Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

ACC 2024 Congress

Catch up on all the top stories and latest evidence in cardiology research with our ACC 2024 Congress hub page.
ADVANCED SEARCH
Log in
Top
Gut Pathogens
Published in: Gut Pathogens 1/2012

Open Access 01-12-2012 | Research

Lactase persistence, NOD2 status and Mycobacterium avium subsp. paratuberculosis infection associations to Inflammatory Bowel Disease

Authors: Natalia Elguezabal, Susana Chamorro, Elena Molina, Joseba M Garrido, Ander Izeta, Luis Rodrigo, Ramón A Juste

Published in: Gut Pathogens | Issue 1/2012

Login to get access

Abstract

Background

Inflammatory Bowel Disease (IBD), which includes both Crohn’s disease (CD) and ulcerative colitis (UC), is caused by a complex interplay involving genetic predisposition, environmental factors and an infectious agent. Mycobacterium avium subsp. paratuberculosis (MAP) is a promising pathogen candidate since it produces a chronic intestinal inflammatory disease in ruminants that resembles CD in humans. MAP is a ubiquitous microorganism, although its presence in the food chain, especially in milk from infected animals, is what made us think that there could be an association between lactase persistence (LP) and IBD. The LCT mutation has brought adaptation to dairy farming which in turn would have increased exposure of the population to infection by MAP. NOD2 gene mutations are highly associated to CD.

Methods

In our study, CD and UC patients and controls from the North of Spain were genotyped for the lactase gene (LCT) and for three NOD-2 variants, R702W, G908R and Cins1007fs. MAP PCR was carried out in order to assess MAP infection status and these results were correlated with LCT and NOD2 genotypes.

Results

As for LP, no association was found with IBD, although UC patients were less likely to present the T/T−13910 variant compared to controls, showing a higher C-allele frequency and a tendency to lactase non-persistence (LNP). NOD2 mutations were associated to CD being the per-allele risk higher for the Cins1007fs variant. MAP infection was more extended among the healthy controls (45.2%) compared to CD patients (21.38%) and UC patients (19.04%) and this was attributed to therapy. The Asturian CD cohort presented higher levels of MAP prevalence (38.6%) compared to the Basque CD cohort (15.5%), differences also attributed to therapy. No interaction was found between MAP infection and LCT or NOD2 status.

