Definition of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic inflammatory condition affecting the gastrointestinal tract, encompassing two major subtypes: Crohn’s disease (CD) and ulcerative colitis (UC).

Over the past twenty years, IBD incidence has considerably increased, becoming a global public health problem; prevalence is estimated to be 0,3%.^1,2 Up to 2 million Europeans and 1.6 million Americans suffer from IBD, making these regions and Oceania the zones of highest prevalence ^1,3. Canada is one of the most affected country with approximately 29 per 100’000 person-years suffering from IBD and an incident cases per year of approximately 10’000.⁴ In Switzerland, about 0,41% of the population (12’000-15’000 adult patients) has been diagnosed with IBD. Data from the Swiss IBD cohort study (SIBDC) suggest that overall incidence continues to increase.^5,6 The rising incidence of IBD in all newly industrialized countries result from Westernization of lifestyles.^1,7

Figure 1. Age-standardized prevalence rate (per 100000 population) of IBD, both sexes, for 195 countries and territories, 2017 (published in GBD 2017 Inflammatory Bowel Disease Collaborators. Lancet Gastroenterol Hepatol 2020⁸)

6 1.2 Pathogenesis of inflammatory bowel disease

While the cause of IBD is still unclear, it seems to be produced by complex interactions between four pivotal factors: the genome; the exposome; the microbiome; and, the

immunome.^9-13 Genetic susceptibility and environmental triggers lead to inappropriate and continuous immune response against the host microbiota, facilitated by disruption of the intestinal barrier. Below, I describe factors of IBD pathogenesis key to understanding therapeutic targets enabling personalized care of IBD patients.

1.2.1 The genome

Family history is a risk factor for developing IBD. People with relatives who suffer from IBD are at higher risk of developing the disease, suggesting a genetic predisposition.¹⁴ Relative risk of developing the disease is five-fold higher among first degree relatives of IBD patients.

15 The inheritable component seems stronger for CD; the concordance rate in monozygotic twins reaches 30-58%, while it is only 10-15% for UC. Patients with very early-onset IBD, who usually develop a more severe form of the disease, often report a positive family history.

Rare genetic variants that interfere with pathways, causing intestinal inflammation have been identified in this situation.¹⁶

IBD is a complex polygenic disorder driven by multiple common genetic polymorphisms. ¹⁷ Functional gene polymorphisms influence innate and adaptive immunity and regulation of the intestinal barrier. ¹⁸ Genome-wide association studies (GWASs) revealed more than 250 significant genetic risk loci, demonstrating its immense complexity.^19,20,21 Up to 80-90% of GWASs-identified loci are noncoding variations, exerting pathogenic effects by modulating gene expression. Specific IBD loci are involved in biological processes like barrier function, microbial defense, innate and adaptative immune regulation, and autophagy. ²² Around 68%

of these loci are associated with both CD and UC, indicating that they have common

pathways of inflammation. ²³ Some loci are different, contributing to the clinical, endoscopic, and histological discrepancies between the diseases. The first mutation thought to be associated with CD development was identified in the gene NOD2/CARD15, which revealed a peptidoglycan that modulates innate and adaptive immune responses, reinforcing the argument that the epithelial barrier is involved in mucosal homeostasis.^{9, 24} Many loci overlap with other inflammatory diseases, like psoriasis and spondylitis.^20,23 While genetic testing is possible, it is not yet used to diagnose IBD since it can identify a person’s potential risk for IBD, but cannot predict if they will suffer from IBD - many people carry these genes but

7 never develop IBD. IBD genetic studies must meet the challenge of translating these genetic discoveries into useful clinical tools.

1.2.2 The exposome

The incomplete concordance of IBD between monozygotic twins makes clear that genetics are not the only factors that influence the disease. ^17,25 Several environmental risk factors (=exposome) may contribute to IBD pathogenesis, but study results are inconsistent and limited. Since the rate of IBD increases in newly industrialized countries with high migrant populations, the role of “westernization” of the environment may be central to disease development. The exposome mediates the pathogenesis of IBD through its effect on intestinal microbiota (microbiome).^1,26,27,11

Environmental exposures continue over the life course, and many environmental factors have been associated with IBD including early life events (mode of delivery, breastfeeding, early exposition to antibiotics), exposure to pets and infections (the “hygiene hypothesis”), and smoking and diet. ²⁸ Smoking is the most studied environmental IBD trigger. Tobacco smoking is particularly damaging for patients with CD, likely because the smoke is toxic to immune and mucus-producing cells, impairs autophagy, and changes the microbiome.^11,

22,29-31 Medications, like antibiotics, increase risk of developing IBD by changing the intestinal microbiome. The effect is more severe if antibiotics are administered early in life, when the microbiota helps shape immunity.32,33,34,35 Contraceptives, non-steroidal anti-inflammatory drugs and statins have also been incriminated.^36,37 Diets rich in saturated fatty acids, processed food and red meats are also reported to increase IBD risk. High fiber diets, in contrast, may be protective and reduce CD risk by 40% due to their anti-inflammatory properties; colonic bacteria metabolize dietary fiber into light chain fatty acids. 38-40,37,41

1.2.3 The microbiome

IBD risk may also be influenced by the gut microbiome, which comprises all microorganisms, bacteria, viruses, protozoa, and fungi, and their collective genetic material present in the gastrointestinal tract. The microbiome establishes the connection between intestinal mucosa and the outside environment. In IBD patients, a decrease of microbiota diversity called

“dysbiosis” has been repeatedly reported. ⁴² In comparison to healthy people, those with IBD have fewer anti-inflammatory bacteria like Firmicutes and more bacteria with inflammatory capacities like Proteobacteria and Bacteroidetes in their microbiota. ⁴³ Faecalibacterium prausnitzzi, a bacterium that produces short-chain fatty acids is also less common in the microbiota of IBD patients; this may inhibit epithelial cell growth and damage T regs cells.

8 Lower counts of this bacteria were associated with higher ileal CD recurrence rate after surgery. ^44,45 An increase of certain Proteobacteria, like E. coli, can affect the permeability of the intestine, reduce the diversity of the microbiota, and provoke inflammatory responses by regulating the expression of inflammatory genes. ⁴⁶ IBD patients may also have more mucosa-associated bacteria. ⁴⁷ Finally, augmentation of sulfate-reducing bacteria like Desulfovibrio can damage the intestinal barrier and activate mucosal inflammation by producing hydrogen-sulfate. ⁴⁸ The microbiome is still a domain of intensive investigation and it is unclear if these associations are a cause or a consequence of IBD. Further study is required to identify the mechanisms that may reverse dysbiosis.

1.2.4 The immunome

Immune dysregulation plays a central role in IBD pathogenesis. The digestive tract is a crucial immunological interface. It preserves an immunologically complex balance between recognition and tolerance of commensal bacteria, antigens from food, self-antigens

(tolerogenic response), and pathogen identification (immunogenic response). ⁹ Several innate immune factors contribute to the persistence of inflammation like impairment of the intestinal barrier. Microbiome changes can cause inappropriate and continuing inflammation, epithelial neutrophil accumulation, defective antigen clearance by macrophages and

impaired conditioning of dendritic cells.^9,49,50,13 Antigens that trigger inflammation are caught by antigen-presenting cells and intracellular degradation in the proteasomes exposes the epitope, the antigenic fraction that triggers a T cell mediated immune response. ^13,51 The balance between effector T cells (TH1, TH2, TH17 and TH9) and regulatory T (Treg) cells is crucial to maintaining tolerance or promoting chronic inflammation. ⁵⁰ T cells contribute to chronic intestinal inflammation and are a potential therapeutic target in IBD.