide new options on developing next generation antimicrobial alternatives against NE.
Highlights
Antimicrobial resistance is one of the emerging challenges requiring immediate and sustainable counter-actions from agriculture to healthcare[1]
The Tryptic Soy Broth (TSB) was supplemented with various concentrations of bile acids, including conjugated primary bile acid TCA, primary bile acid CA, and secondary bile acid deoxycholic acid (DCA)
We examined whether other secondary bile acids were bacteriostatic in TSB
Summary
Antimicrobial resistance is one of the emerging challenges requiring immediate and sustainable counter-actions from agriculture to healthcare[1]. Withdrawing antimicrobials in chicken production, has caused new problems for the chicken industry by reducing production efficiency and increasing diseases, such as Eimeria maxima- and Clostridium perfringens-induced necrotic enteritis (NE)[3]. Mouse anaerobes and their metabolic product DCA has been found to prevent and treat Campylobacter jejuni-induced intestinal inflammation in germ-free mice through attenuating host inflammatory signaling pathways[20]. Non-selective COX inhibitor, aspirin, is used to prevent various chronic diseases, it inflicts intestinal inflammation to the healthy intestine[37]. We found that DCA decreased NE-induced intestinal inflammation, C. perfringens invasion, intestinal cell death, and body weight loss. Blocking the inflammatory COX signaling pathways by aspirin reduced NE-induced intestinal inflammation. These novel findings of microbiome DCA and COX inhibitor against NE offer new strategies to prevent and treat C. perfringens-induced diseases
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