Fast Facts: Inflammatory Bowel Disease: Translating the science into compassionate IBD care

By D.S. Rampton and F. Shanahan

Inflammatory bowel disease (IBD) comprises two idiopathic chronic relapsing and remitting inflammatory disorders of the gastrointestinal tract: ulcerative colitis and Crohn’s disease. Understanding of the etiopathogenesis of IBD, and how best to treat it, continues to advance rapidly and has led to the need for this new edition. Chapter 1 has been substantially revised, emphasizing recent data that indicate how the gut microbiome and its human host may interact to cause IBD in genetically susceptible people. In later chapters, the latest thinking on how best to use immunomodulatory and biological drugs is discussed, along with new sections on recently introduced and imminent therapies. This book is aimed at non-specialist doctors (particularly primary care providers and hospital doctors in training), nurses, stoma therapists, dieticians, psychologists, counselors, social workers and other professionals involved in the care of patients with IBD. Contents: • Etiopathogenesis • Clinical features and intestinal complications • Extraintestinal manifestations and complications • Diagnosis • Drugs used to treat IBD • Principles of management • Medical management of ulcerative colitis • Medical management of Crohn’s disease • Surgery • IBD in pregnancy, childhood and old age • Prognosis

• Language: English
• Publisher: S. Karger
• Release date: Jan 26, 2021
• ISBN: 9783318066562

Book preview

Introduction

Inflammatory bowel disease (IBD) comprises two idiopathic chronic relapsing and remitting inflammatory disorders of the gastrointestinal tract: ulcerative colitis and Crohn’s disease. Our understanding of the etiopathogenesis of IBD, and how best to treat it, continues to advance rapidly and has led to the need for this new edition.

We have substantially revised the opening chapter, emphasizing recent data that indicate how the gut microbiome and its human host may interact to cause IBD in genetically susceptible people. We also discuss the latest thinking on how best to use immunomodulatory and biological drugs, whether alone or in combination, along with new sections on recently introduced and imminent therapies.

Converting the concept of personalized therapy from an aim into a reality will continue to be a focus of clinical research. Detailed assessment of the genotype, immune function and other features of the individual will help us to identify who will respond well and who will be at risk of side effects from specific drugs: treatment for individual patients will then be selected more appositely.

We must also continue to embrace the holistic approach to management of these chronic diseases. Doctors often used to overlook problems such as anemia, mood disturbance, fatigue and osteoporosis, yet each of these is a common if not always easily reversible contributor to impaired quality of life for people with IBD. In this time of increasing specialization, high-technology diagnostics, molecular therapeutics and evidence-based everything, the doctor–patient relationship will come under increasing scrutiny and change. Technology helps to clarify the objective aspects of the disease but not the unique subjective experience of the person with the illness.

Health professionals caring for people with IBD need to care about people with IBD. This requires an interest in the condition, a commitment to long-term follow-up and more than a little compassion. This book is aimed at non-specialist doctors (particularly primary care providers and hospital doctors in training), nurses, stoma therapists, dieticians, psychologists, counselors, social workers and other professionals involved in the care of patients with IBD. Medical students should also find it helpful. We hope, too, that people with IBD may benefit from reading this overview of their illness.

1Etiopathogenesis

Overview

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 modifiers, the most proximate of which is the indigenous gut microbiota (Figure 1.1). The importance of the role of the gut microbiome in the etiopathogenesis of IBD is being increasingly recognized as researchers unravel its complexity and its multiple interactions with the human host (Table 1.1).¹

Early human lifestyle and risk of IBD

The epidemiological features of Crohn’s disease and ulcerative colitis in modern societies are well established (Table 1.3), but hide key insights derived from global studies.³ The most consistent observation has been the abrupt increase in incidence and prevalence of both forms of IBD within one to two generations in societies undergoing socioeconomic development. This cannot be attributed to genetic changes alone.

Evidence from migration. Studies of migrants from developing to developed countries have shown that the influence of modern lifestyle and the environment begins during birth and infancy, long before the onset of disease. The younger a migrant is when moving from a country with a low risk of IBD to a region with high frequencies of IBD, the greater the risk of developing IBD.

Figure 1.1 Combined events (‘perfect storm’) leading to cycles of IBD. Lifestyle influences associated with socioeconomic development operate in early childhood, particularly the first 3–4 years when the gut microbiome is being assembled and the immune and other systems within the host are maturing. External triggers such as infections, drugs and tobacco may act directly on the host and/or on the microbiome. Dietary changes in modern societies include consumption of low-fiber, processed, energy-dense, high-animal-fat foods. The genetics of IBD is outlined in Table 1.2.

TABLE 1.1

The gut microbiome¹

•The gut contains more than 1000 bacterial species, bacteriophages (phageome), viruses (virome) and fungi (mycobiome), the importance of which to human health and disease is only just being realized.

•The gut (mainly the colon) contains more bacteria than the human body has cells. The number of genes in the microbiome (metagenome) is threefold higher than in the human genome.

•The gut microbiome interacts widely with the human host, influencing not only digestion and absorption, but also the host’s mucosal defence mechanisms, immune function and metabolism.

•The composition and function of the microbiome is influenced by diet, drugs and disease processes, as well as, during their consumption, prebiotic and probiotic organisms (see page 74 and Table 5.10 ).

•To date, the microbiome has been implicated in the etiopathogenesis of obesity, type 2 diabetes, fatty liver disease, Parkinson’s disease, multiple sclerosis and depression, as well as IBD, irritable bowel syndrome and colon cancer.

