ORIGINAL PAPER
Effect of pidotimod on growth performance, immune function,
intestinal epithelial barriers and microbiota of piglets
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1
Zhejiang University, College of Animal Sciences, Institute of Animal Nutrition and Feed Sciences, Key Laboratory of Molecular
Animal Nutrition of the Ministry of Education, National Engineering Laboratory of Biological Feed Safety and Pollution Prevention
and Control, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, Zhejiang Province, China
2
Department of General Surgery, Chun’an First People’s Hospital (Zhejiang Provincial People’s Hospital Chun’an Branch),
Hangzhou 311700, Zhejiang Province, China
Publication date: 2021-03-15
Corresponding author
L. Fu
Zhejiang University, College of Animal Sciences, Institute of Animal Nutrition and Feed Sciences, Key Laboratory of Molecular
Animal Nutrition of the Ministry of Education, National Engineering Laboratory of Biological Feed Safety and Pollution Prevention
and Control, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, Zhejiang Province, China
W. Li
Zhejiang University, College of Animal Sciences, Institute of Animal Nutrition and Feed Sciences, Key Laboratory of Molecular
Animal Nutrition of the Ministry of Education, National Engineering Laboratory of Biological Feed Safety and Pollution Prevention
and Control, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, Zhejiang Province, China
J. Anim. Feed Sci. 2021;30(1):64-75
KEYWORDS
TOPICS
ABSTRACT
Pidotimod (PTD) is a synthetic immunomodulatory dipeptide
widely used for immune regulation. This study aimed to investigate the effect
of PTD on growth performance, immune function, intestinal epithelial barriers
and microbiota in piglets. In total, 120 piglets with a weight of 25.26 ± 5.96 kg
and genetic makeup were selected and randomly divided into 4 groups with
3 replicates per group and 10 piglets per replicate. All piglets were weighed,
and from 3 piglets from each replicate (9 piglets per group) tissues were
collected. Piglets were fed for 44 days basal diet alone or supplemented with
50, 100 or 200 mg/kg PTD. It was found that the PTD addition increased the
average daily weight gain of piglets (P < 0.05 and P < 0.01 for dose 50 and
100 mg/kg, respectively). So, for further studies only dose 50 mg/kg PTD
was used. It was found that such dose decreased serum levels of interleukin
(IL)-6 (P < 0.05) and interferon (IFN)-γ (P < 0.01), but increased antiinflammatory cytokine IL-10 level (P < 0.05). Transmission electron micrographs
further revealed that supplementation with PTD at a dose of 50 mg/kg
enhanced intercellular connectivity, characterized by longer tight junction (TJ)
proteins, thicker adhesive tapes (AB) and desmosomes (D) in the jejunum.
This phenomenon was validated by the up-regulated protein expression of
occludin and ZO-1 in the jejunum. Furthermore, supplementation with PTD
at a dose of 50 mg/kg altered the α diversity of intestinal microbiota in piglets
(Observed_species, Chao1, PD_whole_tree, Ace). Particularly, the abundance
of Spirochaetes, Verrucomicrobia, Succinispira and Treponema was decreased,
but that of Lactobacillus and Collinsella was increased. Overall, dietary
supplementation with 50 mg/kg PTD improves the growth performance of
piglets by enhancing immune function, intestinal epithelial barrier and regulating
microbiota composition.
ACKNOWLEDGEMENTS
The present work was supported by the
grants from the planning subject of ‘the Twelfth
Five-year-plan’ in National Science and Technology
for the Rural Development in China (grant no. 2013BAD10B03). The authors thank Baikui Wang
for the microbial analysis of the manuscript.
CONFLICT OF INTEREST
The authors declare that there is no conflict of
interests.
REFERENCES (50)
1.
Amadori M., Zanotti C., 2016. Immunoprophylaxis in intensive farming systems: the way forward. Vet. Immunol. Immunopathol. 181, 2−9,
https://doi.org/10.1016/j.veti....
2.
Anderson R.C., Cookson A.L., McNabb W.C., Kelly W.J., Roy N.C., 2010. Lactobacillus plantarum DSM 2648 is a potential probiotic that enhances intestinal barrier function. FEMS Microbiol. Lett. 309, 184−192,
https://doi.org/10.1111/j.1574....
3.
Beninger C., Naqvi S.A., Naushad S., Orsel K., Luby C., Derakhshani H., Khafipour E., De Buck J., 2018. Associations between digital dermatitis lesion grades in dairy cattle and the quantities of four Treponema species. Vet. Res. 49, 111,
https://doi.org/10.1186/s13567....
4.
Camilleri M., Madsen K., Spiller R., Van Meerveld B.G., Verne G.N., 2012. Intestinal barrier function in health and gastrointestinal disease. Neurogastroenterol. Motil. 24, 503−512,
https://doi.org/10.1111/j.1365....
5.
Caporaso J.G., Kuczynski J., Stombaugh J. et al., 2010. QIIME allows analysis of high-throughput community sequencing data. Nat. Methods 7, 335−336,
https://doi.org/10.1038/nmeth.....
