Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2017 Sep 1.
Published in final edited form as: Inflamm Bowel Dis. 2016 Sep;22(9):2191–2199. doi: 10.1097/MIB.0000000000000852

Environmental Hygiene and Risk of Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis

Aurada Cholapranee 1, Ashwin N Ananthakrishnan 2,3
PMCID: PMC4992453  NIHMSID: NIHMS790406  PMID: 27482977

Abstract

Background

According to the hygiene hypothesis, individuals raised in a sanitary environment have a higher risk of developing inflammatory bowel diseases (IBD). However, results have been inconsistent. We conducted this systematic review of factors related to environmental hygiene and risk of IBD, Crohn's disease (CD) and ulcerative colitis (UC).

Methods

A systematic search was performed on MEDLINE between 1980-2015 to identify studies of the association between IBD and contact with pets and farm animals, number of siblings, bedroom sharing in childhood, access to personal toilet and hot water. Random or fixed effect meta-analyses were performed, and analysis further stratified based on ethnicity of the included cohort.

Results

A total of 29 relevant studies were included. Having a pet (Odds Ratio (OR) 0.76, 95% confidence interval (CI) 0.63 – 0.88) and contact with farm animals was inversely associated with risk of IBD (OR 0.45, 95% CI 0.31 – 0.60). However, the strength of association with farm animals was statistically stronger in non-white cohorts (OR 0.27, 95% CI 0.02 – 0.53) than white cohorts (OR 0.55, 95% CI 0.45 – 0.65) (p=0.028). Access to toilet (OR 0.71, 95% CI 0.56 – 0.85) and hot water (OR 0.67, 95% CI 0.44 – 0.89) was inversely associated with UC in non-white populations but not Caucasians. Having more than 2 siblings was inversely associated with risk of CD.

Conclusions

Several factors pertaining to reduced environmental hygiene are inversely associated with risk of IBD. However, underlying ethnicity influences susceptibility to the effect of these factors.

Keywords: Hygiene, Crohn's disease, ulcerative colitis, farm, pets, Inflammatory bowel disease, toilet

Introduction

Inflammatory bowel diseases (IBD) are immune-mediated diseases characterized by chronic relapsing-remitting inflammation involving the small and large intestines1, 2. Comprised of Crohn's disease (CD) and ulcerative colitis (UC), IBD affects 1.5 million individuals in the United States, 2.2 million in Europe, and several thousands more worldwide2, 3. There is an increasing incidence of IBD in cohorts from diverse settings throughout the world3, 4, hypothesized to be due to changes in the lifestyle and the external environment of individuals resembling westernized industrial society. Paralleling the rise in incidence of IBD has been a similar increase in other immune-mediated illnesses, highlighting the importance of environmental influences that affect a spectrum of diseases5, 6. In 1989, Strachan et al. proposed the ‘hygiene hypothesis’ characterized by an alteration in T-helper cell 1 (Th1), Th2 and regulatory T-cell balance favoring autoimmune diseases in response to reduced environmental antigenic exposure with improvements in hygiene7. Several such hygiene-related parameters have been studied in the context of risk of IBD. However, studies examining such risk factors have yielded inconsistent results, often limited by lack of statistical power.

The key pathogenic mechanism in IBD is a dysregulated immune response to the commensal gut microbiome in a genetically susceptible host8. Genome-wide association studies have identified nearly 200 risk alleles that modify risk of CD and UC. There also appears to be a heterogeneity in effect with incomplete sharing of risk alleles between Caucasian and non-Caucasian populations, potentially highlighting distinct pathways of inflammation9, 10. Consequently, there may also be variability in susceptibility to the effect of the external environment. To our knowledge, such variability has not been examined before in the context of hygiene-related factors. Additionally, there has been no prior meta-analysis of factors pertaining to the hygiene hypothesis in the context of risk of IBD.

We conducted this systematic review and meta-analysis of exposures related to environmental hygiene to examine the pooled association with IBD, and separately for CD and UC. We also examined if there was variation in effect based on the ethnicity of the population as well as timing of exposure in infancy or early childhood compared to later years. Through such analyses, we aimed to provide a robust estimate of the association between environmental hygiene and IBD and additionally inform our understanding of the mechanisms of effect.

