Crohn’s disease and ulcerative colitis: understanding inflammatory bowel disease

Healthy state

In the gut, the immune system lives in close quarters with trillions of bacteria without attacking them. Several layers make this possible. A mucus layer Mucus layer A gel layer of mucins on the gut wall that keeps bacteria at a distance. In the colon, the inner layer is almost free of microbes. More in the chapter “The mucus layer and additives” keeps most bacteria away from the gut wall. The cells of the wall are tightly joined. Special cells deep in the folds of the small intestine, the Paneth cells, release defence substances that keep bacteria at a distance. And regulatory T cells make sure the immune system reacts calmly to harmless bacteria and food.

Inflammation is really a repair programme. When pathogens get in, the immune system reacts, clears the damage and then switches off again. After a stomach bug, the lining is calm again within days to weeks. The gut bacteria themselves are important for switching off: strictly oxygen-avoiding species such as Faecalibacterium prausnitzii ferment fibre into butyrate Butyrate A short-chain fatty acid and the main energy source for the cells of the colon wall. It strengthens the barrier and dampens inflammation. More in the chapter “Butyrate and other short-chain fatty acids”, which feeds the gut wall and strengthens the calming T cells.

In irritable bowel syndrome Irritable bowel syndrome Recurring abdominal pain linked to bowel movements, without tests finding another cause. Today it is understood as a disorder of gut–brain interaction. More in the chapter “The gut-brain axis” the symptoms can be similar, but the lining is not inflamed. This can be measured: calprotectin Calprotectin A protein from white blood cells measured in stool. Raised levels point to inflammation in the gut. More in the chapter “Gut tests: what they show and what they do not” is a protein from immune cells that rises in the stool when there is inflammation. In irritable bowel syndrome it usually stays low; in active inflammatory bowel disease Inflammatory bowel disease Umbrella term for Crohn’s disease and ulcerative colitis: long-term, relapsing inflammation of the gut that needs medical treatment. More in the chapter “Immune system and inflammation” it is almost always raised.

Disrupted state: causes and effects

In inflammatory bowel disease, IBD for short, the inflammation no longer switches off. The immune system attacks the gut wall permanently or in flares. The two main forms are Crohn’s disease and ulcerative colitis. In 2017, around 6.8 million people worldwide were living with IBD. It is most common in North America and Western Europe, with around 450 people affected per 100,000 inhabitants in the USA and the UK. In countries that are industrialising rapidly, new cases are rising. The disease usually starts in young adults, but can occur at any age.

Crohn’s disease can affect the whole digestive tract from mouth to anus, most often the end of the small intestine and the start of the large intestine. The inflammation is patchy, with healthy sections in between, and reaches through all layers of the gut wall. That is why, over the years, narrowings, fistulas (channels to other organs or to the skin) and abscesses can develop. Typical are abdominal pain, often lower right, diarrhoea, weight loss and fatigue. Ulcerative colitis, by contrast, always starts in the rectum and spreads without gaps to varying extents into the colon. It affects only the lining. Typical are bloody, mucous diarrhoea and strong urgency.

Genes play a role but do not explain everything. A large analysis found 163 places in the genome that influence risk. Many of them concern how the body deals with bacteria, and a striking number overlap with the defence against mycobacteria, the relatives of the tuberculosis germ. In identical twins, a Swedish study found that the second twin also developed Crohn’s disease in around half the cases, but ulcerative colitis in just under one fifth. So the same genes are not enough; the environment has to play its part, even more so in colitis than in Crohn’s.

Smoking has opposite effects on the two forms. People who smoke develop Crohn’s disease almost twice as often. In ulcerative colitis, by contrast, current smokers are affected less often, and former smokers more often than people who never smoked. Antibiotics also increase the risk: in Sweden, people with three or more antibiotic prescriptions had around a 50 percent higher risk, more so with broad-spectrum antibiotics. Compared with siblings the effect was smaller, so part of it is due to shared genes or environment. There are also signs pointing to ultra-processed foods and to a very clean environment in childhood, both from observational studies.

The gut microbiota Microbiome, gut microbiota The community of all microbes in the gut, mainly bacteria, plus viruses, fungi and archaea. Most live in the colon. More in the chapter “Building microbial diversity” is altered in IBD. In the Integrative Human Microbiome Project, 132 people were followed for a year and examined up to 24 times. In active phases, bacteria that tolerate oxygen increased at the expense of strictly oxygen-avoiding species, and the microbiota fluctuated more. Faecalibacterium prausnitzii is often reduced in Crohn’s disease. Whether the altered microbiota triggers the inflammation or is merely its consequence cannot yet be separated in humans. Probably, in predisposed people, a leakier barrier meets an unfavourable microbiota and an immune system that no longer applies the brakes.

An old, disputed idea is that a germ from cattle, Mycobacterium avium paratuberculosis (MAP), helps trigger Crohn’s disease. In a large study with 331 people, 37 percent reached remission after 26 weeks on a triple antibiotic combination, compared with 22 percent on placebo Placebo A dummy treatment without an active ingredient. Comparing with it shows how much a remedy achieves beyond expectation and chance. . The study was paid for by the manufacturer, the drug coloured the urine and may thus have given away the blinding, and after 52 weeks the difference was no longer certain. An older Australian study had initially been judged negative. The therapy is not standard treatment, and the question remains open.

Flares often come without an obvious trigger. In a study with 417 people, new stress and stressful life events were more often followed by flares in the next three months, while long-term stress as such was not. Whether painkillers like ibuprofen trigger flares is disputed; many experts nevertheless advise caution in IBD.

IBD often affects more than the gut. Iron deficiency and anaemia are the most common companions. Joints, skin, eyes and bile ducts can become inflamed too. If the end of the small intestine is inflamed or has been removed in Crohn’s disease, bile acids Bile acids Substances made by the liver that make fat digestible. About 95 percent are reabsorbed in the last part of the small intestine; gut bacteria transform the rest. More in the chapter “Bile acids: when bile causes diarrhoea” and vitamin B12 are lost. Around one third of those affected have anxiety symptoms and one quarter depressive symptoms, clearly more in active phases. And about one third still have IBS-like symptoms in remission. So not every abdominal pain is a new flare, and measuring calprotectin helps tell them apart.

In ulcerative colitis the risk of colorectal cancer is increased. In a Scandinavian study with more than 96,000 patients it was around two thirds higher than in the rest of the population, but it has fallen markedly over the decades, probably thanks to better treatment and regular surveillance colonoscopies. The same applies to Crohn’s disease affecting the colon.

Treatment has changed a lot. Today the goal is not only for the symptoms to go away, but for the lining to visibly heal, because this prevents later damage. A British study with 386 people with newly diagnosed Crohn’s disease showed how much an early start matters: with a biologic plus an immunomodulator from the beginning, 79 percent were in remission after one year without steroids and without surgery, compared with only 15 percent with a step-by-step approach. After about five years, 6 people in the early-treatment group needed bowel surgery, compared with 26 in the step-by-step group. In ulcerative colitis, despite many new drugs, 10 to 20 percent still eventually need the colon removed.