Environmental factors affecting IBD Have we made progress? Peter Laszlo Lakatos 1st Department of Medicine Semmelweis University Budapest Hungary

Environmental factors affecting IBD Have we made progress? Peter Laszlo Lakatos 1st Department of Medicine Semmelweis University Budapest Hungary

Environmental factors in IBD Are associated with disease susceptibility? Predicting disease phenotype? During the course of the disease, are they of any value in predicting relapse? short-long term prognosis and risk for complications?

IBD a complex phenotype

Environmental factors in IBD flora stress smoking drugs (OC, NSAID) appendectomy IBD infections (measles, mycobacterium, pharyngitis, tonsillitis,) diet hygiene (refined sugar, fat, fast food, corn flakes, chocolate, cocacola, toothpaste)

Disease susceptibility

Diet? Evidence suggesting a relationship between sugars and onset of Crohn's disease was inconsistent and subject to important methodological limitations. There was a clear lack of distinction between reporting of current, as opposed to, retrospective intakes. There appeared to be no clinical advantage to the use of reduced sugar diets in Crohn's disease treatment Riordan AM Eur J Clin Nutr 1998;52:229-38.

Developed hygiene? Bernstein CN Am J GE 2006

Developed hygiene? Bernstein CN Am J GE 2006

Developed hygiene? OR for IBD 95%CI male gender 1.44 1.24-1.67 urban environment 1.38 1.02-1.78 number of siblings (1 vs 5 or more) higher birth order (5 or higher vs 1) 2.63 1.49-4.62 2.35 1.47-3.77 Klement E Am J GE 2008

Baron S Gut 2005 Developed hygiene?

Vaccination? Davis RL Arch Ped Adolesc Med 2001

Drugs, oral contraceptive use Bernstein CN Am J GE 2006

Oral contraceptive use OR CD : 1.44, OR CD : 1.51, (14 studies) 95%CI: 1.12-1.86 95%CI: 1.17-1.96 OR UC : 1.29, 95%CI: 0.94-1.77 Godet PG Gut 1995 Cornish JA Am J GE 2008

Appendectomy and risk of UC Rate of appendectomy in UC: 1/174 (0.6%) Rate of appendecytomy in controls: 41/161 (25.4%) OR: 59.1 (95% CI, 18-189) Rutgeerts NEJM 1994 Koutrobakis IBD 2002

Life events Lerebours E IBD 2007

Smoking

current vs never smoking 1.76 95%CI: 1.40-2.22 P<0.001 former vs never smoking 1.30 95%CI: 0.97-1.76 P=0.08 Mahid SS Mayo Clin Proc 2006

current vs never smoking 0.58 95%CI: 0.45-0.75 P<0.001 former vs never smoking 1.79 95%CI: 1.37-2.34 P<0.001 Mahid SS Mayo Clin Proc 2006

Passive childhood smoking Mahid SS IBD 2007

Is it infectious? Virus, bacteria or worms?

Dysbiosis in Crohn s disease? Faecal flora Bacteroides vulgatus Eubacteria Peptostreptococci Coprococci E.coli Bifidobacteria Lactobacilli

Mucosa associated bacteria are common in Crohn s disease 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% n = Asymptomatic controls Self-limiting colitis Intermediate colitis UC 40 28 104 119 CD 54 In 40% CD patients > 10 000 cfu/ml 0 <1000 cfu/μl 1000 <10000 cfu/μl 10000 <50000 cfu/μl >50000 cfu/μl Swidzsinski et al. Gastroenterology 2002

Cold chain is it a hypothesis? Epidemiological data allow assessment of familial environmental risk factors related to western lifestyle, diet, bacteria, and domestic hygiene. All findings point to refrigeration as a potential risk factor for Crohn s disease. Furthermore, cold-chain development paralleled the outbreak of Crohn s disease during the 20th century. The cold chain hypothesis suggests that psychrotrophic bacteria such as Yersinia spp and Listeria spp contribute to the disease. Hugot JP Lancet 2003

History of genetic research in IBD 1980 IBD is a (poly)genic and multifactorial disorder 1990 Genome-wide Linkage Scans Identification of susceptibility regions in CD Scepticism!!! 2001 NOD2/CARD15 CD becomes example of Success story Innate Immunity and Pattern Recognition Receptors Common pathways between inflammatory diseases 2006 Genome-wide Association Scans ATG16L1, IRGM, 24