Methods

Data Sources and Study Selection

A systematic electronic search was performed for relevant full text articles in English using the MEDLINE database between January 1, 1980 and September 1, 2015. We used search terms associated with IBD and environmental hygiene including “inflammatory bowel disease”, “Crohn's disease”, or “ulcerative colitis” in combination with “hygiene”, “siblings”, “family size”, “pets”, “farm”, “cattle”, “toilet” and “water”. Reference lists from retrieved studies as well as review articles were examined to identify additional studies of relevance. Our search was restricted to studies available as full text, in English, and encompassed both pediatric- and adult-onset IBD. All abstracts were reviewed by both authors and confirmation eligible and ineligible abstracts was made independently. A supplemental search was made on EMBASE to identify potential articles that may have not have been listed on MEDLINE. Studies could be included if they were of cross-sectional, case-control or cohort design, and were in the English language. To be eligible for inclusion, the study had to provide total numbers of patients with Crohn's disease, ulcerative colitis or a pooled number for all IBD, and describe frequency of occurrence of the exposure of interest in the cases and controls. Where adjusted odds ratios or risk ratios were available, the maximally adjusted one was used for analyses. Studies were excluded if the total number of participants (cases and controls) was not provided, if frequency of exposure or odds ratios were not available, or if it focused on specific populations (such as only those with a family history of IBD).

Exposures of interest

We examined six different exposures of interest – (i) exposure to pets, and when available specifically dogs and cats; (ii) contact with farm animals; (iii) birth order and number of siblings (when number of older and younger siblings was presented separately, we included data on older siblings); (iv) sharing of the house or bedroom in childhood; (v) availability of personal toilet; and (vi) access to hot water. For exposure to pets, if frequencies and odds ratios were not available for all pets but presented for specific pet animals, these values were extrapolated to represent exposure to pets. While recognizing that other exposures may also represent markers of environmental hygiene, as many such as rural or urban residence and socioeconomic status had been recently reviewed in meta-analyses, we did not include them in our search.

Data Abstraction

From each eligible study, we abstracted data on type of IBD (CD, UC, all IBD), number of cases and controls, and age of exposure (defining exposure in infancy and early childhood as that between the ages of 0-5 years). From each study, we used the maximally adjusted odds ratios (OR) or relative risk (RR) estimates when provided. If this was not available, univariate OR and 95% confidence intervals (CI) were calculated based on frequency of exposure among cases and controls. We performed an exploratory subgroup analysis to examine if the effect of environmental factors differed based on ethnic origin of the majority of study participants. Studies were subdivided as those being in predominantly white populations if the region of study was from Europe or North America or if the study population was explicitly indicated as Caucasian. In contrast, studies from South America, Africa, and Asia-Pacific were marked as being in non-white populations, recognizing that this was likely the dominant ethnicity of origin in the study region despite potential admixture between individuals of different ethnicities.

Statistical Analysis

All data were analyzed using Stata 13.2 (StataCorp, College Station, TX). The DerSimonian and Laird random-effects model was used to estimate pooled odds ratios for outcomes with significant heterogeneity between studies (I2 ≥ 50 or χ2 for heterogeneity p < 0.05)11. A fixed effects model was used for outcomes otherwise. A priori specified subgroup analyses were performed stratifying by ethnic origin of included participants (white or non-white), and timing of exposure (infancy or early childhood (0-5 years) compared to later years) with p-values calculated by meta-regression. Meta-regression was performed to assess the influence of covariates on the strength of association between exposures and outcomes. A two-sided p-value < 0.05 indicated independent statistical significance. Both the Begg's and Egger's test were used to identify publication bias.

Results

Literature Search

Our search yielded 7,606 potential articles. On review of the titles and abstracts, 7,526 were excluded and the full text of 80 articles was reviewed. After excluding articles that represented duplicate analyses (different covariates in separate manuscripts from the same cohort), those that did not provide sufficient information (frequencies of exposure or odds ratios), our final analysis included 29 studies (Figure 1).

Figure 1. Flowchart of search strategies to identify relevant studies investigating association between measures of environmental hygiene and risk of inflammatory bowel diseases.

Figure 1

Open in a new tab

Exposure to Pets and Farm Animals

Fifteen studies examined this association with CD, 11 with UC, and 1 with all IBD (Table 1)12-28. Nine examined exposure during infancy early childhood and 8 included non-white populations13, 20-22, 24, 26. The included literature comprised 5,391 cases of CD, 2,504 of UC, and 179 with IBD. There was no publication bias based on Begg's and Egger's tests (Supplemental Figure 1).

Table 1. Studies examining the association between various environmental exposures and risk of Inflammatory Bowel Diseases.

Author Publication Year Region Study Period Study Type Age at exposure (in years) Number of cases Exposures studied†
Crohn's disease Ulcerative colitis All IBD
Rigas A 1993 North America 1986 - 90 Case Control 68 39 107 S
Gent A 1994 Europe Case Control 133 213 346 HW
Duggan A 1998 Europe 1993 - 94 Case Control 11 - 16 110 213 323 HW, BS
Feeny M 2001 Europe Case Control 0-5 139 137 276 P, S
Sicilia B 2001 Europe 1992 - 95 Case Control 103 - 103 HW
Hampe J 2003 Europe 1996 - 98 Case Control - - 2351 S, HW
Baron S 2004 Europe 1988 - 1997 Case Control 222 60 282 BS
Van Cruiningen H 2005 Europe 1999 Case Control < 20 74 - 74 P
Amre D 2006 North America 1995-2004 Case Control Childhood 194 - 194 P, BS, HW
Bernstein CN 2006 North America Case Control <12 364 217 579 P, HW
Montgomery S 2006 Europe 1935 - 98 Case Control 12668 15823 28491 S
Hafner S 2007 Europe 1999 - 2003 Case Control <16 73 48 121 P
Radon K 2007 Europe 2005 - 06 Case Control < 6 444 304 748 P
Klement E 2008 Asia 1998-2004 Cross-sectional <17 - - 768 S, BS
Sicilia B 2008 Europe 1992 - 95 Case Control < 18 - 205 205 HW
Han DY 2010 Australia 2006 Case Control 0-16 315 - 315 P
Lopez-Serrano P 2010 Europe 2004 Case Control Primary School Age 124 146 270 P, S, BS
Pugazhendhi S 2011 Asia 2006 - 08 Case Control 0 - 5 200 0 200 P, HW
Boneberger A 2011 South America 2009 - 2010 Case Control < 1 - 52 52 P
Castiglione F 2011 Europe 2010 - 11 Case Control Childhood 468 527 995 P, BS
Wang YF 2012 Asia 2007 -10 Case Control - 1308 1308 HW
Hlavaty T 2013 Europe 2008-2009 Case Control >13 190 148 338 P, BS
Jakobsen C 2013 Europe 2007 - 10 Case Control <15 59 - 118 S, BS
Ng S 2014 Asia 2011 - 13 Case Control <20 186 256 442 P, S, HW
Timm S 2014 Europe Cohort Study >11 - - 179 P
Basson A 2014 Africa 2011 - 2013 Case Control >12 194 - 194 P, HW, BS
Sood A 2014 Asia 2005 -09 Case Control - 513 513 P, HW, BS, S
Ko Y 2015 Australia 2006 Cohort Study 0 - 16 160 156 316 P, HW, BS
Open in a new tab
†

P – Pets and Farm animals; HW – personal toilets and hot water; BS – bedroom sharing; S – number of siblings and birth order

IBD – Inflammatory bowel diseases; NA – not applicable

Exposure to pets was inversely associated with a risk of all IBD (OR 0.76, 95% CI 0.63 – 0.88), and separately with CD (OR 0.77, 95% CI 0.59 – 0.94) and UC (OR 0.75, 95% CI 0.56 – 0.94) (Figure 2). There was a similar effect among non-white (4 studies, OR 0.70, 95% CI 0.41 – 0.99) and white populations (7 studies, OR 0.76, 95% CI 0.63 – 0.89) (p=0.34). Exposure during early childhood was associated with a similar reduction in risk for all IBD as in the later years. An inverse association for all IBD was seen with either dogs (OR 0.70, 95% CI 0.57 – 0.83) or cats (OR 0.75, 95% CI 0.63 – 0.88) as pets.

Figure 2. Association between exposure to pets and risk of Crohn's disease and ulcerative colitis.

Figure 2

Figure 2

Open in a new tab

(a) Crohn's disease

(b) Ulcerative colitis

A similar strong inverse association was also observed for contact with farm animals and IBD (OR 0.45, 95% CI 0.29 – 0.62), CD (OR 0.46, 95% CI 0.20 – 0.72) and UC (OR 0.44, 95% CI 0.14 – 0.74). Interestingly, the magnitude of association was significantly greater among non-white cohorts (3 studies, OR 0.27, 95% CI 0.02 – 0.53) compared to whites (5 studies, OR 0.58, 95% CI 0.47 – 0.69) (p=0.037) (Figure 3). The relationship between farm animal contact and IBD did not differ between early childhood compared to later years (data not shown). There was evidence of weak publication bias on the Egger's test (Supplemental Figure 2).

Figure 3. Effect of ethnicity on association between exposure to farm animals and risk of inflammatory bowel diseases.

Figure 3

Figure 3

Open in a new tab

(a) Whites

(b) Non-whites

Bedroom and Home sharing

A total of 10, 8, and 3 studies provided information on association between home or bedroom sharing and CD, UC, or IBD respectively (Table 1)12, 13, 15, 19, 20, 24, 28-32. Five examined exposure during early childhood and six were in a non-white population. These comprised 1,721 cases of CD, 1,763 of UC, and 1,654 with IBD. Sharing a home was inversely associated with a risk of all IBD (OR 0.53, 95% CI 0.30 – 0.76), and separately with CD (0.49, 95% CI 0.25 - 0.75) but not UC (OR 0.74, 95% CI 0.09 – 1.39). Bed sharing was inversely association with all IBD (OR 0.66, 95% CI 0.46 – 0.87), CD (OR 0.54, 95% CI 0.43 – 0.65) and UC (OR 0.53, 95% CI 0.24 – 0.82). This was statistically similar in non-whites and whites, and for exposure during early childhood and in later years. Begg's test revealed no publication bias.

Toilet and Hot water

Access to personal toilet or hot water was evaluated by 10 studies for CD, 9 studies for UC, and 1 study for IBD comprising 1,644, 3,081, and 133 cases respectively (Table 1)12-14, 20-22, 24, 29, 33-36. Eight studies were in non-white populations. In a random effects model, we found an inverse association between access to personal toilet and risk of IBD overall (OR 0.82, 95% CI 0.69 – 0.95). Disease specific analyses showed a statistically significant inverse association with UC (OR 0.73, 95% CI 0.59 – 0.88) but not CD (OR 1.11, 95% CI 0.81 – 1.40). Further stratifying by ethnic origin, a significant association with UC was observed only in non-whites (OR 0.71, 95% CI 0.43 – 0.93) but not among Caucasians (OR 1.26, 95% CI 0.61 – 1.91) (Figure 4). Egger's test revealed the presence of weak publication bias (p < 0.05).

Figure 4. Effect of ethnicity on association between access to toilets and risk of ulcerative colitis.

Figure 4

Figure 4

Open in a new tab

(a) Whites

(b) Non-whites

Access to hot water did not meet statistical significance for association with all IBD (OR 0.86, 95% CI 0.71 – 1.01). However, disease specific associations showed a significant inverse association with UC (OR 0.76, 95% CI 0.57 – 0.95) but not for CD (OR 1.00, 95% CI 0.73 – 1.27). This association with UC was observed only in non-whites (OR 0.67, 95% CI 0.44 – 0.89) but not among cohorts comprising of white participants (OR 0.98, 95% CI 0.63 – 1.34).

Number of siblings

A total of 8 studies comprising 5 of CD, 6 of UC, and 2 of IBD were included in this analysis, contributing 13,058 CD, 16,714 UC, and 933 IBD patients (Table 1)12-14, 20-22, 24, 29, 33-38. Nearly all studies provided data comparing < 2 siblings to ≥ 2 siblings with two studies comparing < 3 siblings to ≥ 3 siblings. We did not observe an association between greater number of siblings and risk of IBD (OR 0.95, 95% CI 0.84 – 1.06). However, disease-specific analyses suggested a significant inverse association for CD (OR 0.93, 95% CI 0.88 – 0.98) but not UC (OR 0.98, 95% CI 0.94 – 1.03).

Metaregression and Subgroup Analyses

As most studies used a case-control design, meaningful subgroup analyses by study design was not possible for all outcomes due to paucity of cohort studies. However, where sufficient studies could be included, no heterogeneity was observed based on study type (case-control or cohort), or setting (population-based or hospital based) (data not shown). Meta-regression revealed no significant predictors (year of publication, study design, region of study, type of IBD, and number of included participants) for association with farm animals, number of siblings, toilet or hot water access. Only number of included cases was associated with the outcome in studies examining association with pets (p=0.01).

Discussion

Environmental factors play an important role in the development of CD and UC39. The ‘hygiene hypothesis’ was proposed by Strachan et al. who noted an inverse association between number of older children and risk of hay fever and eczema7. Such associations have since been described for several immune mediated diseases and supported by experimental data6, 40, 41. Here, we present a systematic review and meta-analysis of such factors with IBD in a diverse set of cohorts.

The first key finding of our meta-analysis is the strong protective association between IBD and several measures associated with lower environmental hygiene – bedroom sharing, exposure to farm animals and pets, and multiplicity of siblings. There are several mechanisms how such factors modify risk of immune-mediated diseases, and in particular, IBD. The first is that lack of exposure to infectious antigenic stimuli in childhood favors a Th2 mediated immune response characterized by production of interleukins-4, 5, 6, and 13 in contrast to the dominant Th1 helper T-cell (TNF-α, IFN-γ, IL-2) mediated response in environments with lower hygiene40. However, the relevance of this in the pathogenesis of IBD is unclear given the role of Th1, Th2, and Th17 immune responses in its pathogenesis2, 8. Other mechanisms proposed include antigenic competition and influence on regulatory T-cell function6, 40; for example newborns of mothers exposed to farming demonstrate up-regulation of regulatory T cells42. Patients in parasite endemic areas have high levels of IL-10 and regulatory T-cell activity and lower levels of pro-inflammatory cytokines43, 44. A third mechanism may be through modification of the gut microbiome. An alteration in the gut flora characterized by reduced diversity and depletion of phyla such as firmicutes underlies the development of IBD45. Pre-natal or postnatal exposure to farming environments may be associated with colonization by bacteria such as Acinetobacter lwoffii and lactococcus lactis which can, in turn, influence Th1-mediated immune responses46. House dust exposure in households with dogs was associated with a distinct gut microbiome enriched in lactobacillus johnsonii which led to reduced Th2 mediated cytokine production and fewer activated T-cells47.

A second interesting exploratory finding is the potential heterogeneity in susceptibility to the effect of environmental influences based on ethnicity. While some measures demonstrated a strong inverse association in non-white cohorts, the effect was often more modest or non-significant in predominantly white populations. Similar results have been demonstrated for other factors. For example, smoking consistently increases risk of CD among whites but not among Israeli Jews48 and Indians22.The cause for this heterogeneity is likely two fold. First, genetic pathways involved in IBD pathogenesis may differ between white and non-white populations. While there is broad overlap of risk alleles between both groups, there appear to be distinct risk alleles within specific ethnic groups9, 10. In a recent trans-ethnic study of non-white participants, 38 risk alleles for IBD were identified that did not achieve significance in previous studies of white populations10. Conversely, alleles with strong effect sizes in Caucasian populations such as the NOD2 or IL-23R gene are not associated with disease risk in Asian populations10, 49. Toll-like receptor (TLR) polymorphisms in TLR-2 and TLR-4 influencing antigen presentation and regulation of immune responses demonstrated an association with UC only in Caucasians, not in Asians50. Second, there may be differences in metabolizing or other intermediary enzymes in the pathway of influence of such environmental exposures51.

Importantly, caution must be adopted in attributing such differences to ethnicity alone. Given that the likely ethnicity of origin in our analysis was assigned based on the region of study, it is possible that the heterogeneity in effects identified may not be a reflection of ethnicity itself as a modifier of the environmental influences but competing environmental stimuli during childhood and adult life. Specific hygiene related parameters may have a stronger or weaker effect depending on the prevailing level of hygiene, susceptibility to infections, or other socioeconomic factors that vary between the different regions. For example, antibiotic exposure has been consistently associated with increased risk of IBD in developed countries52, yet in developing countries with frequent childhood infections, antibiotic exposure was associated with a decreased risk of disease21. However, in the one study which examined the differences in association between middle-eastern migrants and resident Caucasian Australians, a similar heterogeneity in association was identified suggesting that there is at least a partial contribution from ethnicity of origin.

There are a few implications to our findings. First, we robustly demonstrate the protective association with various measures of impaired environmental hygiene and IBD. Further studies on the mechanisms underlying such influences, and in particular, their effect on the composition of the infant and childhood microbiome and immune responses are warranted. Second, with the heterogeneity in effect by type of IBD and underlying ethnic background, it is important to recognize that future studies on the topic should necessarily account for such variations in design and analysis. Such differential effects may be particularly valuable in defining the specific role of genetics and environment in the development of IBD. Such heterogeneity may also play a role in the efficacy of therapies, particularly those that are directed towards the microbiome or immune responses to such stimuli. Differences in the lag interval between exposure and development of CD or UC could also explain heterogeneity in effects between the two diseases.

We readily acknowledge several limitations to our study. First, we examined only a subset of environmental hygiene exposures, however, focusing on those where inconsistency in previous results could be due to inadequate sample size. Nevertheless, as epidemiologic data accrues, particularly from non-white populations, it is important to update the effect of such risk factors. Second, though we were able to separately examine the effect based on white and non-white races, it is possible that further differences exist even with the broad category of non-whites. Additionally, immigration to developed countries may also affect the susceptibility of such populations to environmental exposures by modifying the competing environmental stimuli20. Third, heterogeneity was noted between the studies and may have influenced our results as may have publication bias. Studies may have examined specific risk factors but failed to report them in the publication if no association was observed. Fourth, most studies were of a case-control design or recruited patients from the hospital, thereby being more susceptible to bias in recall as well as by severity of underlying IBD. The paucity of cohort studies precluded meaningful subgroup analyses, but where more than one cohort study was available, no heterogeneity in results was noted. Fifth, the number of covariates adjusted for also varied between studies and was not uniform, introducing another source of heterogeneity. As in any observational study, there is the potential for confounders. As many environmental exposures grow uncommon (such as lack of access to toilets or clean water), it is possible that there are other differences between patients with and without such exposures that mediate the association with IBD through confounding rather than the exposure under study itself. Finally, in regions with increasing incidence of IBD, an initial rise is often noted with UC preceding a rise in CD. Thus, specificity of exposures with an IBD-subtype may also reflect, in part, temporal changes in exposures along with the changing UC/CD ratio.

In conclusion, we demonstrate a robust inverse association between exposure to pets, farm animals, sharing of bedrooms, number of siblings and risk of IBD. Importantly, for some exposures, namely access to toilets or hot water, a statistically significant effect was seen only in non-white populations while for others such as exposure to farm animals, a statistically stronger effect was seen among non-whites. Such differences may reflect an effect modification by ethnicity of origin but could also represent differences in socioeconomic factors or prevailing competing environmental influences between the different regions. There is a need for larger studies including non-white populations to establish this effect robustly. Future studies on the mechanism of effect of measures of environmental hygiene as well as the reason behind variations in effect are warranted.

Supplementary Material

Supplemental Data File_1

Supplemental Figure 1: Egger's test assessing publication bias among studies examining association between pet exposure and inflammatory bowel diseases

Supplemental Figure 2: Egger's test assessing publication bias among studies examining association between farm animal exposure and inflammatory bowel diseases

Supplemental Data File_2

Acknowledgments

Financial support: This work is supported by funding from the US National Institutes of Health (K23 DK097142 to AA). Ananthakrishnan has served on scientific advisory boards for Abbvie, Cubist and Exact Sciences.

Footnotes

Conflicts of interest: Cholapranee has no conflicts of interest to declare.

Authorship: AC: study design, data acquisition, analysis and interpretation of data, drafting of the manuscript critical revision of the manuscript.

AA: study concept and design, study supervision, analysis and interpretation of data, critical revision of the manuscript.

AC and AA take overall responsibility for the integrity of the manuscript.

References

  • 1.Cosnes J, Gower-Rousseau C, Seksik P, et al. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011;140:1785–94. doi: 10.1053/j.gastro.2011.01.055. [DOI] [PubMed] [Google Scholar]
  • 2.Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361:2066–78. doi: 10.1056/NEJMra0804647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46–54 e42. doi: 10.1053/j.gastro.2011.10.001. quiz e30. [DOI] [PubMed] [Google Scholar]
  • 4.Thia KT, Loftus EV, Jr, Sandborn WJ, et al. An update on the epidemiology of inflammatory bowel disease in Asia. Am J Gastroenterol. 2008;103:3167–82. doi: 10.1111/j.1572-0241.2008.02158.x. [DOI] [PubMed] [Google Scholar]
  • 5.Cooper GS, Bynum ML, Somers EC. Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. J Autoimmun. 2009;33:197–207. doi: 10.1016/j.jaut.2009.09.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med. 2002;347:911–20. doi: 10.1056/NEJMra020100. [DOI] [PubMed] [Google Scholar]
  • 7.Strachan DP. Hay fever, hygiene, and household size. BMJ. 1989;299:1259–60. doi: 10.1136/bmj.299.6710.1259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474:307–17. doi: 10.1038/nature10209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–24. doi: 10.1038/nature11582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Liu JZ, van Sommeren S, Huang H, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47:979–86. doi: 10.1038/ng.3359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88. doi: 10.1016/0197-2456(86)90046-2. [DOI] [PubMed] [Google Scholar]
  • 12.Amre DK, Lambrette P, Law L, et al. Investigating the hygiene hypothesis as a risk factor in pediatric onset Crohn's disease: a case-control study. Am J Gastroenterol. 2006;101:1005–11. doi: 10.1111/j.1572-0241.2006.00526.x. [DOI] [PubMed] [Google Scholar]
  • 13.Basson A, Swart R, Jordaan E, et al. The association between childhood environmental exposures and the subsequent development of Crohn's disease in the Western Cape, South Africa. PLoS One. 2014;9:e115492. doi: 10.1371/journal.pone.0115492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Bernstein CN, Rawsthorne P, Cheang M, et al. A population-based case control study of potential risk factors for IBD. Am J Gastroenterol. 2006;101:993–1002. doi: 10.1111/j.1572-0241.2006.00381.x. [DOI] [PubMed] [Google Scholar]
  • 15.Castiglione F, Diaferia M, Morace F, et al. Risk factors for inflammatory bowel diseases according to the “hygiene hypothesis”: a case-control, multi-centre, prospective study in Southern Italy. J Crohns Colitis. 2012;6:324–9. doi: 10.1016/j.crohns.2011.09.003. [DOI] [PubMed] [Google Scholar]
  • 16.Feeney MA, Murphy F, Clegg AJ, et al. A case-control study of childhood environmental risk factors for the development of inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2002;14:529–34. doi: 10.1097/00042737-200205000-00010. [DOI] [PubMed] [Google Scholar]
  • 17.Hafner S, Timmer A, Herfarth H, et al. The role of domestic hygiene in inflammatory bowel diseases: hepatitis A and worm infestations. Eur J Gastroenterol Hepatol. 2008;20:561–6. doi: 10.1097/MEG.0b013e3282f495dd. [DOI] [PubMed] [Google Scholar]
  • 18.Han DY, Fraser AG, Dryland P, et al. Environmental factors in the development of chronic inflammation: a case-control study on risk factors for Crohn's disease within New Zealand. Mutat Res. 2010;690:116–22. doi: 10.1016/j.mrfmmm.2009.09.002. [DOI] [PubMed] [Google Scholar]
  • 19.Hlavaty T, Toth J, Koller T, et al. Smoking, breastfeeding, physical inactivity, contact with animals, and size of the family influence the risk of inflammatory bowel disease: A Slovak case-control study. United European Gastroenterol J. 2013;1:109–19. doi: 10.1177/2050640613478011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Ko Y, Kariyawasam V, Karnib M, et al. Inflammatory Bowel Disease Environmental Risk Factors: A Population-Based Case-Control Study of Middle Eastern Migration to Australia. Clin Gastroenterol Hepatol. 2015;13:1453–63 e1. doi: 10.1016/j.cgh.2015.02.045. [DOI] [PubMed] [Google Scholar]
  • 21.Ng SC, Tang W, Leong RW, et al. Environmental risk factors in inflammatory bowel disease: a population-based case-control study in Asia-Pacific. Gut. 2015;64:1063–71. doi: 10.1136/gutjnl-2014-307410. [DOI] [PubMed] [Google Scholar]
  • 22.Pugazhendhi S, Sahu MK, Subramanian V, et al. Environmental factors associated with Crohn's disease in India. Indian J Gastroenterol. 2011;30:264–9. doi: 10.1007/s12664-011-0145-1. [DOI] [PubMed] [Google Scholar]
  • 23.Radon K, Windstetter D, Poluda AL, et al. Contact with farm animals in early life and juvenile inflammatory bowel disease: a case-control study. Pediatrics. 2007;120:354–61. doi: 10.1542/peds.2006-3624. [DOI] [PubMed] [Google Scholar]
  • 24.Sood A, Amre D, Midha V, et al. Low hygiene and exposure to infections may be associated with increased risk for ulcerative colitis in a North Indian population. Ann Gastroenterol. 2014;27:219–223. [PMC free article] [PubMed] [Google Scholar]
  • 25.Timm S, Svanes C, Janson C, et al. Place of upbringing in early childhood as related to inflammatory bowel diseases in adulthood: a population-based cohort study in Northern Europe. Eur J Epidemiol. 2014;29:429–37. doi: 10.1007/s10654-014-9922-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Boneberger A, Weiss EH, Calvo M, et al. Environmental factors in infancy and ulcerative colitis in the Central South of Chile: a case-control study. J Crohns Colitis. 2011;5:392–6. doi: 10.1016/j.crohns.2011.03.005. [DOI] [PubMed] [Google Scholar]
  • 27.Van Kruiningen HJ, Joossens M, Vermeire S, et al. Environmental factors in familial Crohn's disease in Belgium. Inflamm Bowel Dis. 2005;11:360–5. doi: 10.1097/01.mib.0000158536.31557.90. [DOI] [PubMed] [Google Scholar]
  • 28.Lopez-Serrano P, Perez-Calle JL, Perez-Fernandez MT, et al. Environmental risk factors in inflammatory bowel diseases. Investigating the hygiene hypothesis: a Spanish case-control study. Scand J Gastroenterol. 2010;45:1464–71. doi: 10.3109/00365521.2010.510575. [DOI] [PubMed] [Google Scholar]
  • 29.Duggan AE, Usmani I, Neal KR, et al. Appendicectomy, childhood hygiene, Helicobacter pylori status, and risk of inflammatory bowel disease: a case control study. Gut. 1998;43:494–8. doi: 10.1136/gut.43.4.494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Jakobsen C, Paerregaard A, Munkholm P, et al. Environmental factors and risk of developing paediatric inflammatory bowel disease -- a population based study 2007-2009. J Crohns Colitis. 2013;7:79–88. doi: 10.1016/j.crohns.2012.05.024. [DOI] [PubMed] [Google Scholar]
  • 31.Klement E, Lysy J, Hoshen M, et al. Childhood hygiene is associated with the risk for inflammatory bowel disease: a population-based study. Am J Gastroenterol. 2008;103:1775–82. doi: 10.1111/j.1572-0241.2008.01905.x. [DOI] [PubMed] [Google Scholar]
  • 32.Baron S, Turck D, Leplat C, et al. Environmental risk factors in paediatric inflammatory bowel diseases: a population based case control study. Gut. 2005;54:357–63. doi: 10.1136/gut.2004.054353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Gent AE, Hellier MD, Grace RH, et al. Inflammatory bowel disease and domestic hygiene in infancy. Lancet. 1994;343:766–7. doi: 10.1016/s0140-6736(94)91841-4. [DOI] [PubMed] [Google Scholar]
  • 34.Hampe J, Heymann K, Krawczak M, et al. Association of inflammatory bowel disease with indicators for childhood antigen and infection exposure. Int J Colorectal Dis. 2003;18:413–7. doi: 10.1007/s00384-003-0484-1. [DOI] [PubMed] [Google Scholar]
  • 35.Sicilia B, Arribas F, Nerin J, et al. Risk factors for ulcerative colitis: A population-based, case-control study in Spain. J Crohns Colitis. 2008;2:158–61. doi: 10.1016/j.crohns.2008.01.003. [DOI] [PubMed] [Google Scholar]
  • 36.Wang YF, Ou-Yang Q, Xia B, et al. Multicenter case-control study of the risk factors for ulcerative colitis in China. World J Gastroenterol. 2013;19:1827–33. doi: 10.3748/wjg.v19.i11.1827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Montgomery SM, Lambe M, Wakefield AJ, et al. Siblings and the risk of inflammatory bowel disease. Scand J Gastroenterol. 2002;37:1301–8. doi: 10.1080/003655202761020588. [DOI] [PubMed] [Google Scholar]
  • 38.Rigas A, Rigas B, Glassman M, et al. Breast-feeding and maternal smoking in the etiology of Crohn's disease and ulcerative colitis in childhood. Ann Epidemiol. 1993;3:387–92. doi: 10.1016/1047-2797(93)90066-d. [DOI] [PubMed] [Google Scholar]
  • 39.Ananthakrishnan AN. Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol. 2015;12:205–17. doi: 10.1038/nrgastro.2015.34. [DOI] [PubMed] [Google Scholar]
  • 40.Okada H, Kuhn C, Feillet H, et al. The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clin Exp Immunol. 2010;160:1–9. doi: 10.1111/j.1365-2249.2010.04139.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Kondrashova A, Seiskari T, Ilonen J, et al. The ‘Hygiene hypothesis’ and the sharp gradient in the incidence of autoimmune and allergic diseases between Russian Karelia and Finland. APMIS. 2013;121:478–93. doi: 10.1111/apm.12023. [DOI] [PubMed] [Google Scholar]
  • 42.Schaub B, Liu J, Hoppler S, et al. Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J Allergy Clin Immunol. 2009;123:774–82e5. doi: 10.1016/j.jaci.2009.01.056. [DOI] [PubMed] [Google Scholar]
  • 43.Maizels RM, McSorley HJ, Smyth DJ. Helminths in the hygiene hypothesis: sooner or later? Clin Exp Immunol. 2014;177:38–46. doi: 10.1111/cei.12353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Wammes LJ, Hamid F, Wiria AE, et al. Regulatory T cells in human lymphatic filariasis: stronger functional activity in microfilaremics. PLoS Negl Trop Dis. 2012;6:e1655. doi: 10.1371/journal.pntd.0001655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology. 2014;146:1489–99. doi: 10.1053/j.gastro.2014.02.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Debarry J, Garn H, Hanuszkiewicz A, et al. Acinetobacter lwoffii and Lactococcus lactis strains isolated from farm cowsheds possess strong allergy-protective properties. J Allergy Clin Immunol. 2007;119:1514–21. doi: 10.1016/j.jaci.2007.03.023. [DOI] [PubMed] [Google Scholar]
  • 47.Fujimura KE, Demoor T, Rauch M, et al. House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection. Proc Natl Acad Sci U S A. 2014;111:805–10. doi: 10.1073/pnas.1310750111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Reif S, Lavy A, Keter D, et al. Lack of association between smoking and Crohn's disease but the usual association with ulcerative colitis in Jewish patients in Israel: a multicenter study. Am J Gastroenterol. 2000;95:474–8. doi: 10.1111/j.1572-0241.2000.01771.x. [DOI] [PubMed] [Google Scholar]
  • 49.Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–24. doi: 10.1038/nature11582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Cheng Y, Zhu Y, Huang X, et al. Association between TLR2 and TLR4 Gene Polymorphisms and the Susceptibility to Inflammatory Bowel Disease: A Meta-Analysis. PLoS One. 2015;10:e0126803. doi: 10.1371/journal.pone.0126803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Ananthakrishnan AN, Nguyen DD, Sauk J, et al. Genetic polymorphisms in metabolizing enzymes modifying the association between smoking and inflammatory bowel diseases. Inflamm Bowel Dis. 2014;20:783–9. doi: 10.1097/MIB.0000000000000014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Ungaro R, Bernstein CN, Gearry R, et al. Antibiotics associated with increased risk of new-onset Crohn's disease but not ulcerative colitis: a meta-analysis. Am J Gastroenterol. 2014;109:1728–38. doi: 10.1038/ajg.2014.246. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Data File_1

Supplemental Figure 1: Egger's test assessing publication bias among studies examining association between pet exposure and inflammatory bowel diseases

Supplemental Figure 2: Egger's test assessing publication bias among studies examining association between farm animal exposure and inflammatory bowel diseases

NIHMS790406-supplement-Supplemental_Data_File_1.tif (2MB, tif)
Supplemental Data File_2
NIHMS790406-supplement-Supplemental_Data_File_2.tif (2MB, tif)

RESOURCES