Conclusions

We conclude that LP is not significantly associated with IBD, but that MAP infection and NOD2 do show not mutually interacting associations with IBD.
Literature
1.
Goyette P, Labbe C, Trinh TT, Xavier RJ, Rioux JD: Molecular pathogenesis of inflammatory bowel disease: genotypes, phenotypes and personalized medicine. Ann Med. 2007, 39: 177-199.CrossRefPubMed
2.
Packey CD, Sartor RB: Commensal bacteria, traditional and opportunistic pathogens, dysbiosis and bacterial killing in inflammatory bowel diseases. Curr Opin Infect Dis. 2009, 22: 292-301.PubMedCentralCrossRefPubMed
3.
Chacon O, Bermudez LE, Barletta RG: Johne's disease, inflammatory bowel disease, and Mycobacterium paratuberculosis. Annu Rev Microbiol. 2004, 58: 329-363.CrossRefPubMed
4.
Greenstein RJ: Is Crohn's disease caused by a mycobacterium? Comparisons with leprosy, tuberculosis, and Johne's disease. Lancet Infect Dis. 2003, 3: 507-514.CrossRefPubMed
5.
Mendoza JL, Lana R, Diaz-Rubio M: Mycobacterium avium subspecies paratuberculosis and its relationship with Crohn's disease. World J Gastroenterol. 2009, 15: 417-422.PubMedCentralCrossRefPubMed
6.
Crohn BB, Ginzburg L, Oppenheimer G: Regional enteritis a pathologic and clinical entity. JAMA. 1932, 99: 1323-1329.CrossRef
7.
Dalziel TK: Chronic interstitial enteritis. Br Med J. 1913, ii: 1068-1070.
8.
Mendoza JL, San Pedro A, Culebras E, Cies R, Taxonera C, Lana R, Urcelay E, de la Torre F, Picazo JJ, Diaz-Rubio M: High prevalence of viable Mycobacterium avium subspecies paratuberculosis in Crohn's disease. World J Gastroenterol. 2010, 16: 4558-4563.PubMedCentralCrossRefPubMed
9.
Sechi LA, Scanu AM, Molicotti P, Cannas S, Mura M, Dettori G, Fadda G, Zanetti S: Detection and Isolation of Mycobacterium avium subspecies paratuberculosis from intestinal mucosal biopsies of patients with and without Crohn's disease in Sardinia. Am J Gastroenterol. 2005, 100: 1529-1536.CrossRefPubMed
10.
Bentley RW, Keenan JI, Gearry RB, Kennedy MA, Barclay ML, Roberts RL: Incidence of Mycobacterium avium subspecies paratuberculosis in a population-based cohort of patients with Crohn's disease and control subjects. Am J Gastroenterol. 2008, 103: 1168-1172.CrossRefPubMed
11.
Di Sabatino A, Paccagnini D, Vidali F, Rosu V, Biancheri P, Cossu A, Zanetti S, Corazza GR, Sechi LA: Detection of Mycobacterium avium subsp. paratuberculosis (MAP)-specific IS900 DNA and antibodies against MAP peptides and lysate in the blood of Crohn's disease patients. Inflamm Bowel Dis. 2011, 17: 1254-1255.CrossRefPubMed
12.
Juste RA, Elguezabal N, Garrido JM, Pavon A, Geijo MV, Sevilla I, Cabriada JL, Tejada A, Garcia-Campos F, Casado R: On the prevalence of M. avium subspecies paratuberculosis DNA in the blood of healthy individuals and patients with inflammatory bowel disease. PLoS One. 2008, 3: e2537-PubMedCentralCrossRefPubMed
13.
Juste RA, Elguezabal N, Pavon A, Garrido JM, Geijo M, Sevilla I, Cabriada JL, Tejada A, Garcia-Campos F, Casado R: Association between Mycobacterium avium subsp. paratuberculosis DNA in blood and cellular and humoral immune response in inflammatory bowel disease patients and controls. Int J Infect Dis. 2009, 13: 247-254.CrossRefPubMed
14.
Naser SA, Ghobrial G, Romero C, Valentine JF: Culture of Mycobacterium avium subspecies paratuberculosis from the blood of patients with Crohn's disease. Lancet. 2004, 364: 1039-1044.CrossRefPubMed
15.
Cho JH, Brant SR: Recent insights into the genetics of inflammatory bowel disease. Gastroenterology. 2011, 140: 1704-1712.CrossRefPubMed
16.
Nakase H, Tamaki H, Matsuura M, Chiba T, Okazaki K: Involvement of Mycobacterium avium subspecies paratuberculosis in TNF-alpha production from macrophage: possible link between MAP and immune response in Crohn's disease. Inflamm Bowel Dis. 2011, 17: E140-E142.CrossRefPubMed
17.
Economou M, Trikalinos TA, Loizou KT, Tsianos EV, Ioannidis JP: Differential effects of NOD2 variants on Crohn's disease risk and phenotype in diverse populations: a metaanalysis. Am J Gastroenterol. 2004, 99: 2393-2404.CrossRefPubMed
18.
Wong SH, Hill AV, Vannberg FO: Genomewide association study of leprosy. N Engl J Med. 2010, 362: 1446-1447.CrossRefPubMed
19.
Zhang FR, Huang W, Chen SM, Sun LD, Liu H, Li Y, Cui Y, Yan XX, Yang HT, Yang RD: Genomewide association study of leprosy. N Engl J Med. 2009, 361: 2609-2618.CrossRefPubMed