Pattern recognition receptors (PRRs) Important role in innate immunity Recognition and response against Gramnegative bacteria Extracellular membrane bound, Toll Like Receptors (TLR) Intracellular in the cytosol, NOD2/CARD15 Some mutations predispose to bacterial infections, others to immune mediated diseases

Mucosa associated bacteria are common in Crohn s disease Barnich N World J GE 2007

Mucosa associated bacteria are common in Crohn s disease Darfeuille-Michaud A Gastroenterology 2004

But bacterial profile is not different between ulcerated and normal mucose in Crohn s disease dominant microbiotas do not differ qualitatively between ulcerated and nonulcerated mucosae. Biodiversity remains high in ulcerated mucosa. Vasquez N IBD 2007 Seksik J Clin Microbiol 2005

Trichuris suis in the treatment of IBD Summers RW Gut 2005 29 CD and 54 adult patients 2500 Trichuris suis ova/placebo every 2-3 w. for 12 w. Primary endpoint: CDAI<150 at week 24 improvement of UCDAI to 4 at 12 weeks Summers RW GE 2005

Predicting disease phenotype/disease course?

Indolent course Crohn s disease active 8% 48% inactive 44% D sis 1 2 3 4 5 6 7 8 Years after diagnosis Munkholm P, et al. Scand J Gastroenterol 1995:30:699 706

Aggressive course Crohn s disease active p <0.001 45% 50% inactive D sis 1 2 3 4 5 6 7 8 Years after diagnosis 5% Munkholm P, et al. Scand J Gastroenterol 1995:30:699 706

Is diet predicting the relapse rate in UC? Jowett SL Gut 2004

Is diet predicting the relapse rate in UC? Jowett SL Gut 2004

Is education level associated with time to relapse in UC? Hoie O Am J GE 2007

Stress

Is stress associated with disease course in IBD?

Is stress associated with disease course in CD? Bitton Gut 2008

Is stress associated with disease course in CD? Bitton Gut 2008

Smoking is associated with probability of flares in CD Cosnes J Gastroenterology 2001

Smoking and disease phenotype in CD % without stricture % without complicated disease Aldhous M. Am J GE 2007

Association between smoking, azathioprine/biological use and need for surgery in patients with Crohn`s disease 1,0 0,8 no IM / no smoking IM / no smoking no IM / smoking IM / smoking censored censored censored censored Survival without surgery 0,6 0,4 0,2 0,0 0,00 50,00 100,00 150,00 200,00 250,00 300,00 follow-up (months) plogrank<0.001, pbreslow<0.001 Szamosi T ECCO 2009

Summary of cox model: factors affecting time to first surgery Gender 0.671 Disease location 0.017 p Hazard Ratio 95%CI L1 0.865 1.04 0.70-1.53 L2 0.013 0.58 0.38-0.89 L3 Disease behavior <0.001 reference B1 <0.001 0.28 0.19-0.42 B2 0.09 0.70 0.46-1.06 B3 Smoking / Azathioprine-biological use <0.001 reference noaza-biological/no smoking 0.004 2.20 1.28-3.78 AZA-biological/no smoking 0.75 1.10 0.61-1.99 noaza-biological/smoking <0.001 3.19 1.86-5.47 AZA-biological/ smoking reference Szamosi T ECCO 2009

Smoking and disease phenotype in UC Aldhous M. Am J GE 2007

Association between smoking and colectomy in UC OR: 0.57 (95%CI: 0.38-0.85) Cosnes J Best Pract Res Clin GE 2004

Association between smoking and colectomy in UC 1,0 0,8 Survival without colectomy 0,6 0,4 0,2 0,0 no-smoking smoking censored censored 0,00 100,00 200,00 300,00 400,00 Szamosi T ECCO 2009 follow-up (months) plogrank=0.042, pbreslow=0.08

Appendectomy and disease course in UC Cosnes J Gut 2002

Environmental factors in IBD Disease susceptibilty: Conclusions Evidence supports the association between early life hygene, some dietary factors, smoking, appendectomy and oral contraceptive use (in females) and the development of IBD The role for dysbiosis or a specific infectious agent in the disease susceptibility is controversial Prediction of disease phenotype&course: Smoking is associated with relapse rate, change in disease behavior /extent and risk for surgery/colectomy Appendectomy seems to be preventive against colectomy Studies indicate that chronic stress, adverse life events, and avoidance coping can cause relapse in patients with IBD.