Gastrointestinal disorders like inflammatory bowel disease (IBD) have been consistently on the rise since the peak of industrialization. Early epidemiological data of the 1960s and 1970s only give us insight into North America, Europe, and Oceania, whereas more recent work has highlighted how IBD has progressed to become a global disease. Nations such as India and China have seen rising rates with changing lifestyles. Here, we review two gastrointestinal disorders and how our understanding of these has changed with time.
Inflammatory Bowel Disease (IBD)
Close to 260,000 Canadians live with IBD, and its prevalence continues to rise worldwide. IBD encompasses two chronic gastrointestinal diseases, Crohn’s disease (CD) and ulcerative colitis (UC). These are characterized by a dysregulated immune response to the intestinal microbiota and breakdown of the intestinal barrier, processes influenced by a number of genetic and environmental factors. CD may present anywhere throughout the gastrointestinal tract, but it is most commonly observed in the distal small intestine or in the large intestine; UC presents exclusively in the large intestine. Both diseases are usually first diagnosed in teenagers or young adolescents, but onset may occur earlier in childhood or even shortly after birth. Abdominal pain, cramping, weight loss, and diarrhea are common symptoms during active phases of the disease. Symptoms can be debilitating and often have a profound impact on individuals’ quality of life.
While the earliest descriptions of IBD-like illness date back to Greek antiquity, we only began to fully understand this illness in the past hundred years. With the advent of modern medicine and randomized controlled trials, great strides have been made in our knowledge of IBD etiology and pathology, resulting in improved treatments and diagnostics. In the early 1900s, the use of sigmoidoscopy, an early form of colonoscopy, allowed the physician to directly observe ulcers and inflammation in the rectum and lower colon. More recently, diagnosis has become less invasive through the invention of swallowable wireless pill-sized cameras and the development of non-invasive virtual endoscopy mediated by computer tomography (CT) or magnetic resonance imaging (MRI). Treatment for IBD has only been available for a few decades, but has resulted in greatly improved outcomes for this once fatal disease. At the beginning of the 20th century, surgical resections of inflamed tissue were common. These are still practiced today, yet to a lesser extent and on a case-by-case basis. Corticosteroids were later discovered as the first class of drugs to be effective in suppressing disease, followed by cell metabolism and proliferation inhibitors and anti-inflammatory drugs. The next major chapter of drug discovery came with the advent of biologics, particularly an antibody directed against tumour necrosis factor (TNF). TNF is known to be increased in subsets of IBD patients contributing to exacerbated inflammation. Further biologics under development aim to target other aspects of immune function, including cell trafficking and inflammatory cytokine production. Still, no cure (aside from full colon resection in UC) has been found, and a large number of IBD patients do not respond to treatment. Complicating this is the consistent global rise of IBD with progressive industrialization, urbanization, and subsequent changing lifestyles.
Looking towards the future
Where molecular and cellular biology alongside immunology informed development of therapeutics in the 20th to early 21st centuries, systems biology and omics studies are informing therapeutics of the future. Already, genome-wide association studies (GWAS) have identified more than 200 genetic factors associated with IBD risk and have identified which patients may benefit from anti-TNF therapy based on their underlying genetic make-up. GWAS, epigenetics studies, and microbiota analyses give us insight into how genetic factors interact with environmental factors in changing both the epigenetic landscape and the gut microbiota composition, ultimately affecting IBD risk and course of disease. While still in its infancy, studying the epigenome and microbiota gives us a view at how our environmental changes affect our biology and the heritability of these effects. For example, mouse studies have indicated that the maternal diet influences their progeny’s epigenetic regulation of transcription in the colon. Additionally, IBD patient microbiomes are distinct from healthy individuals, promising the potential of microbiota-targeted treatments, such as fecal transplants.
