Introduction

Crohn’s Disease is a long-term, non-infectious condition that causes inflammation of the gastrointestinal (GI) tract (the gut), which carries food from the mouth to the anus.¹ While inflammation is a normal part of healing, it can become harmful when prolonged in otherwise healthy tissues.² In Crohn’s disease, this chronic inflammation can lead to digestive problems, diarrhoea, and stomach pain.¹

Crohn’s disease in children and adolescents (paediatric Crohn’s disease) is on the rise, with cases doubling in some parts of the UK over the last decade.³ This is concerning as the condition can cause malnutrition, impair growth and significantly impact wellbeing.⁴

Understanding how paediatric Crohn’s Disease develops is therefore essential to reduce the burden of the disease, with scientists becoming increasingly interested in the role of the gut microbiome in disease onset.⁵

This article will cover what the gut microbiome is, how its dysregulation can contribute to Crohn’s, why children may be especially vulnerable, and how current research on the paediatric gut microbiome is shaping treatments for the disorder.

What is the gut microbiome?

Every person has trillions of microorganisms – tiny living things like bacteria and fungi - living on and inside their body.⁶ While some of these microorganisms can cause illness, many of them carry out processes essential for keeping us healthy.⁷

One of the most important communities of microorganisms is in the GI tract, particularly the large intestine - known as the gut microbiome.⁸ The gut microbiome is purposefully diverse, like a bustling village, with many different types of microbes working together, each with its own role. Some help us to break down food and metabolise nutrients, while others play crucial roles in nervous system signalling and immunity.^{7, 8}

No two people’s gut microbiomes are the same - the number of different species of microorganisms, and the amount of each type, can vary hugely from person to person according to their genes and environment.⁹ Importantly, if one type of microorganism is disrupted – whether by illness, medication or diet - it can upset the balance of the individual’s entire gut microbiome, which can harm both the gut and the rest of the body.¹⁰

The microbiome in crohn’s: from dysbiosis to disease

An imbalance of the gut microbiome is known as dysbiosis. Dysbiosis is common in both children and adults with Crohn’s disease, though it is unclear if dysbiosis causes Crohn’s or is merely an effect of the condition.⁵ Below, we will explore some of the ways that dysbiosis manifests in Crohn’s disease, and how they may contribute to Crohn’s disease development.

Lower diversity

In Crohn’s Disease, there are usually fewer types of microorganisms living in the gut. Some studies have found that the number of different types of bacteria can be reduced anywhere from 40-70% in Crohn’s patients.^{8, 11} This loss of diversity can be very harmful - if entire groups of bacteria are missing in action, jobs that are essential for gut health will go undone. In turn, it becomes significantly harder for the remaining microorganisms to keep the gut stable and healthy, making it more vulnerable to diseases like Crohn’s.¹²

Reduction in “good” bacteria

Most bacteria are not inherently good or bad - whether they help us or harm us often depends on factors like their location in the body and our genes.¹³ But, in the gut microbiome, the species of bacteria known as Faecalibacterium prausnitzii is generally thought of as one of the “good” guys. These bacteria turn the fibre we eat into a molecule called butyrate, which is the main energy source for the cells lining the intestine, which form a protective barrier (intestinal epithelial cells).¹⁴ In addition to feeding and strengthening the gut lining, butyrate also has powerful anti-inflammatory effects, as do other chemicals like IL-10, which are released by Faecalibacterium prausnitzii.¹⁴

Unfortunately, children with Crohn’s disease tend to have a reduced supply of Faecalibacterium prausnitzii in their gut microbiome.¹⁵ The resulting lack of energy and anti-inflammatory agents in the gut could be responsible for the intestinal swelling and reduced ability to fight off infections often seen in Crohn’s patients.¹⁶

Increase in “bad” bacteria

Dysbiosis in the gut of Crohn’s patients can also be caused by an increase in harmful bacteria. For example, the amount of Escherichia coli (E. Coli) in the gut is often elevated in cases of paediatric Crohn’s disease.¹⁵ Specifically, a type of E. Coli called Adherent-invasive E. Coli (AIEC) is found in high numbers in the mucus lining the intestines of Crohn’s patients.¹⁷ AEIC can invade and replicate within intestinal epithelial cells, making the barrier that these cells form more prone to leaks and susceptible to infection.¹⁸ Additionally, AEIC can invade and survive within macrophages, the immune cells responsible for defending the gut.¹⁹ This can cause macrophages to over-release pro-inflammatory chemicals, which may cause the gut inflammation characteristic of Crohn’s disease.¹⁹

While the exact nature of their relationship remains uncertain, gut dysbiosis has been consistently linked to inflammation and other key symptoms of Crohn’s, suggesting it may play a role in the origins of the disease.

The childhood microbiome: more vulnerable to crohn’s?

To understand why cases of Crohn’s disease in children and adolescents are on the rise, we must consider when and how the gut microbiome develops.

At the time of birth, microbes from the birth canal or skin, depending on the delivery method, are transferred to the infant and make their way to the gut.⁵ The gut microbiome continues to grow and change in the early years of life as it is exposed to new foods and environments, until it stabilises around age four.⁵

While it develops, the gut microbiome is particularly vulnerable to factors that may disrupt its balance, like ultra-processed foods,²⁰ thereby increasing the risk of Crohn’s disease. Additionally, the overuse of antibiotics during early infancy may inadvertently reduce the numbers of healthy bacteria in the gut, which can have a lasting negative impact on the gut microbiome.⁵ Meanwhile, some research suggests that babies born by caesarean section are more likely to experience gut dysbiosis as they can miss out on exposure to parental microbes essential for healthy development of the gut microbiome.²¹ However, the evidence for this is mixed, with other studies finding no link between caesarean section and risk of paediatric Crohn’s disease.²²

In short, childhood is a particularly sensitive time for the gut microbiome, and disruptions during this period - which may be becoming more common in modern life – could be increasing the prevalence of paediatric Crohn’s disease.

Clinical implications of current research

Our growing knowledge of the role of the gut microbiome in Crohn’s disease may help explain why some therapies are effective and others less so, and even point to new treatment options.

One of the first-line treatments recommended for paediatric Crohn’s disease is exclusive enteral nutrition (EEN), where all nutrition is provided through special liquid formulas.⁴ Successful EEN treatment in children with Crohn’s reduces the amount of E. Coli and brings the gut microbiome composition closer to that of healthy individuals, suggesting that the therapy’s beneficial effects may come from restoring balance to the gut microbiome.⁵ Other diet-based interventions, such as the Mediterranean diet are known to increase the number of bacteria producing anti-inflammatory agents like butyrate.²³ Sticking to a Mediterranean diet can reduce the risk of Crohn’s disease onset in adults with a family history of the disease,²⁴ though more research is needed to see if this preventative measure is effective in children.

On the other hand, the limited effectiveness of antibiotics in treating moderate to severe Crohn’s disease may be explained by their effect on the gut microbiome. While antibiotic therapy may help relieve symptom flare-ups by targeting acute infections by harmful bacteria, its long-term use may worsen gut dysbiosis,⁵ increasing the risk of relapse when treatment is stopped.⁴

Faecal microbiota transplantation (FMT) – which involves transferring a stool sample from a healthy individual to the Crohn’s patient to restore gut microbiome balance – is showing promising results as a new treatment option for Crohn’s disease in adults (though research in children is lacking).⁵ However, the success of the treatment may depend on the severity of gut dysbiosis, suggesting that microbiome analysis prior to treatment could help clinicians decide whether FMT is likely to help.

Summary

• Crohn’s disease is a chronic condition that causes inflammation of the GI tract
• Crohn’s disease in children is on the rise, making it important to understand potential causes so that treatments can be developed
• The gut microbiome is the community of microorganisms living in the GI tract, which supports functions like digestion and immunity
• Crohn’s patients present with gut microbiome imbalance (dysbiosis), including reduced microbe diversity, a loss of beneficial bacteria and an increase in harmful ones, though more research is needed to determine if they cause the illness
• The success of treatments like EEN and the Mediterranean diet may be explained by their ability to rebalance the gut microbiome, while the effectiveness of FMT and antibiotic therapy may be limited by the severity of gut dysbiosis before treatment
• Ultimately, though further research in children is needed, understanding the gut microbiome could aid the development of new paediatric Crohn’s disease therapies and help clinicians to tailor treatment plans