Top

Published in:

01-02-2018 | Original Contribution

Donkey milk consumption exerts anti-inflammatory properties by normalizing antimicrobial peptides levels in Paneth’s cells in a model of ileitis in mice

Authors: Sophie Yvon, Maïwenn Olier, Mathilde Leveque, Gwenaëlle Jard, Helene Tormo, Djamila Ali Haimoud-Lekhal, Magali Peter, Hélène Eutamène

Published in: European Journal of Nutrition | Issue 1/2018

Abstract

Purpose

In this study, we showed the beneficial effects of donkey milk (DM) on inflammatory damages, endogenous antimicrobial peptides levels and fecal microbiota profile in a mice model of Crohn’s disease. Nowadays, new strategies of microbiome manipulations are on the light involving specific diets to induce and/or to maintain clinical remission. Interest of DM is explained by its high levels of antimicrobial peptides which confer it anti-inflammatory properties.

Methods

C57BL/6 mice were orally administered with or without indomethacin for 5 days and co-treated with vehicle, DM or heated DM during 7 days. Intestinal length and macroscopic damage scores (MDSs) were determined; ileal samples were taken off for microscopic damage (MD), lysozyme immunostaining and mRNA α-defensin assessments. Ileal luminal content and fecal pellets were collected for lysozyme enzymatic activity and lipocalin-2 (LCN-2) evaluations. Fecal microbiota profiles were compared using a real-time quantitative PCR-based analysis.

Results

Administration of indomethacin caused an ileitis in mice characterized by (1) a decrease in body weight and intestinal length, (2) a significant increase in MDS, MD and LCN-2, (3) a reduction in both α-defensin mRNA expression and lysozyme levels in Paneth’s cells reflected by a decrease in lysozyme activity in feces, and (4) a global change in relative abundance of targeted microbial communities. DM treatment significantly reduced almost of all these ileitis damages, whereas heated DM has no impact on ileitis.

Conclusions

DM consumption exerts anti-inflammatory properties in mice by restoring the endogenous levels of antimicrobial peptides which contribute in turn to reduce microbiota imbalance.

Available only for authorised users

Radford-Smith G, Pandeya N (2006) Associations between NOD2/CARD15 genotype and phenotype in Crohn’s disease-Are we there yet? World J Gastroenterol 12:7097CrossRef

Lichtenstein GR, Hanauer SB, Sandborn WJ, Practice Parameters Committee of American College of Gastroenterology (2009) Management of Crohn’s disease in adults. Am J Gastroenterol 104(465–483):484. doi:10.1038/ajg.2008.168

Sartor RB (2011) Efficacy of probiotics for the management of inflammatory bowel disease. Gastroenterol Hepatol 7:606

Korzenik JR (2007) Is Crohn’s disease due to defective immunity? Gut 56:2–5. doi:10.1136/gut.2006.095588 CrossRef

Kamada N, Seo S-U, Chen GY, Núñez G (2013) Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol 13:321–335. doi:10.1038/nri3430 CrossRef

Schaubeck M, Clavel T, Calasan J et al (2015) Dysbiotic gut microbiota causes transmissible Crohn’s disease-like ileitis independent of failure in antimicrobial defence. Gut. doi:10.1136/gutjnl-2015-309333

Hold GL (2014) Role of the gut microbiota in inflammatory bowel disease pathogenesis: what have we learnt in the past 10 years? World J Gastroenterol 20:1192. doi:10.3748/wjg.v20.i5.1192 CrossRef

Kleessen B, Kroesen AJ, Buhr HJ, Blaut M (2002) Mucosal and invading bacteria in patients with inflammatory bowel disease compared with controls. Scand J Gastroenterol 37:1034–1041CrossRef

Scanlan PD, Shanahan F, O’Mahony C, Marchesi JR (2006) Culture-independent analyses of temporal variation of the dominant fecal microbiota and targeted bacterial subgroups in Crohn’s disease. J Clin Microbiol 44:3980–3988. doi:10.1128/JCM.00312-06 CrossRef

10.