6.
Capsoni F., Minonzio F., Ongari A.M., Girardello R., Zanussi C., 1992. Evaluation of the kinetics of the immunomodulating activity of pidotimod on human phagocytes. Pharmacol. Res. 26, Suppl. 2, 172−173,
https://doi.org/10.1016/1043-6....
7.
Caramia G., Clemente E., Solli R., Mei V., Cera R., Carnelli V., Venturoli V., Corsini A., 1994. Efficacy and safety of pidotimod in the treatment of recurrent respiratory infections in children. Arzneimittel-Forschung 44, 1480−1484.
8.
Chiarenza A., Iurato M.P., Barbera N., Lempereur L., Cantarella G., Scapagnini U., Scapagnini G., Bernardini R., 1994. Effects of pidotimod on the immune and the neuroendocrine system in the aging rat. Arzneimittel-Forschung 44, 1437−1440.
9.
Clemente E., Solli R., Mei V., Cera R., Caramia G., Carnelli V., Ruffini E., Venturoli V., Corsini A., 1994. Therapeutic efficacy and safety of pidotimod in the treatment of urinary tract infections in children. Arzneimittel-Forschung 44, 1490−1494.
10.
Coppi G., Amico-Roxas M., Berte F., Bussi R., Gnemi P., Harling R., Mailland F., Manzardo S., Massey J., Spencer-Briggs D., 1994. Toxicological evaluation of pidotimod. Arzneimittel-Forschung 44, 1448−1453.
11.
Coppi G., Silingardi S., 1994. Pharmacokinetics of pidotimod in rats and dogs. Arzneimittel-Forschung 44, 1460−1464.
12.
de Jong M.D., Simmons C.P., Thanh T.T. et al., 2006. Fatal outcome of human influenza a (H5N1) is associated with high viral load and hypercytokinemia. Nat. Med. 12, 1203−1207,
https://doi.org/10.1038/nm1477.
14.
Esposito S., Garziano M., Rainone V. et al., 2015. Immunomodulatory activity of pidotimod administered with standard antibiotic therapy in children hospitalized for community-acquired pneumonia. J. Transl. Med. 13, 288,
https://doi.org/10.1186/s12967....
16.
Fu L.Q., Fu A.K., Li L., Hu S.L., Li W.F., 2016. Detection and stability of pidotimod by high performance liquid chromatography. Chin. J. Prev. Vet. Med. 38, 381−384,
https://doi.org/10.3969/j.issn....
17.
Fulde M., Hornef M.W., 2014. Maturation of the enteric mucosal innate immune system during the postnatal period. Immunol. Rev. 260, 21−34,
https://doi.org/10.1111/imr.12....
18.
Giagulli C., Noerder M., Avolio M., Becker P.D., Fiorentini S., Guzman C.A., Caruso A., 2009. Pidotimod promotes functional maturation of dendritic cells and displays adjuvant properties at the nasal mucosa level. Int. Immunopharmacol. 9, 1366−1373,
https://doi.org/10.1016/j.inti....
19.
Kamada N., Chen G.Y., Inohara N., Nunez G., 2013. Control of pathogens and pathobionts by the gut microbiota. Nat. Immunol. 14, 685−690,
https://doi.org/10.1038/ni.260....
21.
Kim H.B., Borewicz K., White B.A., Singer R.S., Sreevatsan S., Tu Z.J., Isaacson R.E., 2011. Longitudinal investigation of the age-related bacterial diversity in the feces of commercial pigs. Vet. Microbiol. 153, 124−133,
https://doi.org/10.1016/j.vetm....
22.
Kobasa D., Jones S.M., Shinya K. et al., 2007. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 445, 319−323,
https://doi.org/10.1038/nature....
23.
Li E., Ruan Y., Chen Q., Cui X., Lv L., Zheng P., Wang L., 2015. Streptococcal infection and immune response in children with Tourette’s syndrome. Child. Nerv. Syst. 31, 1157−1163,
https://doi.org/10.1007/s00381....
24.
Li Y.L., Fu A.K., Chen H.L., Li W.F., Fu L.Q., 2016. Potentiating effect of pidotimod on immune responses of chickens to live attenuated Newcastle disease vaccines. Ital. J. Anim. Sci. 15, 536−544,
https://doi.org/10.1080/182805....
25.
Li J., Yu Y., Jiang X., Lu Y., Tian Z., 2017. Fusobacterium nucleatum prompts colonic tumorigenesis in mice and its potential mechanism. Chin. J. Gastroenter. 22, 396−401,
https://doi.org/10.3969/j.issn....
26.
Mahashur A., Thomas P.K., Mehta P., Nivangune K., Muchhala S., Jain R., 2019. Pidotimod: In-depth review of current evidence. Lung India 36, 422−433,
https://doi.org/10.4103/lungin....
27.