Genetics and proteomics, the latter being employed to find specific diagnostic biomarkers of disease, will likely play a bigger role in the diagnostics, classification, and prevention of IBD. Two Canadian-led studies, the GEM and GEMINI projects, which are based at Toronto’s Mount Sinai hospital and the University of Toronto, aim to identify the environmental, microbial, and genetic factors that influence disease acquisition. The GEM project tracks CD diagnosis in individuals with first-degree relatives who have CD, whereas the GEMINI project focuses on newcomers to Canada from countries with lower incidence in CD. (More information on the GEMINI project can be found in page 10 of this issue of IMMpress.)
Not to be confused with IBD: Irritable Bowel Syndrome
The first description of gastrointestinal symptoms with no obvious underlying cause was noted 200 years ago; this is now widely known as irritable bowel syndrome (IBS). Population-wide studies have indicated that up to 10% of people worldwide display symptoms of IBS, with prevalence being highest in South America at 20% and lowest in South-East Asia at 7%. Women and young people are more likely to be affected. This widespread prevalence and the socioeconomic impact of this disease beg for a better understanding of IBS. Key findings in recent decades have hinted at various underlying pathologies that may be driving IBS, disproving an early hypothesis that IBS is largely psychosomatic due to a lack of identifiable pathology.
Currently, IBS is diagnosed based on characteristic symptoms (pain, changes in bowel habits, stool consistency, and bloating) and then further classified into four categories according to the patient’s bowel habits. While this method has been useful in finding ways to treat the symptoms, it does little in furthering our understanding of IBS. In particular, it does not address the diseases that may be underlying IBS. IBS can occur in isolation, after a gastrointestinal infection, or with psychological disorders, but also less commonly as a comorbidity alongside other gastrointestinal disorders like inflammatory bowel disease (IBD). Childhood trauma has been found to increase risk of IBS, but the long-standing approach of considering IBS a result of psychological disease is not fully accepted anymore, as several IBS patients only develop mood disorders after onset of IBS.
Some identified underlying pathologies include changes in peristalsis, intestinal permeability, immune activation, inflammation, bile acid malabsorption, serotonin metabolism, and possible decreased diversity of the microbiota. Inflammatory cytokines released by gut innate immune cells, mast cells and dendritic cells act on the enteric nervous system, which affects neuromuscular function resulting in constipation or diarrhea, as well as signalling leading to sensation of pain. Genetic changes have been difficult to identify. In 2014, the first GWAS was performed to find underlying genetic risk factors of IBS. Potential risk-contributing variants were identified, and the study also showed nominal significance of genetic risk factors previously found in smaller patient cohorts. However, the underlying disease variability and lack of large disease cohorts has made it difficult to clearly identify significant genetic contributions.
Given that research has only recently begun to identify potential pathological causes of IBS, it shouldn’t come as a surprise that treatment options are largely symptoms-based and imperfect. First steps include dietary changes; a subset of IBS patients have non-coeliac gluten sensitivity, while others have symptoms exacerbated by fermentable oligo-, di-, mono-saccharides and polyols (FODMAPs) found in legumes, stone fruits, lactose-containing foods, and artificial sweeteners. Increased intake of soluble fibre has also been recommended for IBS patients. Medical therapies target abnormal gastrointestinal mobility, fluid secretion, constipation, and diarrheal symptoms. Anti-depressants or psychotherapy are also used to address both psychological symptoms and management of IBS-related symptoms. Although anti-depressants can also target intestinal transit time and symptoms of pain while addressing psychological symptoms, the benefit of psychotherapy on IBS is not well understood, and studies looking at cognitive-behavioural and hypno-therapy likely overestimated their respective effects.
While research has greatly increased our understanding of IBD and IBS, resulting in better diagnostics, treatments, and outcomes for patients, many people still suffer, and we lack knowledge in both curative and preventative measures. Will it be possible for researchers with 21st century tools to curtail the rising incidence of IBD, or is this the price we pay for living in our modern society?
Elisabeth Foerster
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