Manichanh C, Rigottier-Gois L, Bonnaud E et al (2006) Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut 55:205–211. doi:10.1136/gut.2005.073817 CrossRef

11.

Sokol H, Seksik P, Furet JP et al (2009) Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm Bowel Dis 15:1183–1189. doi:10.1002/ibd.20903 CrossRef

12.

Swidsinski A, Loening-Baucke V, Vaneechoutte M, Doerffel Y (2008) Active Crohn’s disease and ulcerative colitis can be specifically diagnosed and monitored based on the biostructure of the fecal flora. Inflamm Bowel Dis 14:147–161. doi:10.1002/ibd.20330 CrossRef

13.

Sokol H, Pigneur B, Watterlot L et al (2008) Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA 105:16731–16736. doi:10.1073/pnas.0804812105 CrossRef

14.

Salzman NH, Bevins CL (2013) Dysbiosis–a consequence of Paneth cell dysfunction. Semin Immunol 25:334–341. doi:10.1016/j.smim.2013.09.006 CrossRef

15.

Menendez A, Willing BP, Montero M et al (2013) Bacterial stimulation of the TLR-MyD88 pathway modulates the homeostatic expression of ileal Paneth cell a-defensins. J Innate Immun 5:39–49. doi:10.1159/000341630 CrossRef

16.

Salzman NH (2010) Paneth cell defensins and the regulation of the microbiome: détente at mucosal surfaces. Gut Microbes 1:401–406. doi:10.4161/gmic.1.6.14076 CrossRef

17.

Guaní-Guerra E, Santos-Mendoza T, Lugo-Reyes SO, Terán LM (2010) Antimicrobial peptides: general overview and clinical implications in human health and disease. Clin Immunol 135:1–11. doi:10.1016/j.clim.2009.12.004 CrossRef

18.

Jäger S, Stange EF, Wehkamp J (2010) Antimicrobial peptides in gastrointestinal inflammation. Int J Inflamm 2010:1–11. doi:10.4061/2010/910283 CrossRef

19.

Wehkamp J, Salzman NH, Porter E et al (2005) Reduced Paneth cell α-defensins in ileal Crohn’s disease. Proc Natl Acad Sci USA 102:18129–18134CrossRef

20.

Wehkamp J, Wang G, Kübler I et al (2007) The Paneth cell α-defensin deficiency of ileal Crohn’s disease is linked to Wnt/Tcf-4. J Immunol 179:3109–3118CrossRef

21.

Cadwell K, Patel KK, Komatsu M et al (2009) A common role for Atg16L1, Atg5, and Atg7 in small intestinal Paneth cells and Crohn disease. Autophagy 5:250–252. doi:10.4161/auto.5.2.7560 CrossRef

22.

D’Haens GR, Sartor RB, Silverberg MS et al (2014) Future directions in inflammatory bowel disease management. J Crohns Colitis 8:726–734. doi:10.1016/j.crohns.2014.02.025 CrossRef

23.

Ren W-K, Yin J, Zhu X-P et al (2013) Glutamine on intestinal inflammation: a mechanistic perspective. Eur J Inflamm 11:315–326. doi:10.1177/1721727X1301100201 CrossRef

24.

Frøslie KF, Jahnsen J, Moum BA, Vatn MH (2007) Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 133:412–422. doi:10.1053/j.gastro.2007.05.051 CrossRef

25.

Ren W, Chen S, Yin J et al (2014) Dietary arginine supplementation of mice alters the microbial population and activates intestinal innate immunity. J Nutr 144:988–995. doi:10.3945/jn.114.192120 CrossRef

26.

Guo HY, Pang K, Zhang XY et al (2007) Composition, physiochemical properties, nitrogen fraction distribution, and amino acid profile of donkey milk. J Dairy Sci 90:1635–1643. doi:10.3168/jds.2006-600 CrossRef

27.

