Dataset Information

Butyrate and Forskolin Augment Host Defense, Barrier Function, and Disease Resistance Without Eliciting Inflammation

ABSTRACT: Host defense peptides (HDPs) are an integral part of the innate immune system with both antimicrobial and immunomodulatory activities. Induction of endogenous HDP synthesis is being actively explored as an antibiotic-alternative approach to disease control and prevention. Butyrate, a short-chain fatty acid, and forskolin, a phytochemical, have been shown separately to induce HDP gene expression in human cells. Here, we investigated the ability of butyrate and forskolin to induce the expressions of chicken HDP genes and the genes involved in barrier function such as mucin 2 and claudin 1 both in vitro and in vivo. We further evaluated their efficacy in protecting chickens from Clostridium perfringens-induced necrotic enteritis. Additionally, we profiled the transcriptome and global phosphorylation of chicken HD11 macrophage cells in response to butyrate and forskolin using RNA sequencing and a kinome peptide array, respectively. Our results showed a strong synergy between butyrate and forskolin in inducing the expressions of several, but not all, HDP genes. Importantly, dietary supplementation of butyrate and a forskolin-containing plant extract resulted in significant alleviation of intestinal lesions and the C. perfringens colonization in a synergistic manner in a chicken model of necrotic enteritis. RNA sequencing revealed a preferential increase in HDP and barrier function genes with no induction of proinflammatory cytokines in response to butyrate and forskolin. The antiinflammatory and barrier protective properties of butyrate and forskolin were further confirmed by the kinome peptide array. Moreover, we demonstrated an involvement of inducible cAMP early repressor (ICER)-mediated negative feedback in HDP induction by butyrate and forskolin. Overall, these results highlight a potential for developing butyrate and forskolin, two natural products, as novel antibiotic alternatives to enhance intestinal health and disease resistance in poultry and other animals.

SUBMITTER: Robinson K

PROVIDER: S-EPMC8579826 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:OBJECTIVES:To determine whether synthetic phosphorylated hexa-acyl disaccharides provide antimicrobial protection in clinically relevant models of bacterial infection. DESIGN:Laboratory study. SETTING:University laboratory. SUBJECTS:BALB/c, C57BL/10J, and C57BL/10ScNJ mice. INTERVENTIONS:Mice were treated with lactated Ringer's (vehicle) solution, monophosphoryl lipid A, or phosphorylated hexa-acyl disaccharides at 48 and 24 hours prior to intraperitoneal Pseudomonas aeruginosa or IV Staphylococcus aureus infection. Leukocyte recruitment, cytokine production, and bacterial clearance were measured 6 hours after P. aeruginosa infection. In the systemic S. aureus infection model, one group of mice was monitored for 14-day survival and another for S. aureus tissue burden at 3 days postinfection. Duration of action for 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide was determined at 3, 10, and 14 days using a model of intraperitoneal P. aeruginosa infection. Effect of 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide on in vivo leukocyte phagocytosis and respiratory burst was examined. Leukocyte recruitment, cytokine production, and bacterial clearance were measured after P. aeruginosa infection in wild-type and toll-like receptor 4 knockout mice treated with 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide or vehicle to assess receptor specificity. MEASUREMENTS AND MAIN RESULTS:During intraperitoneal P. aeruginosa infection, phosphorylated hexa-acyl disaccharides significantly attenuated infection-induced hypothermia, augmented leukocyte recruitment and bacterial clearance, and decreased cytokine production. At 3 days post S. aureus infection, bacterial burden in lungs, spleen, and kidneys was significantly decreased in mice treated with monophosphoryl lipid A or phosphorylated hexa-acyl disaccharides, which was associated with improved survival. Leukocyte phagocytosis and respiratory burst functions were enhanced after treatment with monophosphoryl lipid A or phosphorylated hexa-acyl disaccharides. A time course study showed that monophosphoryl lipid A- and 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide-mediated protection against P. aeruginosa lasts for up to 10 days. Partial loss of augmented innate antimicrobial responses was observed in toll-like receptor 4 knockout mice treated with 3-deacyl 6-Acyl phosphorylated hexa-acyl disaccharide. CONCLUSIONS:Phosphorylated hexa-acyl disaccharides significantly augment resistance against clinically relevant Gram-negative and Gram-positive infections via enhanced leukocyte recruitment, phagocytosis, and respiratory burst functions of innate leukocytes. Improved antimicrobial protection persists for up to 10 days and is partially mediated through toll-like receptor 4.

Project description:BackgroundThe emergence of antimicrobial resistance has necessitated the development of effective alternatives to antibiotics for livestock and poultry production. This study investigated a possible synergy between butyrate and forskolin (a natural labdane diterpene) in enhancing innate host defense, barrier function, disease resistance, growth performance, and meat quality of broilers.MethodsThe expressions of representative genes involved in host defense (AvBD9 and AvBD10), barrier function (MUC2, CLDN1, and TJP1), and inflammation (IL-1β) were measured in chicken HD11 macrophages in response to butyrate and forskolin in the presence or absence of bacterial lipopolysaccharides (LPS). Intestinal lesions and the Clostridium perfringens titers were also assessed in C. perfringens-challenged chickens fed butyrate and forskolin-containing Coleus forskohlii (CF) extract individually or in combination. Furthermore, growth performance and carcass characteristics were evaluated in broilers supplemented with butyrate and the CF extract for 42 d.ResultsButyrate and forskolin synergistically induced the expressions of AvBD9, AvBD10, and MUC2 in chicken HD11 cells (P < 0.05) and the synergy was maintained in the presence of LPS. Butyrate and forskolin also suppressed LPS-induced IL-1β gene expression in HD11 cells in a synergistic manner (P < 0.05). The two compounds significantly reduced the intestinal lesions of C. perfringens-challenged chickens when combined (P < 0.05), but not individually. Furthermore, butyrate in combination with forskolin-containing CF extract had no influence on weight gain, but significantly reduced feed intake (P < 0.05) with a strong tendency to improve feed efficiency (P = 0.07) in a 42-d feeding trial. Desirably, the butyrate/forskolin combination significantly decreased abdominal fat deposition (P = 0.01) with no impact on the carcass yield, breast meat color, drip loss, or pH of d-42 broilers.ConclusionsButyrate and forskolin has potential to be developed as novel antibiotic alternatives to improve disease resistance, feed efficiency, and carcass composition of broilers.

Dataset Information

Butyrate and Forskolin Augment Host Defense, Barrier Function, and Disease Resistance Without Eliciting Inflammation

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets