What's new in IBD?

Inflammatory bowel disease (IBD) is the general term for a subset of intestinal disorders including Crohn’s disease and ulcerative colitis. There are also subcategories based on the location of the disorder within the gastrointestinal tract, and when a definitive diagnosis cannot be made the term indeterminate colitis is sometimes used. The cause of IBD is unknown, but it is associated with dysfunction of the immune system, which can cause lifelong discomfort with symptoms ranging from mild to severe, including intestinal bloating, pain, cramping, diarrhoea, bloody stools, fatigue, or unintended weight loss. Treatment may consist of dietary changes, probiotic supplementation, or medications such as anti-inflammatory drugs, steroids, antibiotics, antispasmodics, immune suppressors, and antibodies/cytokine inhibitors. Such treatments may help to relieve symptoms in patients, but nothing is curative, durability is often an issue, and there is a risk of deleterious side effects and the onset of other diseases. 

A 2015 report by the Centers for Disease Control and Prevention (CDC) estimated that 1.3% of American adults had been diagnosed with IBD. Other sources and reports have estimated the global incidence to be >0.3%, which is somewhat ambiguous. It has also been reported that the incidence of IBD is increasing over time, particularly among non-Hispanic black people. However, statistical analyses can be misleading and prone to error and/or bias. For example, disease prevalence (of any disease) is often variable among geographical regions, ethnicities within a country, social and economic classes, education and employment status, and access to medical facilities. Is the increasing prevalence due to better diagnostic tests compared to 20 or 30 years ago, greater access to medical care (especially for ethnic minorities or in low-income countries), or due to external factors such as increased exposure to chemicals and toxins? There is also the possibility that some IBD patients were previously misdiagnosed and told that their symptoms were the result of lifestyle such as partying and drinking. Attitudes of medical professionals may have changed over the last 30 years, leading to more tests and better diagnoses.

So, what underlies the onset and progression of IBD? Despite some recent attention-grabbing headlines, including BBC News, that seemed to suggest a cure may be on the horizon, our understanding of IBD is actually very limited. Targeted, therapeutic treatment is also similarly limited. Unfortunately, there is no indication that safe and effective treatments will be available anytime soon, let alone a cure. New research has, however, identified a potential genetic (DNA) link to IBD. Interestingly, this is not in a coding region of the DNA (a gene that is expressed and translated into a functional protein within cells) but in a specific non-coding region known as an enhancer. This may be a little confusing, so let’s briefly review this process. DNA includes genetic elements for life, and it contains two copies of genes that are inherited from parents. These genes are copied and decoded by specialised molecules in the cell (like molecular machines) resulting in the manufacture of proteins. It really is like a molecular production line. However, genes alone are not sufficient for this mechanism to proceed, since they require specific helpers in specific non-coding regions of DNA known as enhancers and promoters. Changes to the DNA sequence (mutations) in a gene, enhancer, or promoter can affect how that gene is regulated and how much protein is produced or how its protein product functions. Activity of the protein (gene product) may be increased or decreased depending on the change in its sequence, and either way this can lead to disease. In this latest research, published in the scientific journal Nature, it was found that the DNA change in the enhancer (non-coding DNA region) was associated with increased protein activity leading to upregulated inflammation and an excessive immune response via macrophage activation.

What does this new scientific identification mean? Well, it is a positive step in our understanding of how the immune system is dysregulated in IBD, and it provides a scope for the development of new compounds to target and inhibit the overactive protein or other molecules that influence the protein either earlier or later in the pathway (known as upstream and downstream effectors, respectively). However, this is not trivial since it is very unlikely that a single factor is responsible for IBD. Furthermore, macrophages are an important part of the innate immune system, and their downregulation (including via medication) can increase infection risk. Moreover, there are different classes of macrophages, which exhibit distinct functionality among tissues (for example, in the heart one type of macrophage is important for cardiac homeostasis and function). Like all medications, there will be side effects of any possible future therapeutic treatments, so it will be important to elucidate the pros and cons via thorough scientific research and development.

BBC News and other outlets further reported that the DNA mutation is present in 95% of IBD patients, but how was this data obtained? Has the DNA of every IBD patient on the planet been sequenced? Were all people with or without symptoms that may have IBD but have not yet been diagnosed included? Were people included from multiple geographical locations and various ethnic backgrounds? The answer is no, and it is highly likely that there will be significant differences among nationalities. Gene transcription and protein production is regulated by multiple mechanisms, including transcription factors, methylation or acetylation, and the body’s internal clock (circadian rhythm). Inflammation is similarly complicated and can be upregulated or downregulated by many factors, such as genetics, epigenetics, diet, microbiota, lifestyle, immunity, diseases, and infections.

So, what is known about contributing factors to IBD onset and progression, and what can be done to inhibit the onset or alleviate symptoms? These are difficult questions to answer, and many patients find themselves trying multiple therapeutic approaches over time, including various medications, probiotic supplements, and dietary interventions. Below is a summary of some factors that have been associated with either the improvement or worsening of symptoms.

The composition of the gut microbiota has been strongly associated with IBD and some bacterial strains, such as Klebsiella pneumoniae, some Firmicutes, and Bacteroidetes, have been linked to disease severity. in contrast, other bacterial strains have been associated with reduced symptoms, which primarily include Bifidobacteria and Lactobacilli. However, some IBD patients exhibit dysbiosis and others do not, so a microbiome analysis can be misleading (see Microbiota Mania blog post). In clinical trials, some probiotic supplements containing specific species of Bifidobacteria and Lactobacilli have exhibited treatment efficacy. It is important to note, however, that dietary supplements from shops do not require medical testing to support their claims, which can be and often are bogus. Furthermore, bacteria have multiple subtypes, so just because one type of Bifidobacterium or Lactobacillus has shown efficacy in testing does not mean another type will be beneficial. On the contrary, a related strain could be detrimental. Moreover, a strain that works for one IBD patient might not work for another due to incompatibility with their genome, immune system, or current microbiota. Unfortunately, science and medicine are not black and white and it's never the case that one treatment works for everyone. Ideally, probiotic supplementation should be performed in a clinical setting by an expert in the field with treatment based on reproducible and, preferably, double-blind, placebo-controlled clinical trials. But (there's always a but) it is important that any clinical trials were not biased by company funding, and it is even more important that clinics or doctors performing treatment are not receiving financial incentives for prescribing a certain company's products. Do not self-prescribe by purchasing probiotic supplements in shops or online. Unregulated supplements may be ineffective and can be potentially dangerous.

So, what non-treatment things can be done to alleviate symptoms and potentially avoid IBD in the first place? Well, infections cause immune activation, inflammation, and potential damage to intestinal cells. Therefore, try to avoid contaminated foods and drinks by thorough washing before preparation and consumption, and store cooked food carefully and consume within a few days. There have also been reports that physical activity and healthy lifestyle behaviours can reduce the risk of developing IBD and alleviate symptoms in IBD patients. There certainly is some logic to this because exercise promotes overall good health and can reduce inflammation, and a healthy diet also reduces inflammation, reduces exposure to food additives, and provides prebiotic nutrients to feed and nurture the gut microbiota. When attempting to alter the microbiota via probiotic supplementation, it is therefore a prerequisite that prebiotic intake should be increased to optimise any therapeutic effects. Beneficial gut bacteria are unlikely to thrive on a diet of ultra-processed foods, confectionery, and soft drinks, so make sure to incorporate plenty of fruits, vegetables, and whole grains.

For the ultimate nutritional guide for improved overall health and information on IBD, please refer to the OneLife Diet Meal Plan (eBook).

Further reading:

OneLife Diet Meal Plan: Total Nutritional Guide. Link

Prevalence of Inflammatory Bowel Disease Among Adults Aged ≥18 Years — United States, 2015. CDC Link

Prevalence of Inflammatory Bowel Disease Among Medicare Fee-For-Service Beneficiaries — United States, 2001−2018. CDC Link

The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Link

Major cause of inflammatory bowel disease found. BBC News Link

A disease-associated gene desert directs macrophage inflammation through ETS2. Link

Macrophages and the maintenance of homeostasis. Link

Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation. Link

Heat-inactivated Bifidobacterium bifidum MIMBb75 (SYN-HI-001) in the treatment of irritable bowel syndrome: a multicentre, randomised, double-blind, placebo-controlled clinical trial. Link

Benefits of multistrain bacteria formulations for health. Link

Association of healthy lifestyle behaviours with incident irritable bowel syndrome: a large population-based prospective cohort study. Link