20.
Mishkin B, Yalovsky M, Mishkin S: Increased prevalence of lactose malabsorption in Crohn's disease patients at low risk for lactose malabsorption based on ethnic origin. Am J Gastroenterol. 1997, 92: 1148-1153.PubMed
21.
Pironi L, Callegari C, Cornia GL, Lami F, Miglioli M, Barbara L: Lactose malabsorption in adult patients with Crohn's disease. Am J Gastroenterol. 1988, 83: 1267-1271.PubMed
22.
von Tirpitz C, Kohn C, Steinkamp M, Geerling I, Maier V, Moller P, Adler G, Reinshagen M: Lactose intolerance in active Crohn's disease: clinical value of duodenal lactase analysis. J Clin Gastroenterol. 2002, 34: 49-53.CrossRefPubMed
23.
24.
Shrier I, Szilagyi A, Correa JA: Impact of lactose containing foods and the genetics of lactase on diseases: an analytical review of population data. Nutr Cancer. 2008, 60: 292-300.CrossRefPubMed
25.
Park RH, Duncan A, Russell RI: Hypolactasia and Crohn's disease: a myth. Am J Gastroenterol. 1990, 85: 708-710.PubMed
26.
Pfefferkorn MD, Fitzgerald JF, Croffie JM, Gupta SK, Corkins MR, Molleston JP: Lactase deficiency: not more common in pediatric patients with inflammatory bowel disease than in patients with chronic abdominal pain. J Pediatr Gastroenterol Nutr. 2002, 35: 339-343.CrossRefPubMed
27.
Poulter M, Hollox E, Harvey CB, Mulcare C, Peuhkuri K, Kajander K, Sarner M, Korpela R, Swallow DM: The causal element for the lactase persistence/non-persistence polymorphism is located in a 1 Mb region of linkage disequilibrium in Europeans. Ann Hum Genet. 2003, 67: 298-311.CrossRefPubMed
28.
Buning C, Ockenga J, Kruger S, Jurga J, Baier P, Dignass A, Vogel A, Strassburg C, Weltrich R, Genschel J: The C/C(−13910) and G/G(−22018) genotypes for adult-type hypolactasia are not associated with inflammatory bowel disease. Scand J Gastroenterol. 2003, 38: 538-542.PubMed
29.
Nolan DJ, Han DY, Lam WJ, Morgan AR, Fraser AG, Tapsell LC, Ferguson LR: Genetic adult lactase persistence is associated with risk of Crohn's Disease in a New Zealand population. BMC Res Notes. 2010, 3: 339-PubMedCentralCrossRefPubMed
30.
Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Jarvela I: Identification of a variant associated with adult-type hypolactasia. Nat Genet. 2002, 30: 233-237.CrossRefPubMed
31.
Lember M, Torniainen S, Kull M, Kallikorm R, Saadla P, Rajasalu T, Komu H, Jarvela I: Lactase non-persistence and milk consumption in Estonia. World J Gastroenterol. 2006, 12: 7329-7331.PubMedCentralPubMed
32.
Sahi T: Genetics and epidemiology of adult-type hypolactasia. Scand J Gastroenterol Suppl. 1994, 202: 7-20.CrossRefPubMed
33.
Almon R, Alvarez-Leon EE, Engfeldt P, Serra-Majem L, Magnuson A, Nilsson TK: Associations between lactase persistence and the metabolic syndrome in a cross-sectional study in the Canary Islands. Eur J Nutr. 2010, 49: 141-146.CrossRefPubMed
34.
Agueda L, Urreizti R, Bustamante M, Jurado S, Garcia-Giralt N, Diez-Perez A, Nogues X, Mellibovsky L, Grinberg D, Balcells S: Analysis of three functional polymorphisms in relation to osteoporosis phenotypes: replication in a Spanish cohort. Calcif Tissue Int. 2010, 87: 14-24.CrossRefPubMed
35.
Rasinpera H, Savilahti E, Enattah NS, Kuokkanen M, Totterman N, Lindahl H, Jarvela I, Kolho KL: A genetic test which can be used to diagnose adult-type hypolactasia in children. Gut. 2004, 53: 1571-1576.PubMedCentralCrossRefPubMed
36.
Gerbault P, Liebert A, Itan Y, Powell A, Currat M, Burger J, Swallow DM, Thomas MG: Evolution of lactase persistence: an example of human niche construction. Philos Trans R Soc Lond B Biol Sci. 2011, 366: 863-877.PubMedCentralCrossRefPubMed
37.
Glassman MS, Newman LJ, Berezin S, Gryboski JD: Cow's milk protein sensitivity during infancy in patients with inflammatory bowel disease. Am J Gastroenterol. 1990, 85: 838-840.PubMed
38.
Kumar D, Repucci A, Wyatt-Ashmead J, Chelimsky G: Allergic colitis presenting in the first day of life: report of three cases. J Pediatr Gastroenterol Nutr. 2000, 31: 195-197.CrossRefPubMed
39.
Juste RA, Elguezabal N, Chamorro S, Molina E, Garrido JM, Riestra S, de Francisco R, Rodrigo L: Associations between CARD15 polymorphisms, MAP DNA in blood and lactase persistence in a Crohn's disease case–control study in North Spain. 2009, In Proceedings of the 10th International Colloquim on Paratuberculosis, Minnesota, 269-9-14 August 2009