Uniacke-Lowe T, Huppertz T, Fox PF (2010) Equine milk proteins: chemistry, structure and nutritional significance. Int Dairy J 20:609–629. doi:10.1016/j.idairyj.2010.02.007 CrossRef

28.

Muraro MA, Giampietro PG, Galli E (2002) Soy formulas and nonbovine milk. Ann Allergy Asthma Immunol 89:97–101CrossRef

29.

Carroccio A, Cavataio F, Montalto G et al (2000) Intolerance to hydrolysed cow’s milk proteins in infants: clinical characteristics and dietary treatment. Clin Exp Allergy 30:1597–1603CrossRef

30.

Tidona F, Sekse C, Criscione A et al (2011) Antimicrobial effect of donkeys’ milk digested in vitro with human gastrointestinal enzymes. Int Dairy J 21:158–165. doi:10.1016/j.idairyj.2010.10.008 CrossRef

31.

Zhang X-Y, Zhao L, Jiang L et al (2008) The antimicrobial activity of donkey milk and its microflora changes during storage. Food Control 19:1191–1195. doi:10.1016/j.foodcont.2008.01.005 CrossRef

32.

Mao X, Gu J, Sun Y et al (2009) Anti-proliferative and anti-tumour effect of active components in donkey milk on A549 human lung cancer cells. Int Dairy J 19:703–708. doi:10.1016/j.idairyj.2009.05.007 CrossRef

33.

Craven M, Egan CE, Dowd SE et al (2012) Inflammation drives dysbiosis and bacterial invasion in murine models of ileal Crohn’s Disease. PLoS One 7:e41594. doi:10.1371/journal.pone.0041594 CrossRef

34.

Wallace JL, MacNaughton WK, Morris GP, Beck PL (1989) Inhibition of leukotriene synthesis markedly accelerates healing in a rat model of inflammatory bowel disease. Gastroenterology 96:29–36CrossRef

35.

Fabia R, Ar’Rajab A, Johansson ML et al (1993) The effect of exogenous administration of Lactobacillus reuteri R2LC and oat fiber on acetic acid-induced colitis in the rat. Scand J Gastroenterol 28:155–162CrossRef

36.

Chassaing B, Srinivasan G, Delgado MA et al (2012) Fecal lipocalin 2, a sensitive and broadly dynamic non-invasive biomarker for intestinal inflammation. PLoS One 7:e44328. doi:10.1371/journal.pone.0044328 CrossRef

37.

Bergström A, Licht TR, Wilcks A et al (2012) Introducing GUt low-density array (GULDA)—a validated approach for qPCR-based intestinal microbial community analysis. FEMS Microbiol Lett 337:38–47. doi:10.1111/1574-6968.12004 CrossRef

38.

Bergstrom A, Skov TH, Bahl MI et al (2014) Establishment of intestinal microbiota during early life: a longitudinal, explorative study of a large cohort of danish infants. Appl Environ Microbiol 80:2889–2900. doi:10.1128/AEM.00342-14 CrossRef

39.

Hendrickson BA, Gokhale R, Cho JH (2002) Clinical aspects and pathophysiology of inflammatory bowel disease. Clin Microbiol Rev 15:79–94CrossRef

40.

Danese S, Fiocchi C (2006) Etiopathogenesis of inflammatory bowel diseases. World J Gastroenterol 12:4807–4812CrossRef

41.

Hotamisligil GS, Erbay E (2008) Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol 8:923–934. doi:10.1038/nri2449 CrossRef

42.

Trinchese G, Cavaliere G, Canani RB et al (2015) Human, donkey and cow milk differently affects energy efficiency and inflammatory state by modulating mitochondrial function and gut microbiota. J Nutr Biochem. doi:10.1016/j.jnutbio.2015.05.003

43.

Tafaro A, Magrone T, Jirillo F et al (2007) Immunological properties of donkey’s milk: its potential use in the prevention of atherosclerosis. Curr Pharm Des 13:3711–3717CrossRef

44.

