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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

Perhaps the biggest mystery in ulcerative colitis (UC) is why it develops in the first place. Decades of research have pulled back the curtain a little, but other than identifying some risk factors and potential mechanisms, medicine still has no solid answer for the newly diagnosed patient who asks, "Why me?" Here we review the current state of knowledge about UC's etiology that may help inform discussions with patients -- both to answer questions about how it arose and to help with self-care.

While a number of associations with UC are beyond dispute -- living in an industrialized country, diet, smoking cessation, family history, certain microbiome profiles, and a few others -- none have been firmly established as actually causative. Even when a mechanistic pathway can be identified, it's still difficult to determine conclusively that it triggers UC in a previous healthy person versus aggravating preexisting subclinical pathology.

If an individual has suffered some damage to the colonic epithelium that exposes underlying layers in the colon wall, the possibilities become almost limitless for other factors to come into play that lead to overactive or self-directed immune responses. Several involve feeding them agents that damage the intestinal epithelium, after which UC-like inflammation develops -- thus highlighting the importance of an intact epithelium.

Thus, studies indicating that dietary red meat, for example, increase the risk of developing UC are not proof that red meat causes UC -- it may be that the immune system was already primed to react to red-meat antigens as a result of some existing pathology.

Risk factors that could be causative may be categorized as follows:

• Environmental

• Genetic

• Microbial

• Smoking cessation

Environmental

The global epidemiology of UC could hardly be clearer: incidence is highest in developed countries, and individuals who emigrate to these countries from places with low rates soon develop UC at a frequency like that of long-time residents.

While to some extent this observation could result from ascertainment bias -- greater healthcare access may increase the likelihood of diagnosis. However, most scholars consider the increased risk in industrialized nations to be real.

"Western life" comprises countless factors that could trigger (or at least aggravate) UC. Diet is the most obvious, but others include pollution, stress, and better sanitation. "No data support psychological stress as a trigger for onset or relapse of ulcerative colitis," according to a , but there has been plenty to suggest that diet is at least a contributing factor in at least some cases.

Diet, too, is a highly variable entity even within a given Western country, but red meat and processed meat products have been identified in a number of studies as clear risk factors. A , for example, found that risks increased by as much as 18-fold in those whose consumption of sausage and related products was rated as high. A yielded similar results. So did that held up the "Westernized diet," characterized as high in animal protein and low in fiber, as "important in most cases of IBD."

One theory as to how diet may act as a trigger in UC holds that, if the colonic epithelium is at all compromised, food-based antigens can then interact with luminal tissues within the colon wall to activate an immune response leading to inflammation, which then becomes chronic. Cow's milk as well as meat has been implicated in this way. This theory, however, remains largely speculative, and it depends on a preexisting injury to the epithelium, which normally should prevent immune interaction with food molecules as they pass through.

With regard to sanitation as a UC risk factor, similar to that for asthma and other allergic disorders, under which the West's focus on sanitation deprives children of exposure to pathogens, such that their immune responses to exposures in adulthood are increased to the point of pathology. But it has not been suggested as an actual cause of UC, but rather a contributory factor -- say, adding to diet or other risks.

As well, illustrates the difficulty of attributing UC risks to any one dietary factor. Residents of the remote Faroe Islands have the highest IBD incidence in the world, at 81.5 per 100,000 population per year as of 2010. This was initially attributed to residents' unique diet featuring substantial quantities of pilot whale meat and blubber. Yet when researchers analyzed food frequency questionnaires completed as part of a larger study, they found no relation between IBD incidence (including UC separately) and consumption of whale products. Further muddying the picture, previous studies had found that when islanders migrated to mainland Denmark (the Faroes' parent country), they retained the high incidence rate for 10 years, despite lacking access to whale products, after which the rate fell to match that of other Danish citizens. Thus, the reason for the Faroes' high rate remains a puzzle.

Genetic

Family history is the strongest predictor that a person will develop UC. This suggests a genetic basis for the disease.

One of the strongest candidates is the HLA-DQA1*05 haplotype, which a number of studies have linked both to risk of UC development and to impaired responses to biologic therapies such as infliximab (Remicade). A found that the presence of the haplotype was tied to more extensive disease in pediatric UC. However, the authors of that paper noted that the allele is carried by 20-40% of all Europeans -- meaning it merely raises risk somewhat, rather than being directly and uniformly causative. , genetic factors account for, at most, 7.5% of the overall risk.

Broader genomic analyses have identified that correlate with increased UC. Functional studies have indicated that many of these may lead to immune dysregulation. A selective made the case that UC arises from abnormal function in both the innate and adaptive immune systems, leading to excessive reactions to intestinal microbiome components, food-related antigens, or individuals' own epithelial cells. This review did not directly attribute these immune defects to genetic factors, but it did note that UC-like conditions can be generated in mice lacking genes for certain immune factors.

That point could also be gleaned from the review of animal models of UC, which highlighted that mice with the interleukin-10 gene knocked out "develop spontaneous inflammation of the colon characterized by the presence of an inflammatory infiltrate made up of lymphocytes, macrophages, and neutrophils," very much like human UC.

Unfortunately, as has been the case with much genetic research, identifying loci that associate with a disease is only one small step toward understanding its full etiology, let alone finding effective prevention or therapeutic strategies.

Microbial

Among the payoffs from the burst of attention paid recently to the intestinal microbiome is a recognition that it likely plays a strong role in UC. The microbiome is crucial to processing food components as they pass through the intestine, and the bacteria themselves, while normally benign, are potentially antigenic. Moreover, it may evolve over time -- in reaction to diet, pathogenic infection, , or drug therapies, to name just a few influences -- and become less benign as the various populations wax and wane.

That the microbiome plays a role is evidenced by some successes in treating UC with microbial therapies including prebiotics, probiotics, and fecal transplant (a topic for a later installment in this series).

The extent to which pathogen infection can cause UC remains uncertain. Common infections such as Clostridioides difficile don't appear to trigger UC, although the infection can be worse in patients with existing UC. (C. diff can cause a of colitis, however.) There has been that Helicobacter pylori, the bacterium responsible for gastric ulcers, may play a role, as antigens shed from the stomach come into contact with the lower intestine. This research is in its early days.

Smoking Cessation

UC shares with Parkinson's disease the distinction of being the only major diseases for which smoking actually seems to reduce the risk. Moreover, risk for UC increases when a person quits smoking -- by about 80% compared with never-smokers, according to a . (In contrast, Crohn's disease risk is higher among smokers.) One recent review warned darkly that China could soon face an epidemic of UC because so many of its smoker citizens are quitting.

Some research gives insight into possible mechanisms. A recent found that cigarette smoke affected both microbiome composition and patterns of immune activity, such that its deprivation after chronic exposure could be detrimental. It probably goes without saying, though, that other risks from smoking are far greater than the benefit from UC avoidance, and therefore no one feeling vulnerable to possible UC should take up cigarettes. And, the benefits of smoking cessation in terms of respiratory and cardiovascular health far outweigh the risk of new-onset UC.

Read previous installments in this series:

Part 1: UC: Understanding the Epidemiology and Pathophysiology

Part 2: UC: Symptoms, Exams, Diagnosis

Up next: Case studies