Overview
Heterogeneous disorders. The collective term inflammatory bowel disease (IBD) obscures the distinctive nature of Crohn’s disease and ulcerative colitis. These are separate conditions, with some overlapping and several distinct features. Crohn’s disease in particular, and ulcerative colitis to a lesser degree, are heterogeneous, with more than one underlying defect or mechanism leading to a similar clinical outcome. In addition, different mechanisms may account for different subsets of disease. Like many other chronic inflammatory disorders, tissue damage is immune-mediated and arises from a variable interaction between genetic susceptibility factors and environmental triggers or modifiers.
Genetic versus environmental factors. Genetic factors are more important in Crohn’s disease than in ulcerative colitis. This is evident from studies of genetically identical (monozygotic) twins, which show that the concordance rate for Crohn’s disease (risk of second twin developing disease if one is affected) is 40–50%, whereas that for ulcerative colitis is about 10%. These figures also reflect the importance of environmental or lifestyle factors in both conditions, as indicated by the marked rise in the frequency of both forms of IBD in recent decades, particularly in countries undergoing socioeconomic development. The increased incidence and prevalence of these conditions over a relatively short period of time, within one to two generations, can not be accounted for by genetic changes alone.
The indigenous microbiota colonizing the gut from birth is the most immediate environmental modifier of mucosal and systemic immune development, and hence is a pivotal influence on the pathogenesis of IBD. Disturbances in the microbiota, particularly in early life, may affect immune maturation and predispose to microbe-induced immunopathology later in life. Most of the elements of a modern lifestyle and putative risk factors for developing IBD within the wider environment influence the composition of the indigenous microbiota. Furthermore, many of the genetic risk factors for Crohn’s disease and ulcerative colitis either code for sensors of the microbial environment or regulate host responses to that environment or, in the case of ulcerative colitis, influence barrier function at the interface with the intestinal microenvironment. Whether tissue damage results from an abnormal immune reaction to a normal microbiota or from a normal immune response to an abnormal microbiota has been much debated (Figure 1.1). Animal models support both possibilities. Animal models have also shown that while genetic susceptibility and the presence of the microbiota are required for the pathogenesis of chronic inflammation, the timing of onset may be determined by environmental triggers such as chemical injury or viral infection.
Epidemiology
The epidemiological features of Crohn’s disease and ulcerative colitis are similar in most respects (Table 1.1), the most striking exception being tobacco smoking.
Figure 1.1 The complexity of host–microbe interactions in IBD. Animal models have shown that the immune system conditions the composition of the microbiota. In a host with defective innate immunity, the immune system may change the microbiota toward one with colitogenic potential with capacity to transfer colitis to a normal host. Thus, disease may arise either from a normal immune response to an abnormal microbiota or from an abnormal immune response to a normal microbiota.
TABLE 1.1 Epidemiological features of Crohn’s disease and ulcerative colitis | ||
| Crohn’s disease | Ulcerative colitis |
Incidence* | ~5–10 | ~5–10 |
Prevalence† | 100–200 | 100–200 |
Male/female ratio | ~1:1 | ~1:1 |
Age of onset | All ages | All ages |
| Peak at 20–40‡ | Peak at 20–40‡ |
Smoking | Risk factor | Linked with cessation of smoking |
| Aggravates | Modest beneficial effect |
Appendectomy (appendicitis) | No effect | Protective |
Geographic/socioeconomic§ | Common in developed countries | Common in developed countries |
Ethnicity | All ethnic groups affected | All ethnic groups affected |
| More common in Ashkenazi than Sephardic Jews | More common in Ashkenazi than Sephardic Jews |
Infections | Adverse | Adverse |
Psychological stress | Perceived stress aggravates disease | Perceived stress aggravates disease |
Adverse effect of drugs | ||
Antibiotics | Risk factor in early life | Probable but unproven |
Oral contraceptives | Unproven | Unproven |
NSAIDs | Yes, in high doses | Yes, in high doses |
*New cases/105 population/year. †cases/105 population. ‡Some but not all studies report a bimodal age distribution with a later, lesser peak at 60–80 years. In a rare subset of patients who present in very early childhood, a distinct monogenic pattern of inheritance may be involved. §As with other immunoallergic disorders, IBD is more common in urban than in rural areas. Endemic parasitism with helminths and unsanitary conditions seem to be protective. | ||
Appendectomy, particularly when performed early in life, is associated with a reduced risk of developing ulcerative colitis but not Crohn’s disease. It seems that appendicitis and mesenteric lymphadenitis, rather than appendectomy per se, during childhood or adolescence confers protection against subsequent development of ulcerative colitis.
Socioeconomic development. The most consistent epidemiological feature of both Crohn’s disease and ulcerative colitis is the increase in incidence and prevalence of both conditions in societies undergoing socioeconomic development. This probably accounts for epidemiological observations in the past, including notional east–west and north–south geographic gradients. The emergence of IBD with socioeconomic development follows a consistent pattern, first with the appearance of ulcerative colitis, followed by Crohn’s disease. Incidence and prevalence has already peaked in some but not all Western countries, is rising rapidly in developing areas of the globe, and can be predicted to appear in others. This should be seen not only as an epidemiological lesson but also as an opportunity – an imperative for the developed world to try to prevent. Studies of migrant populations moving from low- to high-prevalence areas confirm the influence of modern environmental and lifestyle factors, and suggest that their effect is greatest at the earliest stages of life when the indigenous microbiota is becoming established and the immune system is still developing.
Epidemiological clues to the role of gut microbiota. The possibility that IBD or a subset thereof might be caused by a pathogen waiting to be discovered cannot be fully discounted. However, the involvement of a transmissible agent is at variance with the population distribution of these diseases: overcrowding, large family size and poor sanitary conditions seem to be protective. Therefore, many researchers have moved from a ‘one microbe, one disease’ model toward a more complex concept of mixed microbial patterns or populations within the indigenous microbiota becoming risk factors for disease depending on host susceptibility. Most elements of a modern lifestyle have been shown to influence the composition of the indigenous microbiota (Table 1.2). The link between lifestyle factors, particularly diet, and the risk of developing IBD, is complex and may be indirect, mediated by an influence on the microbiota in early life.
Diet. Dietary changes associated with socioeconomic development have been implicated in the changing epidemiology of IBD. Animal models have demonstrated the influence of specific food ingredients, in particular a high-fat diet, on the composition of the microbiota. A diet high in milk-derived fat but not polyunsaturated fat has been linked with expansion of the pathobiont Bilophila wadsworthia and colitis in interleukin (IL)-10-/--deficient mice. Whether similar gene–diet–microbe interactions occur in humans is less clear, but it is noteworthy that the increased incidence of IBD over recent decades in Japan correlates closely with changes in dietary fat, particularly animal fat. In addition, it has recently been shown that dietary diversity is positively correlated with fecal microbial diversity, both of which are linked with reduced levels of pro-inflammatory markers in healthy adults.
TABLE 1.2 Elements of a modern lifestyle in socioeconomically developed countries with potential to modify host–microbe gut interactions* |
Improved sanitation and hygiene Refrigeration Living on concrete (urbanization) Smoking Decline in ancestral microbes (e.g. Helicobacter pylori, endemic parasitism with helminths) Increased antibiotic usage Vaccinations Smaller family size Delayed exposure to mucosal infections Sedentary lifestyle – obesity Increased likelihood of birth delivery by Cesarean section Diet, including greater use of processed foods with higher fat content |
*In animal models, stress may alter the composition of the microbiota, providing evidence for a microbe–gut-brain axis. |
Antibiotic exposure, particularly in the first year of life, has been linked with up to an eightfold increased risk for development of Crohn’s disease in childhood.
The gut microbiota
Animal models have shown the complexity and heterogeneity of the role of gut microbes in the pathogenesis of IBD.
• The microbiota is necessary for full development and maturation of the immune system, without which an inflammatory response to any cause would not be possible.
• While some microbial products are protective against inflammation, others are pro-inflammatory in susceptible individuals.
• A defect in host immunity may change the composition of the indigenous microbiota toward one with colitogenic properties.
• Gut microbiota and their products may play a role not only in the onset and pathogenesis of IBD, but also in its progression and complications such as stricture formation and adhesions. They may also contribute to the risk of colitis-associated carcinogenesis.
• The microbiota has direct involvement in translocation, sepsis and, as a competitive influence, in the risk of complicating infections such as Clostridium difficile-associated disease.
• Mucosal infections may determine both the onset and subsequent relapses of IBD. Mucosal infection temporarily disrupts barrier function and generates immune responses not only against the pathogen but also against commensal species. Repeated infections may lead to accumulation of commensal-reactive T cells, which eventually shift mucosal homeostasis from controlled or physiological inflammation toward chronic inflammatory disease.
Microbial alterations. The more consistently observed microbial alterations are summarized in Table 1.3. Reduced microbial biodiversity is consistently found but is non-specific. While reduced biodiversity in the gut may have arisen because of reduced acquisition of environmental microbes (the so-called hygiene hypothesis), it is more likely that it reflects progressive loss of ancestral microorganisms, for example helminths and Helicobacter pylori (which was in decline in the Western world long before its discovery in the 1980s).
Increased numbers of mucosal adherent and intramucosal bacteria are found in Crohn’s disease and may reflect defective clearance of bacteria. This may also account for increased rates of detection of Mycobacterium avium paratuberculosis and enteroadherent Escherichia coli in patients with Crohn’s disease. While such co-infections may not cause Crohn’s disease, they may influence its clinical progression. Other organisms such as Faecalibacterium prausnitzii, which has anti-inflammatory properties, are reduced in many patients with IBD, whereas other microbial disturbances may contribute to tissue injury because of their mucolytic or proteolytic properties. It is likely that improvements in traditional culture-based techniques, combined with modern molecular non-culture-dependent strategies such as high-throughput sequencing and metagenomic compositional analysis will provide new microbial biomarkers of risk and IBD subsets in the future. As with animal models, heterogeneity of responses to therapeutic manipulation of the microbiota can be anticipated in patients with IBD. For example, antibiotics have efficacy in colonic Crohn’s disease but not in small-bowel disease (see Chapters 5 and 8), and are the treatment of first choice in pouchitis (Chapter 9) but not in uncomplicated ulcerative colitis.
TABLE 1.3 Examples of the microbiota in inflammatory bowel disease* | |
Increased | Reduced |
Mucosal bacterial numbers (CD) | Bacterial diversity (CD, UC) |
Mycobacterium avium paratuberculosis (CD) | Clostridium groups IV, XIVa (Faecalibacterium prausnitzii) (CD, UC) |
Clostridium difficile (CD, UC) | Bifidobacteria and lactobacilli (CD, UC) |
Ruminococcus gnavus (CD) | Akkermansia (UC, CD) |
Enterobacteriaceae e.g. adherent invasive Escherichia coli (CD) |
|
*Examples of consistently detected changes in the intestinal microbiota in patients with Crohn’s disease (CD) and ulcerative colitis (UC) | |
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