Jirillo F, Jirillo E, Magrone T (2010) Donkey’s and goat’s milk consumption and benefits to human health with special reference to the inflammatory status. Curr Pharm Des 16:859–863CrossRef

45.

Salimei E, Fantuz F (2012) Equid milk for human consumption. Int Dairy J 24:130–142. doi:10.1016/j.idairyj.2011.11.008 CrossRef

46.

Gastaldi D, Bertino E, Monti G et al (2010) Donkey’s milk detailed lipid composition. Front Biosci E 2:537–546

47.

Brumini D, Criscione A, Bordonaro S et al (2015) Whey proteins and their antimicrobial properties in donkey milk: a brief review. Dairy Sci Technol. doi:10.1007/s13594-015-0246-1

48.

Murua A, Todorov SD, Vieira ADS et al (2013) Isolation and identification of bacteriocinogenic strain of Lactobacillus plantarum with potential beneficial properties from donkey milk. J Appl Microbiol 114:1793–1809. doi:10.1111/jam.12190 CrossRef

49.

Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661. doi:10.1096/fj.07-9574LSF CrossRef

50.

Morris AJ, Madhok R, Sturrock RD et al (1991) Enteroscopic diagnosis of small bowel ulceration in patients receiving non-steroidal anti-inflammatory drugs. Lancet Lond Engl 337:520CrossRef

51.

Fujimori S, Seo T, Gudis K et al (2007) Diagnosis and treatment of obscure gastrointestinal bleeding using combined capsule endoscopy and double balloon endoscopy: 1-year follow-up study. Endoscopy 39:1053–1058. doi:10.1055/s-2007-967014 CrossRef

52.

Robert A, Asano T (1977) Resistance of germfree rats to indomethacin-induced intestinal lesions. Prostaglandins 14:333–341CrossRef

53.

Konaka A, Kato S, Tanaka A et al (1999) Roles of enterobacteria, nitric oxide and neutrophil in pathogenesis of indomethacin-induced small intestinal lesions in rats. Pharmacol Res 40:517–524. doi:10.1006/phrs.1999.0550 CrossRef

54.

Bjarnason I, Williams P, So A et al (1984) Intestinal permeability and inflammation in rheumatoid arthritis: effects of non-steroidal anti-inflammatory drugs. Lancet Lond Engl 2:1171–1174CrossRef

55.

Fujimori S, Gudis K, Takahashi Y et al (2010) Distribution of small intestinal mucosal injuries as a result of NSAID administration. Eur J Clin Invest 40:504–510. doi:10.1111/j.1365-2362.2010.02290.x CrossRef

56.

Takeuchi K, Smale S, Premchand P et al (2006) Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 4:196–202CrossRef

57.

Schroder K, Hertzog PJ, Ravasi T, Hume DA (2004) Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 75:163–189. doi:10.1189/jlb.0603252 CrossRef

58.

Lamine F, Fioramonti J, Bueno L et al (2004) Nitric oxide released by Lactobacillus farciminis improves TNBS-induced colitis in rats. Scand J Gastroenterol 39:37–45CrossRef

59.

Derde M, Nau F, Lechevalier V et al (2015) Native lysozyme and dry-heated lysozyme interactions with membrane lipid monolayers: lateral reorganization of LPS monolayer, model of the Escherichia coli outer membrane. Biochim Biophys Acta 1848:174–183. doi:10.1016/j.bbamem.2014.10.026 CrossRef

60.

Ellison RT, Giehl TJ (1991) Killing of gram-negative bacteria by lactoferrin and lysozyme. J Clin Invest 88:1080–1091CrossRef

61.

Ibrahim HR, Kato A, Kobayashi K (1991) Antimicrobial effects of lysozyme against gram-negative bacteria due to covalent binding of palmitic acid. J Agric Food Chem 39:2077–2082. doi:10.1021/jf00011a039 CrossRef

62.

Sokol H, Seksik P, Rigottier-Gois L et al (2006) Specificities of the fecal microbiota in inflammatory bowel disease. Inflamm Bowel Dis 12:106–111. doi:10.1097/01.MIB.0000200323.38139.c6 CrossRef

63.

