Can temperature explain the latitudinal gradient of ulcerative colitis? Cohort of Norway

Ulcerative colitis is characterised by a dysfunction of the intestinal epithelium barrier, resulting in chronic inflammation [1, 2]. It is assumed that the disease is caused by an imbalance between the immune system and the commensal microbial flora in genetically susceptible individuals. Genome-wide association studies have identified several gene variants associated with inflammatory bowel disease including ulcerative colitis [3‐5].

Several risk factors have been identified regarding ulcerative colitis. Among those are socioeconomic status [6], nutrition [7], and microbiology [8]. Recently, studies have shown associations with iron in the drinking water [9] and components as SO₂ in air-pollution for development of ulcerative colitis in young people [10]. Smoking [11], breast feeding [12] and appendectomy [13] have shown to be protective factors, while perinatal infections [14] as well as gastroenteritis early in life [15] have been linked to increased risk for ulcerative colitis, all factors influencing the gut microbiota or the mucosal immune system. Risk factors and their influence on ulcerative colitis are listed in Table 1.

Country of residence and time period are important factors for the development of ulcerative colitis. Incidence rates are reported to be higher in northern Europe than in southern Europe [16] and a similar pattern has been demonstrated in the US [17]. Variability and clustering within countries have also been identified [18‐21].

Temporal changes are even larger, reporting a 2–3 fold increase in the risk of disease from World War II up to now, in Olmsted County, Minnesota [22]. Among children with ulcerative colitis, rising incidence rates have been reported and also differences between countries [23].

In spite of obvious differences in incidence rates and latitude, few studies have focused on which factors that could explain the differences. Some have speculated that sun exposure or ultraviolet exposure and production of vitamin D could be potential factors, but these hypotheses are not tested properly [24].

Temporal trends in incidence rates have been explained by the “hygiene hypothesis”, stating that reduced exposure to microbial agents in childhood and consequently fewer infections, could lead to higher risk for the development of autoimmune diseases - like ulcerative colitis [25, 26]. Relatively few studies have focused on exposure of hygiene-related risk factors such as infections in childhood, pets in childhood, family size, and vaccination and the development of ulcerative colitis, and no clear evidence is found [27‐29]. Bernstein et al. reported significant associations between drinking unpasteurized milk and eating pork and risk of developing ulcerative colitis in univariate analyses, but these factors were probably confounded with factors which are not related to the hygiene [27]. Lopez-Serrano et al. observed that respiratory tract infections and gastroenteritis in childhood were protective factors [29].

Rook and Brunet suggested that a reduced exposure to normal microbes - “old friends” - corresponds to temporal changes in incidence rates for some autoimmune diseases [30]. The old-friends-hypothesis is also named the “extended hygiene hypothesis”. Both of these hypotheses are linked to species richness or biodiversity in our surroundings. Species richness, or biodiversity, is unevenly distributed on Earth, but still distributed according to some basic patterns such as the variability of environmental temperature, precipitation, area-size, and altitude [31].

The aim of the present study was to study the association between climatic factors and the prevalence of ulcerative colitis to improve our understanding of the geographic distribution of the disease in Norway. In a homogenous country like Norway, differences in diagnostic praxis and economic conditions are small, but the ranges of important climatic factors such as environmental temperature, precipitation, and altitude are substantial. Associations between these factors and risk of ulcerative colitis could therefore shed new light on the development of disease, and possibly support the extended hygiene hypotheses.

In this study we have shown that the prevalence of ulcerative colitis is dependent on summer temperature, but not the other climatic variables such as annual precipitation, or altitude. We have not found similar studies investigating the association between ulcerative colitis and climatic variables.

We assume that temperature itself is not directly affecting the development of ulcerative colitis, but that temperature governs mechanisms which again are related to the likelihood for developing the disease. One such biologic mechanism is the number of species which is correlated to environmental temperature. According to the directed acyclic graphs literature, temperature is an instrumental variable for the effect of microbial species richness on ulcerative colitis because i) temperature affects species richness [35], ii) temperature affects the development of ulcerative colitis only through species richness and iii) there are no common cause of both temperature and disease. We can only assume the two latter conditions.

The number of species is not distributed homogeneously on Earth, but seems to follow some patterns [31], such as along a north–south axis. This pattern is characterized by steady decrease in the species richness from the tropics to northern or southern locations, and is called the latitudinal diversity gradient. This phenomenon is present for all taxes, but seems to be stronger for larger organisms than smaller organisms [36]. Other patterns also exist: the number of species is positively related to precipitation; positively related to area-size (islands); and negatively related to altitude. The causes of these patterns are not fully understood. Important for our study, environmental temperature is the strongest factor linked to biodiversity [31].

Our result suggests that the spatial variability in incidence rate is governed by the same factors as those related to species richness; and furthermore, species richness - not temperature - could be a strong force behind the likelihood for developing the disease. An important prerequisite is that a reduced microbial flora of harmless species may induce immunoregulatory reactions which are important for initiating autoimmune diseases like ulcerative colitis [37]. Consequently, reduced number of species to colonize the human gut will increase the likelihood for changes in the balance between gut flora and immunoregulation, which increases the likelihood for developing the disease [38].

Guernier et al. reported strong positive associations between diversity of pathogens known to affect human health and temperature, and negative associations for precipitation [39]. Among six different etiological groups, temperature was significantly related to bacteria, helminths, and viruses. There are no parallel investigations concerning commensals and temperature. However, a comparison of microbiota of children from urban Italy and rural Africa (Burkina Faso) revealed large differences in both composition and biodiversity [40]. In particular, the gut flora for Burkina Faso children had more Bacteriodetes than their Italian peers and less Firmicutes and Enterobacteriaceae [40]. This investigation demonstrated a higher microbial richness and biodiversity in African samples compared to European samples. The extended biodiversity and the increased amount of short-chain fatty acid producing bacteria found in Burkina Faso samples, probably due to the high-fiber diet, protected them from establishment of potentially pathogenic microbes. The authors suggested, in line with Rook et al. [30], that the microbial richness might be protective against, not only gastrointestinal pathogens, but also against autoimmune diseases like ulcerative colitis and Crohn’s disease.

We were not able to identify participants with Crohn’s disease in this study because there was no medication that could be used to identify participants with Crohn’s disease, such as 5-ASA medication prescribed to individuals suffering from ulcerative colitis. However, due to the high correlation between the incidence rates of ulcerative colitis and Crohn’s disease in Norwegian municipalities (0.42) [19] and the shared pathogenesis of the two diseases, it is likely that temperature is also a common risk factor for Crohn’s disease. Other autoimmune diseases such as multiple sclerosis [41], allergy [42], rheumatoid arthritis [43], systemic lupus erythematosus in US [44], but not in UK [45] have shown similar spatial patterns. No systematic studies exist for ankylosing spondylitis or diabetes type 1, but north–south trends or differences have been reported for both disorders [46, 47]. Two studies have shown similar associations between temperature and incidence rates; multiples sclerosis [48] and asthma [49]. The mechanism we have introduced could also explain the geographic distribution observed for some of these diseases.

The hygiene hypothesis is debated mainly because no causal relationships between lifestyle factors associated with “hygiene” and incidence of disease have been revealed; however, animal models are promising (see [50] for review). Recent epidemiological studies have investigated hygiene-related factors and the risk of developing ulcerative colitis, but these potential factors were either not significant or confounded with other known risk factors [27, 28]. In the present study, we investigated patterns of disease rates and temperature and its possible relation to biodiversity rather than single species or events. This highlights a difference between the hygiene hypothesis [26] and the “Old Friends” hypothesis [51]. The latter is more focused on absence or reduced numbers of commensal species rather than presence/absence of pathogens.

We cannot rule out the effect of sun-exposure and production of vitamin D, because sun-exposure is also related to latitude. Several studies have shown immunomodulatory effects of vitamin D, and vitamin D also prevents autoimmune responses (see [52] and references therein). Deficiency in vitamin D is well recognized among inflammatory bowel disease patients, but it is debated if this is a consequence of the disease (reverse causation) or directly causative [53]. In a meta-analysis studying polymorphisms of vitamin D receptor genes and risk of inflammatory bowel disease, Xue et al. found that males with specific genotypes were at higher risk for ulcerative colitis than healthy controls [54]. However, both mechanisms can be true, but we are at the present stage not able to estimate the relative contributions from vitamin D and the “Old friends” hypothesis.

The strength of this study is a relatively large number of cases sampled from a large area spanning the north–south axis and where other factors such as access to health care facilities and economic conditions are relatively equal. Furthermore, the present study comprised a relatively large range for the climatic variables. The span in temperature in this study corresponded to a difference between southern and northern Europe. We also included a set of potential contextual variables in our analyses; however, these variables should be included with care because area could both work as a confounder as well as a collider [55]. In the latter case (collider) the contextual variable would have introduced bias. The fact that more men than women suffered from the disease and that there were significantly less smokers among the affected persons reinforced the assumption that we had identified ulcerative colitis cases [56].

There were several weaknesses in our study. The first and most important was the use of self-reported medication and not diagnoses. Secondly, we have included prevalent and not incident cases. We have no information regarding when the subjects were diagnosed or their history of migration. In Norway, seven out of nine (78%) who moved during 1977–1998 did so within their economic region or within their municipality, the rest between counties [57]. These sources of information bias were most likely independent of temperature and can be classified as non-differential misclassification and will produce smaller effects than actually (attenuation). There are also uncertainties attached to environmental risk factors such as diet [58] and acute gastrointestinal infections [59].

In this study we have investigated the geographic distribution of self-reported medication prescribed to patients with ulcerative colitis. We have found that the prevalence of the disease is associated to summer temperature. Temperature is a strong factor governing species richness, and our speculation is that as temperature decreases, the colonization of microbial species in the human gut also decreases, the likelihood for an imbalance in the gut flora increases, and the likelihood for developing the disease increases. This explanation of the spatial distribution of ulcerative colitis is in accordance with the extended hygiene hypothesis, and that the extended hygiene hypothesis could explain both temporal and spatial distribution of incidence rates of ulcerative colitis.