40.
Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, Philpott DJ, Sansonetti PJ: Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. 2003, 278: 8869-8872.CrossRefPubMed
41.
Ferwerda G, Girardin SE, Kullberg BJ, Le Bourhis L, de Jong DJ, Langenberg DM, van Crevel R, Adema GJ, Ottenhoff TH, Van der Meer JW: NOD2 and toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis. PLoS Pathog. 2005, 1: 279-285.PubMed
42.
Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001, 411: 599-603.CrossRefPubMed
43.
Guagnozzi D, Cossu A, Viscido A, Corleto V, Annese V, Latiano A, Delle FG, Caprilli R: Acute intestinal obstruction and NOD2/CARD15 mutations among Italian Crohn's disease patients. Eur Rev Med Pharmacol Sci. 2004, 8: 179-185.PubMed
44.
Nunez C, Barreiro M, Dominguez-Munoz JE, Lorenzo A, Zapata C, Pena AS: CARD15 mutations in patients with Crohn's disease in a homogeneous Spanish population. Am J Gastroenterol. 2004, 99: 450-456.CrossRefPubMed
45.
Barreiro-de-Acosta M, Mendoza JL, Lana R, Dominguez-Munoz JE, Diaz-Rubio M: NOD2/CARD15: geographic differences in the Spanish population and clinical applications in Crohn's disease. Rev Esp Enferm Dig. 2010, 102: 321-326.PubMed
46.
Cuthbert AP, Fisher SA, Mirza MM, King K, Hampe J, Croucher PJ, Mascheretti S, Sanderson J, Forbes A, Mansfield J: The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology. 2002, 122: 867-874.CrossRefPubMed
47.
Sechi LA, Gazouli M, Sieswerda LE, Molicotti P, Ahmed N, Ikonomopoulos J, Scanu AM, Paccagnini D, Zanetti S: Relationship between Crohn's disease, infection with Mycobacterium avium subspecies paratuberculosis and SLC11A1 gene polymorphisms in Sardinian patients. World J Gastroenterol. 2006, 12: 7161-7164.PubMedCentralPubMed
48.
Alonso-Hearn M, Molina E, Geijo M, Vazquez P, Sevilla I, Juste RA, Garrido JM: Isolation of Mycobacterium avium subsp. paratuberculosis from muscle tissue of naturally infected cattle. Foodborne Pathog Dis. 2009, 6: 513-518.CrossRefPubMed
49.
Eltholth MM, Marsh VR, Van Winden S, Guitian FJ: Contamination of food products with Mycobacterium avium paratuberculosis: a systematic review. J Appl Microbiol. 2009, 107: 1061-1071.CrossRefPubMed
50.
Reddacliff LA, Marsh IB, Fell SA, Austin SL, Whittington RJ: Isolation of Mycobacterium avium subspecies paratuberculosis from muscle and peripheral lymph nodes using acid-pepsin digest prior to BACTEC culture. Vet Microbiol. 2010, 145: 122-128.CrossRefPubMed
51.
Patel A, Shah N: Mycobacterium avium subsp paratuberculosis–incidences in milk and milk products, their isolation, enumeration, characterization, and role in human health. J Microbiol Immunol Infect. 2011, 44: 473-479.CrossRefPubMed
52.
Whittington RJ, Waldron A, Warne D: Thermal inactivation profiles of Mycobacterium avium subsp. paratuberculosis in lamb skeletal muscle homogenate fluid. Int J Food Microbiol. 2010, 137: 32-39.CrossRefPubMed
53.
Bernstein CN, Wang MH, Sargent M, Brant SR, Collins MT: Testing the interaction between NOD-2 status and serological response to Mycobacterium paratuberculosis in cases of inflammatory bowel disease. J Clin Microbiol. 2007, 45: 968-971.PubMedCentralCrossRefPubMed
54.
Borinskaia SA, Rebrikov DV, Nefedova VV, Kofiadi IA, Sokolova MV, Kolchina EV, Kulikova EA, Chernyshov VN, Kutsev SI, Polonikov AV: Molecular diagnosis and frequencies of primary hypolactasia in populations of RUSSIA and neighboring countries. Mol Biol (Mosk). 2006, 40: 1031-1036.
55.
Helio T, Halme L, Lappalainen M, Fodstad H, Paavola-Sakki P, Turunen U, Farkkila M, Krusius T, Kontula K: CARD15/NOD2 gene variants are associated with familially occurring and complicated forms of Crohn's disease. Gut. 2003, 52: 558-562.PubMedCentralCrossRefPubMed
Metadata
Title
Lactase persistence, NOD2 status and Mycobacterium avium subsp. paratuberculosis infection associations to Inflammatory Bowel Disease
Authors
Natalia Elguezabal
Susana Chamorro
Elena Molina
Joseba M Garrido
Ander Izeta
Luis Rodrigo
Ramón A Juste
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Gut Pathogens / Issue 1/2012
Electronic ISSN: 1757-4749
DOI
https://doi.org/10.1186/1757-4749-4-6

Other articles of this Issue 1/2012

Gut Pathogens 1/2012 Go to the issue

Research

Leukocyte-subset counts in idiopathic parkinsonism provide clues to a pathogenic pathway involving small intestinal bacterial overgrowth. A surveillance study

Research

Bacillus coagulans GBI-30, 6086 limits the recurrence of Clostridium difficile-Induced colitis following vancomycin withdrawal in mice

Research

Rapid paracellular transmigration of Campylobacter jejuni across polarized epithelial cells without affecting TER: role of proteolytic-active HtrA cleaving E-cadherin but not fibronectin

Research

Mucosa-associated but not luminal Escherichia coli is augmented in Crohn’s disease and ulcerative colitis

Research

Inactivation of Bacillus cereus vegetative cells by gastric acid and bile during in vitro gastrointestinal transit

Research

KPC-mediated resistance in Klebsiella pneumoniae in two hospitals in Padua, Italy, June 2009-December 2011: massive spreading of a KPC-3-encoding plasmid and involvement of non-intensive care units

ACC 2024 Congress Coverage

Cardiology Video

Highlights from the ACC 2024 Congress

Watch now

Watch official videos from the ACC congress summarizing key highlights from the last year in heart failure, cardiomyopathies, valvular disease, pulmonary vascular disease, and pediatric cardiology.

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