TABLE 1.2

Genetics of IBD²

•Family history. Up to 12% of patients with IBD have a family history of IBD. Many genetic loci are shared between Crohn’s disease and ulcerative colitis, which explains why patients with Crohn’s may have a family member with colitis and vice versa.

•Crohn’s disease vs ulcerative colitis. Genetic factors are more important in Crohn’s disease than in ulcerative colitis. Studies of genetically identical (monozygotic) twins show a higher concordance rate for Crohn’s disease: the risk of the second twin developing the disease if one is affected is 30–40%, whereas for ulcerative colitis it is about 10%.

•Polygenic influences. Genome-wide association studies (GWAS) have found more than 230 single nucleotide polymorphisms (SNPs) linked with IBD, each individually representing a variable but relatively low risk. Some are specific to Crohn’s disease, others are specific to ulcerative colitis and most are shared between both disorders. Some genetic loci seem to be more prominent in different ethnic groups. For example, the NOD2 locus (see pages 14–15 ) has a smaller influence on Crohn’s disease risk in Oriental populations than in Europeans. No single susceptibility gene is necessary or sufficient to cause disease. Distinct genetic susceptibility factors may influence disease distribution; for example, colonic vs small-bowel Crohn’s disease.

•Monogenic subsets. Rare monogenic disorders, including homozygous recessive mutations in the interleukin 10 (IL-10) receptor, are associated with very early onset of IBD, mainly with diffuse colonic disease, which may not fit easily into a Crohn’s/ulcerative colitis classification.

TABLE 1.3

Epidemiological features of Crohn’s disease and ulcerative colitis³,⁴

Note 1. Most epidemiological features are shared, the most striking exception being tobacco smoking, which polarizes Crohn’s disease and ulcerative colitis.

Note 2. Appendectomy, particularly when performed in early life for appendicitis and mesenteric lymphadenitis, appears to protect against subsequent development of ulcerative colitis. Evidence linking appendectomy with an increased risk of Crohn’s disease may be attributable to the operation being undertaken in people with incipient Crohn’s disease misattributed to appendicitis.

*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 rural areas. Endemic parasitism with helminths and unsanitary conditions seem to be protective.

Moreover, children of migrants have a greater risk of developing IBD than children who do not migrate.² Migrants to modern industrialized countries undergo a progressive change in their gut microbiome, including loss of diversity, alterations in bacterial composition with loss of ancestral organisms and loss of bacterial enzymes associated with plant fiber degradation.⁵

Changes to the microbiota. It is noteworthy that indigenous microbiota are assembled during the first 3 years of life at a time when the immune system is maturing and becoming a sensory system for accurately detecting and dealing with danger within the environment. Since the microbiota is the most immediate environmental modifier of mucosal and systemic immune maturation, it has a pivotal influence on the pathogenesis of inflammatory disorders such as IBD.

Most elements of a modern lifestyle, including those linked with a risk of developing IBD, have been shown to modify the microbiota (see Figure 1.1). Disturbances of the microbiota, particularly in early life, may affect immune maturation and predispose to microbe-induced immunopathology later in life. Thus, antibiotic exposure, particularly if repeated in the first year of life, has been linked with an increased risk of Crohn’s disease developing.

Linking genes and microbes with inflammation

Although lifestyle and environmental factors shape the microbiome, host genetic factors also influence the composition of the microbiome.⁶ Furthermore, most of the genetic risk factors for Crohn’s disease and ulcerative colitis code for sensors of the microbial environment or proteins that regulate host responses to that environment, including maintenance of barrier function.⁷

NOD2 is the strongest genetic risk factor. It contributes to the pathogenesis of IBD by modifying immune responses to the gut microbiota. NOD2 codes for a cytosolic pattern recognition receptor that senses and binds to muramyl dipeptide (MDP), a component of bacterial cell wall peptidoglycan. NOD2 is expressed in the intestinal epithelium, Paneth cells and mononuclear cells of the lamina propria. Binding of NOD2 with MDP leads to activation of the nuclear (transcription) factor (NF)-κB, with increased generation of pro-inflammatory cytokines. Since the three common mutations of NOD2 in IBD are within the leucine-rich repeat domain that binds to MDP, it appears that defective bacterial sensing accounts for the increased risk of disease, particularly fibrostenosing small-bowel and right-sided colonic Crohn’s disease.

Autophagy (self-eating) is another mechanism by which host cells deal with microbes. It is a normal cellular event in the homeostatic control of growth and development by which cellular components are degraded or recycled. It also contributes to the processing of intracellular pathogens.

Variants in several genes in the autophagy process, including ATG16L1, LRRK2 and IRGM, are genetic susceptibility factors for Crohn’s disease. Defects in autophagy and an increased intracellular bacterial load may lead to the secondary mucosal T helper cell 1 (Th1) activity that characterizes Crohn’s disease (see page 19).

Other genetic defects that occur at various levels affect immunoregulation, enteric nervous system function and epithelial barrier function, all of which maintain homeostasis of host–microbe interactions, the breakdown of which may lead to inflammatory disease.

Epigenetics is the heritable modification of gene expression, rather than alteration in the genetic code itself. IBD risk-associated genetic factors account for only a minority of the observed heritability of the disease. These genes are common in society and many carriers of these risk alleles never develop IBD. Epigenetic factors may explain the familial occurrence of IBD that is not explained by genetic factors (missing heritability). Environmental factors, including diet and the microbiota, are known to cause epigenetic modifications such as DNA methylation and histone acetylation in intestinal