This study hypothesized that the gut microbial populations, intestinal morphology, and cytokine production are differentially altered in 2 different pig breeds, namely, Chinese native Jinhua pigs and European Landrace pigs, after orally challenge with enterotoxigenic Escherichia coli (ETEC) K88. A total of 12 Jinhua pigs and 12 Landrace pigs were allocated to either the nonchallenged or the challenged groups (6 pigs per group). The challenged pigs were orally administered ETEC K88, and their nonchallenged counterparts were given sterile Luria-Bertani broth. Selected gut microbial populations, intestinal morphology, mRNA expression of tight junction proteins, and the levels of ileal cytokines and secretory immunoglobulin A (sIgA) production were measured in Jinhua and Landrace pigs. The results showed that the challenged Jinhua pigs exhibited a significantly (P < 0.05) lower incidence of diarrhea compared with their Landrace counterparts. The Escherichia coli (E.coli) population and the percentage of E. coli in the total bacteria population were increased in response to ETEC K88 challenge in both Jinhua and Landrace pigs. The challenged Landrace pigs shed more E. coli (P < 0.05) and had higher percentage of E. coli in the total bacteria population in the colon (P < 0.05) compared with their Jinhua counterparts. Both pig breeds tended to exhibit greater villous atrophy and crypt depth reduction in all of the intestinal segments with challenge. The expression of tight junction proteins decreased in response to ETEC K88 challenge in both pig breeds. The levels of the proinflammatory cytokines interferon (IFN)-γ, tumor necrosis factor-α, and IL-6 and the secretion of sIgA were positively altered whereas the levels of the anti-inflammatory cytokine IL-4 and transforming growth factor (TGF)-β were negatively altered by ETEC K88 challenge in both breeds. Jinhua pigs exhibited significantly higher levels of IFN-γ and TGF-β (P < 0.05) in the challenged group. Our findings provide valuable evidence to explain the differences in the intestinal physiology between Jinhua and Landrace pigs; that is, Jinhua pigs appeared to show better growth performance, a lower incidence of diarrhea, and a lower extent of immune activation in response to ETEC K88 challenge and a higher Lactobacillus population, a higher percentage of Lactobacillus in the total bacteria population, a higher ratio of Lactobacillus to E. coli, and higher levels of tight junction proteins with and without challenge.
Diarrhea is a leading cause of death among young mammals, especially during weaning. Here, we investigated the effects of Cathelicidin-WA (CWA) on diarrhea, intestinal morphology, inflammatory responses, epithelial barrier and microbiota in the intestine of young mammals during weaning. Piglets with clinical diarrhea were selected and treated with saline (control), CWA or enrofloxacin (Enro) for 4 days. Both CWA and Enro effectively attenuated diarrhea. Compared with the control, CWA decreased IL-6, IL-8 and IL-22 levels and reduced neutrophil infiltration into the jejunum. CWA inhibited inflammation by down-regulating the TLR4-, MyD88-and NF-κB-dependent pathways. Additionally, CWA improved intestinal morphology by increasing villus and microvillus heights and enhancing intestinal barrier function by increasing tight junction (TJ) protein expression and augmenting woundhealing ability in intestinal epithelial cells. CWA also improved microbiota composition and increased short-chain fatty acid (SCFA) levels in feces. By contrast, Enro not only disrupted the intestinal barrier but also negatively affected microbiota composition and SCFA levels in the intestine. In conclusion, CWA effectively attenuated inflammation, enhanced intestinal barrier function, and improved microbiota composition in the intestines of weaned piglets. These results suggest that CWA could be an effective and safe therapy for diarrhea or other intestinal diseases in young mammals.
Impaired epithelial barrier function disrupts immune homeostasis and increases inflammation in intestines, leading to many intestinal diseases. Cathelicidin peptides suppress intestinal inflammation and improve intestinal epithelial barrier function independently of their antimicrobial activity. In this study, we investigated the effects of Cathelicidin-WA (CWA) on intestinal epithelial barrier function, as well as the underlying mechanism, by using enterohemorrhagic Escherichia coli (EHEC)-infected mice and intestinal epithelial cells. The results showed that CWA attenuated EHEC-induced clinical symptoms and intestinal colitis, as did enrofloxacin (Enro). CWA decreased IL-6 production in the serum, jejunum, and colon of EHEC-infected mice. Additionally, CWA alleviated the EHEC-induced disruption of mucin-2 and goblet cells in the intestine. Interestingly, CWA increased the mucus layer thickness, which was associated with increasing expression of trefoil factor 3, in the jejunum of EHEC-infected mice. CWA increased the expression of tight junction proteins in the jejunum of EHEC-infected mice. Using intestinal epithelial cells and a Rac1 inhibitor in vitro, we demonstrated that the CWA-mediated increases in the tight junction proteins might depend on the Rac1 pathway. Furthermore, CWA improved the microbiota and short-chain fatty acid concentrations in the cecum of EHEC-infected mice. Although Enro and CWA had similar effects on intestinal inflammation, CWA was superior to Enro with regard to improving intestinal epithelial barrier and microbiota in the intestine. In conclusion, CWA attenuated EHEC-induced inflammation, intestinal epithelial barrier damage, and microbiota disruption in the intestine of mice, suggesting that CWA may be an effective therapy for many intestinal diseases.
Butyrate has been used to treat different inflammatory disease with positive outcomes, the mechanisms by which butyrate exerts its anti-inflammatory effects remain largely undefined. Here we proposed a new mechanism that butyrate manipulate endogenous host defense peptides (HDPs) which contributes to the elimination of Escherichia coli O157:H7, and thus affects the alleviation of inflammation. An experiment in piglets treated with butyrate (0.2% of diets) 2 days before E. coli O157:H7 challenge was designed to investigate porcine HDP expression, inflammation and E. coli O157:H7 load in feces. The mechanisms underlying butyrate-induced HDP gene expression and the antibacterial activity and bacterial clearance of macrophage 3D4/2 cells in vitro were examined. Butyrate treatment (i) alleviated the clinical symptoms of E. coli O157:H7-induced hemolytic uremic syndrome (HUS) and the severity of intestinal inflammation; (ii) reduced the E. coli O157:H7 load in feces; (iii) significantly upregulated multiple, but not all, HDPs in vitro and in vivo via histone deacetylase (HDAC) inhibition; and (iv) enhanced the antibacterial activity and bacterial clearance of 3D4/2 cells. Our findings indicate that butyrate enhances disease resistance, promotes the clearance of E. coli O157:H7, and alleviates the clinical symptoms of HUS and inflammation, partially, by affecting HDP expression via HDAC inhibition.
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