Willing BP, Dicksved J, Halfvarson J et al (2010) A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology 139(1844–1854):e1. doi:10.1053/j.gastro.2010.08.049

64.

Rajca S, Grondin V, Louis E et al (2014) Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn’s disease. Inflamm Bowel Dis 20:978–986. doi:10.1097/MIB.0000000000000036

65.

Ganesh BP, Klopfleisch R, Loh G, Blaut M (2013) Commensal Akkermansia muciniphila exacerbates gut inflammation in salmonella typhimurium-infected gnotobiotic mice. PLoS One 8:e74963. doi:10.1371/journal.pone.0074963 CrossRef

66.

Derrien M, Van Baarlen P, Hooiveld G et al (2011) Modulation of mucosal immune response, tolerance, and proliferation in mice colonized by the mucin-degrader akkermansia muciniphila. Front Microbiol 2:166. doi:10.3389/fmicb.2011.00166 CrossRef

67.

Belzer C, de Vos WM (2012) Microbes inside–from diversity to function: the case of Akkermansia. ISME J 6:1449–1458. doi:10.1038/ismej.2012.6 CrossRef

68.

Klein A, Roussel P (1998) O-acetylation of sialic acids. Biochimie 80:49–57CrossRef

69.

Larsson JMH, Karlsson H, Crespo JG et al (2011) Altered O-glycosylation profile of MUC2 mucin occurs in active ulcerative colitis and is associated with increased inflammation. Inflamm Bowel Dis 17:2299–2307. doi:10.1002/ibd.21625 CrossRef

70.

Earley H, Lennon G, Balfe A et al (2015) A preliminary study examining the binding capacity of akkermansia muciniphila and desulfovibrio spp., to Colonic mucin in health and ulcerative colitis. PLoS One 10:e0135280. doi:10.1371/journal.pone.0135280 CrossRef

71.

Wehkamp J, Koslowski M, Wang G, Stange EF (2008) Barrier dysfunction due to distinct defensin deficiencies in small intestinal and colonic Crohn’s disease. Mucosal Immunol 1(Suppl 1):S67–S74. doi:10.1038/mi.2008.48 CrossRef

72.

Simms LA, Doecke JD, Walsh MD et al (2008) Reduced -defensin expression is associated with inflammation and not NOD2 mutation status in ileal Crohn’s disease. Gut 57:903–910. doi:10.1136/gut.2007.142588 CrossRef

73.

Muniz LR, Knosp C, Yeretssian G (2012) Intestinal antimicrobial peptides during homeostasis, infection, and disease. Front Immunol. doi:10.3389/fimmu.2012.00310

Title: Donkey milk consumption exerts anti-inflammatory properties by normalizing antimicrobial peptides levels in Paneth’s cells in a model of ileitis in mice
Authors: Sophie Yvon
Maïwenn Olier
Mathilde Leveque
Gwenaëlle Jard
Helene Tormo
Djamila Ali Haimoud-Lekhal
Magali Peter
Hélène Eutamène
Publication date: 01-02-2018
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Nutrition / Issue 1/2018
Print ISSN: 1436-6207
Electronic ISSN: 1436-6215
DOI: https://doi.org/10.1007/s00394-016-1304-z

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2018

Identification of urinary metabolites with potential blood pressure-lowering effects in lentil-fed spontaneously hypertensive rats

Durum wheat particle size affects starch and protein digestion in vitro

Regularly consuming a green/roasted coffee blend reduces the risk of metabolic syndrome

A high-fat high-sucrose diet affects the long-term metabolic fate of grape proanthocyanidins in rats

Daily supplementation with fresh pomegranate juice increases paraoxonase 1 expression and activity in mice fed a high-fat diet

N-acetylcysteine attenuates intrauterine growth retardation-induced hepatic damage in suckling piglets by improving glutathione synthesis and cellular homeostasis

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage