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American Journal of Epidemiology Advance Access originally published online on January 19, 2007
American Journal of Epidemiology 2007 165(7):776-783; doi:10.1093/aje/kwk067
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American Journal of Epidemiology Copyright © 2007 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.

ORIGINAL CONTRIBUTIONS

A Case-Control Study of Drinking Water and Dairy Products in Crohn's Disease—Further Investigation of the Possible Role of Mycobacterium avium paratuberculosis

Ibrahim Abubakar1, Deborah J. Myhill1, Andrew R. Hart1, Iain R. Lake2, Ian Harvey1, Jonathan M. Rhodes3, Richard Robinson4, Alan J. Lobo5, Christopher S. J. Probert6 and Paul R. Hunter1

1 School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, United Kingdom
2 School of Environmental Sciences, University of East Anglia, Norwich, United Kingdom
3 School of Clinical Science, University of Liverpool, Liverpool, United Kingdom
4 Department of Gastroenterology, Leicester General Hospital, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom
5 Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield, United Kingdom
6 Clinical Science at South Bristol, Bristol Royal Infirmary, Bristol, United Kingdom

Correspondence to Dr. Ibrahim Abubakar, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich NR4 7TJ, United Kingdom (e-mail: i.abubakar{at}uea.ac.uk).

Received for publication April 20, 2006. Accepted for publication September 18, 2006.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Similarities between Johne's disease in ruminants and Crohn's disease in humans have led to speculation that Mycobacterium avium paratuberculosis (MAP) might be a causative agent in Crohn's disease. However, evidence remains inconsistent. In this case-control study (1999–2004), the authors assessed the possible role of drinking water and dairy products potentially contaminated with MAP in the etiology of Crohn's disease. A total of 218 patients with Crohn's disease recruited from nine hospitals in England and 812 controls recruited from the community completed a short questionnaire for evaluation of proxy measures of potential exposure to MAP. Logistic regression showed no significant association with measures of potential contamination of water sources with MAP, water intake, or water treatment. Multivariate analysis showed that consumption of pasteurized milk (per kg/month: odds ratio (OR) = 0.82, 95% confidence interval (CI): 0.69, 0.97) was associated with a reduced risk of Crohn's disease. Meat intake (per kg/month: OR = 1.40, 95% CI: 1.17, 1.67) was associated with a significantly increased risk of Crohn's disease, whereas fruit consumption (per kg/month: OR = 0.78, 95% CI: 0.67, 0.92) was associated with reduced risk. This study does not support a role for water or dairy products potentially contaminated with MAP in the etiology of Crohn's disease. The observed association with meat and the negative association with pasteurized milk need further study.

case-control studies; causality; Crohn disease; dairy products; Mycobacterium paratuberculosis; water supply

Abbreviations: CI, confidence interval; MAP, Mycobacterium avium paratuberculosis; OR, odds ratio; SD, standard deviation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Mycobacterium avium paratuberculosis (MAP) causes Johne's disease, a chronic granulomatous intestinal condition which affects ruminants (1). Although the etiology of Crohn's disease is still unclear, similarities between the paucimicrobial form of Johne's disease and Crohn's disease have raised concern that MAP may be a causative agent. The MAP debate has gathered momentum in recent years because of the more frequent detection of MAP in the blood and tissues of Crohn's disease patients as compared with controls. Several studies have detected MAP DNA in intestinal biopsy samples (2–4), granulomas (5), and blood (6) of patients with Crohn's disease. In contrast, other investigators have reported an absence of MAP (7–9). This lack of consistency in the data has led to controversy as to whether a causal link exists between MAP and Crohn's disease.

Considerable progress has been made in understanding the pathogenesis of Crohn's disease (10, 11). Crohn's disease is thought to result from interaction between intestinal pathogens, foods, and mucosal immunity in a genetically susceptible host, leading to exacerbation of the inflammatory response. It has been hypothesized that the presence of MAP in the gut may initiate this immune reaction. Furthermore, the increased gut "leakiness" that occurs in Crohn's disease may result in MAP infection.

Water and milk supplies have both been suggested as vehicles of MAP transmission between cattle and humans (12). MAP is very difficult to isolate in environmental samples. To date, there is no published evidence suggesting the presence of MAP in drinking water in the United Kingdom (13), although MAP has been previously detected in the municipal water supply of a major US city (14). The resilience of MAP in the environment and its presence in the feces of cattle, with the potential to contaminate surface water sources, suggests that it may not always be eliminated by standard water treatment procedures. Knowledge about similar mycobacteria and the resilience of MAP in water indicate that MAP may survive conventional water treatment and accumulate in biofilms. While we await improved methods for detecting the presence of viable MAP in drinking water, epidemiologic studies must rely on proxy measures of exposure. An alternative postulated mechanism for exposure to MAP is consumption of milk and dairy products. MAP has been isolated from raw (11) and pasteurized commercial (12) milk in the United Kingdom. More recently, viable MAP has been detected in US retail pasteurized milk samples (15). Researchers investigating standard pasteurization procedures have reported that MAP is not completely eradicated from milk during pasteurization (16, 17).

Given the lack of evidence to confirm or refute the MAP hypothesis, we conducted this case-control study to determine whether there is any epidemiologic evidence supporting a role for drinking water or milk and dairy products potentially contaminated with MAP in the etiology of Crohn's disease.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population
Patients with Crohn's disease diagnosed between June 1999 and June 2004 and whose date of symptom onset was within that same 5-year period were recruited from nine hospitals in five regions of England. The diagnosis of Crohn's disease was confirmed using the diagnostic criteria formulated by Lennard-Jones (18).

Community controls were recruited on the basis of the catchment area for each hospital, via general practices in two study centers and the 2004 electoral register in the remaining three centers. Although the general practice route was effective in two study centers, difficulties led to the use of the electoral register as the sampling frame in the other three. For the general practice procedure, the catchment areas were defined by the postcode of each practice referring patients over the preceding 12 months to the medical gastroenterology and lower gastrointestinal surgical clinics of each hospital. For all Crohn's disease patients, two general practitioners were randomly selected from a list of all general practitioners within the boundaries of the catchment area. The general practitioners were asked to identify five randomly selected controls from the practice list, frequency-matched to the age (±1 year of birth) and gender of the Crohn's patient.

To select controls using the electoral register, we allocated a geographic catchment area to each general practice using geographic information systems software (ArcGIS; ESRI, Redlands, California), based on the reasonable assumption that patients living around a practice would register with a general practitioner in the same area. Postcodes falling within each catchment area were identified, and two postcodes in each area were randomly selected. Using these two postcodes, we randomly selected 10 controls of the same gender as the index Crohn's patient from the list of persons living within those specific postcodes and present on the electoral register.

Methods of data collection
Measurement of exposure using geographic information systems.
To obtain proxy measures of potential drinking water exposure to MAP, each participant's water source, based on the postcode of residence during the asymptomatic year, was identified from the water treatment works by subsequently tracing the catchment area from which the water was extracted. Potential risk factors considered included 1) biofilm accumulation in the water supply pipes, for which distance was used as a proxy; 2) type of water treatment; 3) water source (ground, surface, or mixed); 4) density of all livestock in the geographic catchment area of the water treatment works; 5) degree of protection of groundwater from surface water filtration; and 6) number of reports of Johne's disease among cattle, by county, as estimated using United Kingdom Veterinary Laboratories Agency surveillance data.

Questionnaires.
All participants received a short, validated self-administered questionnaire and were blind to the study hypotheses. The questionnaire contained 57 questions relating to six areas: 1) postal addresses over the last 10 years; 2) type of water supply; 3) occupation; 4) types of vacations (holidays) taken; 5) dietary intake, including quantities of water and dairy products consumed; and 6) other factors previously reported to be associated with Crohn's disease, including any family history of Crohn's disease and type of relationship with the affected family member(s), history of ever smoking and of smoking during the year prior to onset of symptoms, number of cigarettes smoked per day, ever use of oral contraceptives before the onset of symptoms, and previous appendectomy. All controls were assigned a pseudo-symptom-onset date based on the year prior to that in which the index case became symptomatic. The same questionnaire was completed for the corresponding period. Postcode data reported by participants were used to assign a census-based area measure of socioeconomic status (derived using the proportions of persons in various occupational groups defined by the United Kingdom Office for National Statistics). Livestock density data were obtained from the United Kingdom Department for Environment, Food and Rural Affairs animal census.

The study received ethical review and approval by the Metropolitan Medical Research Ethics Committee and from local research ethics and governance committees in all study centers. All participants gave written informed consent.

Statistical analysis
We used logistic regression to calculate unadjusted and adjusted odds ratios and 95 percent confidence intervals for Crohn's disease, comparing cases and controls according to self-reported source and quantity of water supply and dietary intakes. To investigate the effect of confounding factors, we included all variables in a stepwise multivariable logistic regression analysis with backward elimination. Logistic regression models were used to investigate potential interaction between the variables. All p values reported are from two-sided tests of statistical significance.

We also calculated unadjusted odds ratios for each proxy measure of MAP water contamination, including water source and treatment, animal density, ground protection, and occurrence of Johne's disease. For these proxy measures of exposure, cases and controls provided postcodes for the year prior to the development of symptoms or the pseudo-symptom-onset date and for 3 years (2000), 5 years (1998), and 10 years (1993) prior to the start of the study to allow the investigation of a longer incubation period. The data were weighted using the volume of water from each site to account for multiple water treatment works and abstraction areas supplying each individual. We used a multivariable logistic regression model to control for the effect of age, gender, study center, family history, and smoking for each proxy measure of risk.

Although the original protocol proposed a matched analysis, the findings presented are for models fitted with unconditional logistic regression, adjusted for the matching criteria. We conducted unmatched analyses because age-matching of controls with cases was not possible for the three study centers using the electoral register procedure. Undertaking a strict matched analysis would have required the exclusion of many participants. Moreover, when data on a risk factor were missing for a case or control, the entire pair would have been excluded from all analyses. Therefore, we ignored the age-matching criteria and used frequency-matching of cases and controls by gender. We reanalyzed the study data using conditional logistic regression with matching by gender, and the results were not shown to be different from the unmatched findings. In addition, for centers where age-matching was possible, results from matched and unmatched analyses were similar; hence, we have presented the unmatched results.

To have statistical power of 80 percent at a 5 percent significance level to detect a doubling of the risk of Crohn's disease associated with a surface water supply, assuming that 60 percent of controls had a groundwater source, a minimum of 104 cases and 208 controls were required. The sample size was determined assuming an incidence of Crohn's disease of 5/100,000/year (19) with 70 percent of patients agreeing to participate. Because of the range of explanatory variables and the uncertainty in exposure data, and to allow for subgroup analyses, a larger sample of 218 cases and 812 controls was recruited.

All statistical analyses were performed using Stata, version 8.0 (Stata Corporation, College Station, Texas).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
The study population included patients diagnosed with Crohn's disease between December 1998 and December 2003. In total, 218 patients (mean age = 42 years (standard deviation (SD), 19.3); 57 percent females) and 812 controls (mean age = 51 years (SD, 18.6); 62 percent females) responded to the questionnaire. Characteristics of the study population are summarized in table 1. Of the 344 patients approached, 218 (63.4 percent) responded, as compared with 812 (38.4 percent) controls out of 2,115 contacted.


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  		TABLE 1. Distribution of risk factors for Crohn's disease and related odds ratios among cases (n = 218) and controls (n = 812), England, 1999–2004

 
Drinking water and food intake
In the univariable model, consumption of unboiled water was associated with an increased risk (per liter per month, odds ratio (OR) = 1.17, 95 percent confidence interval (CI): 1.05, 1.31; p = 0.006), while the use of water filtration was associated with a significant reduction in risk (per liter per month, OR = 0.45, 95 percent CI: 0.27, 0.76; p = 0.003). The effect of unboiled water lost significance after controlling for age, while that of water filtration only became nonsignificant after controlling for age, family history, and smoking. None of the water-related variables remained significant in the multivariable analysis (table 1).

Pasteurized milk was shown to be associated with a significant reduction in risk in the multivariable model (per liter per month, OR = 0.82, 95 percent CI: 0.69, 0.97; p = 0.01). The mean pasteurized milk intake among cases was 22.77 liters (SD, 16.59), as compared with 26.01 liters (SD, 15.81) among controls. Other dairy products were shown to have no effect (table 1).

Other dietary variables were also analyzed. In the final model, intake of meat was significantly associated with the development of Crohn's disease (per kg per month, OR = 1.40, 95 percent CI: 1.17, 1.67; p = 0.0001). Median intake of meat was 2.14 kg (SD, 3.89) for cases versus 1.50 kg (SD, 2.81) for controls. The meat category on the questionnaire included both beef and canned meat products, although the majority of questions referred to consumption of beef. Because of the positive association with meat, analyses were conducted using separate meat variables. In the adjusted model taking into account study center and age, both consumption of beef (per kg per month, OR = 1.21, 95 percent CI: 1.09, 1.36; p = 0.001) and consumption of canned meat (per kg per month, OR = 1.19, 95 percent CI: 1.06, 1.34; p = 0.004) were significantly associated with an increased risk of Crohn's disease. However, fruit consumption (per kg per month, OR = 0.78, 95 percent CI: 0.67, 0.92; p = 0.002) was shown to be associated with a reduced risk (table 1). The mean fruit intake among cases was 6.63 kg (SD, 5.99), as compared with 8.12 kg (SD, 6.54) among controls.

Potentially confounding variables
In the fully adjusted model, smoking during the year of interest (OR = 1.31, 95 percent CI: 1.12, 1.53; p = 0.001) and having a family history of Crohn's disease (OR = 7.13, 95 percent CI: 3.37, 15.08; p = 0.0001) were shown to be significantly associated with Crohn's disease. However, taking vacations (holidays) outside of the United Kingdom was associated with a reduced risk (OR = 0.52, 95 percent CI: 0.32, 0.84; p = 0.002). Appendectomy, use of oral contraceptives, farm vacations and visits, and socioeconomic status prior to the onset of symptoms were not associated with increased risk in the fully adjusted model.

Subgroup analysis
Further analysis was conducted excluding cases of isolated colonic Crohn's disease. The observed associations with smoking (OR = 2.02, 95 percent CI: 1.25, 3.30; p = 0.004), family history (OR = 3.8, 95 percent CI: 1.8, 7.6; p = 0.001), vacationing abroad (OR = 0.44, 95 percent CI: 0.24, 0.74; p = 0.002), consumption of pasteurized milk (OR = 0.80, 95 percent CI: 0.67, 0.96; p = 0.014), and consumption of meat (OR = 1.48, 95 percent CI: 1.22, 1.78; p = 0.001) and fruit (OR = 0.85, 95 percent CI: 0.70, 0.99; p = 0.039) remained significant.

Data from geographic information systems
None of the exposure variables for which data were derived using geographic information systems were significant in the univariable or multivariable regression models (table 2). The variables include a measure of biofilm accumulation, type of water treatment, source of water (ground, surface, or mixed), animal density, degree of protection of groundwater from surface water filtration, borehole depth, and county-level occurrence of Johne's disease in cattle. Similarly, no associations were found for the exposure data collected in relation to 2000, 1998, and 1993 (data not shown).


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  		TABLE 2. Odds ratios for Crohn's disease according to exposure to environmental variables during the year of interest, determined using data derived from geographic information systems, England, 1999–2004

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
The key unanswered question in the etiology of Crohn's disease is, What is the environmental factor that leads to the development of the disease in genetically susceptible persons? The potential role of MAP as an environmental factor is a particularly important unresolved component of this question. For MAP to cause disease in humans, it would have to be able to spread from its reservoir, the intestinal tracts of infected livestock, to humans.

The main supporters of the MAP hypothesis have stated that the most likely pathways for transmission of MAP from livestock to humans are drinking water and dairy products, especially pasteurized milk (12). This large case-control study was designed to test the hypothesis that these two transmission pathways are associated with Crohn's disease. The results did not show a significant association between any of the measures of water intake and Crohn's disease after we controlled for the effect of confounding factors. Despite the initial observation of an association with drinking unboiled water and a negative association with the use of a water filter in the univariable model, the effect was not significant in the multivariable analysis. We examined the risks associated with various water treatment measures, including comparisons of different types of treatment, surface water and groundwater, and animal density. None of the water treatment variables were statistically significant.

A negative association with drinking pasteurized milk was found, though there was no association with any of the other dairy products investigated. In a recent case-control study, Bernstein et al. (20) found no association between consumption of pasteurized milk and the risk of Crohn's disease, despite the isolation of MAP from commercial pasteurized milk in previous studies (15, 17).

In addition to the two main hypotheses, several other variables that may be associated with MAP transmission were included in the questionnaire. The most important of these were contact with farms and farm animals, where no association was observed, and meat consumption. To our knowledge, this is the first study to identify an association with meat consumption. The heterocyclic amine 2-amino-1-methyl-6-phenylimidazopyridine, which is derived from cooked meat, has been shown to increase colonic epithelial apoptosis in rats, providing a potential disease mechanism (21). Prior studies from Japan have suggested an association with total animal protein or total animal fat consumed (22, 23). Shoda et al. (23) demonstrated that an increased animal protein intake was the strongest independent factor contributing to the development of Crohn's disease. Sakamota et al. (22) subsequently showed a positive association with intake of both total fat and fatty acids of various degrees of saturation. The association with protein intake may be related to concomitant fat intake. This mechanism is supported by evidence of lymphatic dilation/obstruction in Crohn's disease and data from an animal model (pig) showing the induction of Crohn's-like lesions with an intervention involving a reversed ileal loop plus a high-fat diet (24).

It is also possible that MAP could be transmitted via meat. A recent study detected MAP DNA in the intestinal lymph nodes and/or feces of healthy beef and dairy cows at slaughter (25). However, in supplementary analyses of data from our study, tinned meat consumption was also associated with increased risk of disease (unpublished data), and the processing of tinned meat would kill any MAP.

As expected from the findings of earlier studies, family history and smoking were both associated with increased risk. It is well recognized that cigarette smoking is associated with the development of Crohn's disease (26, 27). This study demonstrated a significantly increased risk of Crohn's disease among persons who had ever smoked or had smoked during the year of interest. Furthermore, a positive family history was the strongest risk factor for the development of Crohn's disease. This, together with the positive effect of smoking, lends support to the validity of the findings of this study.

As we discussed above, other factors were also analyzed. None of these variables were included as a primary hypothesis, and thus caution in their interpretation is warranted. We observed negative associations with both fruit consumption and travel outside of the United Kingdom and a positive association with meat consumption. The negative association with fruit consumption has been reported previously in more than one study (28, 29), lending weight to this finding. The negative finding associated with travel abroad was not anticipated and currently remains unexplained.

Isolated colonic Crohn's disease may be a different disease in view of its similarities with ulcerative colitis, including the observed association with the class II HLA-DRB1*0103 allele (30, 31) and antineutrophil cytoplasmic antibody (32), the weak association with NOD2 mutations (33), and the lack of association with anti-Saccharomyces cerevisiae antibody (34). Secondary analysis of our data excluding patients with isolated colonic Crohn's disease did not affect the findings.

Neither of the two primary hypotheses was proven, and one factor, milk consumption, was found to be negatively associated with disease risk. As far as we are aware, MAP has not been detected in drinking water (35). However, various microbiologic studies have confirmed the presence of MAP in up to 10 percent of pasteurized milk for sale to the public (15, 36). Although these findings do not confirm or refute the MAP hypothesis in the etiology of Crohn's disease, it is difficult to explain how a food product known to be contaminated with MAP should be negatively associated with Crohn's disease if MAP is indeed the primary cause.

Meat consumption, a possible transmission pathway for MAP, was significantly associated with Crohn's disease in our study. However, other potential transmission pathways for MAP—consumption of fruit and vegetables, having contact with farm animals, and taking farm vacations—were either negatively associated or not associated with disease risk.

Our findings are consistent with results of other recent epidemiologic studies that have also cast doubt on the MAP hypothesis. A randomized, double-blind controlled trial of clarithromycin, rifabutin, and clofazimine for treatment of Crohn's disease failed to find a therapeutic effect (37). A recent study of farm workers failed to find an increased risk of Crohn's disease among persons who had come in contact with cattle infected with Johne's disease (38). There are also reports of particularly high prevalence of Crohn's disease in countries with no endogenous Johne's disease, such as Sweden (39).

On the other hand, the positive association with meat consumption and negative associations with fruit and pasteurized milk consumption suggest that dietary factors may play a major role in the etiology of Crohn's, as was suggested by other recent studies (22, 23, 28, 29). There is an urgent need for further, more detailed epidemiologic studies investigating the association between diet and Crohn's disease.


   ACKNOWLEDGMENTS
 
The authors are grateful to the United Kingdom Department for Environment, Food and Rural Affairs for financial support. The contract was managed by the United Kingdom Drinking Water Inspectorate.

Dr. Paul R. Hunter has received grant funding and undertaken consultancy work for water utilities and the bottled water industry. He is Chair of the Board of Directors of the Institute for Public Health and Water Research (Chicago, Illinois). Dr. Jonathan M. Rhodes, in conjunction with the University of Liverpool, holds a patent for the use of a soluble fiber preparation in the treatment of Crohn's disease.

The views expressed in this article are not necessarily those of the funders. The funders of the study played no role in the design or analysis or the decision to submit the results for publication.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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