Migliorati G., D’Adamio L., Coppi G., Nicoletti I., Riccardi C., 1992. Pidotimod stimulates natural killer cell activity and inhibits thymocyte cell death. Immunopharmacol. Immunotoxicol. 14, 737−748,
https://doi.org/10.3109/089239....
28.
Migliorati G., Nicoletti I., Delfino D., Maggioni A., Coppi G., Riccardi C., 1993. Pidotimod causes apoptotic cell death and inhibits the proliferative activity of YAC-1 tumor cells in vitro. Drugs Exp. Clin. Res. 19, Suppl., 1−7.
29.
Migliorati G., Nicoletti I., Riccardi C., 1994. Immunomodulating activity of pidotimod. Arzneimittelforschung 44, 1421−1424.
30.
Mujagic Z., de Vos P., Boekschoten M.V., Govers C., Pieters H.H., de Wit N.J.W., Bron P.A., Masclee A.A., Troost F.J., 2017. The effects of Lactobacillus plantarum on small intestinal barrier function and mucosal gene transcription; a randomized double blind placebo controlled trial. Sci. Rep. 7, 40128,
https://doi.org/10.1038/srep40....
31.
Murakami M., Kamimura D., Hirano T., 2019. Pleiotropy and specificity: insights from the interleukin 6 family of cytokines. Immunity 50, 812−831,
https://doi.org/10.1016/j.immu....
32.
Niu Q., Li P., Hao S., Kim S., Du T., Hua J., Huang R., 2019. Characteristics of gut microbiota in sows and their relationship with apparent nutrient digestibility. Int. J. Mol. Sci. 20, 870,
https://doi.org/10.3390/ijms20....
33.
NRC (National Research Council), 2012. Nutrient Requirements of Swine. 11th Revised Edition. The National Academies Press. Washington, DC (USA),
https://doi.org/10.17226/13298.
34.
Puggioni F., Alves-Correia M., Mohamed M.F. et al., 2019. Immunostimulants in respiratory diseases: focus on Pidotimod. Multidiscip. Resp. Med. 14, 31,
https://doi.org/10.1186/s40248....
35.
Qu S., Dai C., Qiu M., Zhang R., Wang C., Cui L., Hao Z., 2017. Effects of pidotimod soluble powder and immune enhancement of Newcastle disease vaccine in chickens. Immunol. Lett. 187, 14−18,
https://doi.org/10.1016/j.imle....
40.
Swamy M., Jamora C., Havran W., Hayday A., 2010. Epithelial decision makers: In search of the ‘epimmunome’. Nat. Immunol. 11, 656−665,
https://doi.org/10.1038/ni.190....
41.
Tian X.P., Zeng X.F., 2005. A new synthetic immunomodulator - pidotimod. Chin. New Drugs J. 1, 111−114.
42.
Trabattoni D., Clerici M., Centanni S., Mantero M., Garziano M., Blasi F., 2017. Immunomodulatory effects of pidotimod in adults with community-acquired pneumonia undergoing standard antibiotic therapy. Pulm. Pharmacol. Ther. 44, 24−29,
https://doi.org/10.1016/j.pupt....
43.
Ucciferri C., Falasca K., Reale M., Tamburro M., Auricchio A., Vignale F., Vecchiet J., 2020. Pidotimod and immunological activation in individuals infected with HIV. Curr. HIV Res. 18, 1,
https://doi.org/10.2174/157016....
44.
Wang S., Charbonnier L.M., Rivas M.N., Georgiev P., Ning L., Gerber G., Bry L., Chatila T.A., 2015. MyD88 adaptordependent microbial sensing by regulatory T cells promotes mucosal tolerance and enforces commensalism. Immunity 43, 289−303,
https://doi.org/10.1016/j.immu....
45.
Wojdasiewicz P., Poniatowski Ł.A., Szukiewicz D., 2014. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediat. Inflamm. 2014, 561459,
https://doi.org/10.1155/2014/5....
46.
Wu F., Ding X.Y., Li X.H., Gong M.J., An J.Q., Huang S.L., 2020. Correlation between elevated inflammatory cytokines of spleen and spleen index in acute spinal cord injury. J. Neuroimmunol. 344, 577264,
https://doi.org/10.1016/j.jneu....
47.
Xu X., Gong L., Wang B., Wu Y. et al., 2018. Glycyrrhizin attenuates Salmonella enterica serovar typhimurium infection: new insights into its protective mechanism. Front. Immunol. 9, 2321,
https://doi.org/10.3389/fimmu.....
49.
Zhong T.M., Mao F.J., Sun D.H., 2005. A test on medicine precaution and treatment of diarrhea of early-weaned piglets. Acta Agric. Zhejiangensis 17, 90−93.
50.
Zhong J.F., Wu W.G., Zhang X.Q., Tu W., Liu Z.X., Fang R.J., 2016. Effects of dietary addition of heat-killed Mycobacterium phlei on growth performance, immune status and anti-oxidative capacity in early weaned piglets. Arch. Anim. Nutr. 70, 249−262,
https://doi.org/10.1080/174503....