Once upon a time, bacteria and other microbes were seen as the enemy, but scientists are increasingly discovering a mutual dependence between us and our microbiota. New research out of University of Toronto1 reveals a complex interplay between genetics, environmental factors and gut flora might trigger onset of Crohn’s disease.
Doctors could soon be able to predict whether you are likely to be vulnerable to Crohn’s disease based on the mix of microflora in your gut. Advances in DNA sequencing over the last 20 years have revolutionized research into human microbiota. Powerful new genome technology allows us to identify multiple types of bacteria in a sample and reveal the presence of previously undiscovered variants. While it used to take months to unravel complex mixes of DNA, supercomputers can now assemble genomes from mixed samples within days. For an organ like the gut—a bustling ecosystem, teeming with bacteria, speedy DNA sequencing is proving to be a game changer.
So how can the microbial mix living in your gut help to figure out whether you are at risk of inflammatory bowel disease?
An Inflammatory Disease
Crohn’s disease causes severe inflammation in the gastrointestinal tract, disrupting the body’s capacity to digest food, absorb nutrients, and eliminate waste.2 For a lot of people this means discomfort, severe cramping, diarrhea, rectal bleeding, blood in the stool, weight loss, and reduced appetite. Crohn’s Disease is no transient ailment; it’s a chronic and debilitating illness. Patients continue to experience a cycle of flare-ups of active symptoms and remission when symptoms subside.
As Crohn’s and Colitis Canada puts it “The exact cause of Crohn’s disease and ulcerative colitis remains unknown, and as a result, there is no cure for these diseases”. 3 As we all know, prevention is better than cure. But how do we prevent Crohn’s disease from setting in?
A Family Affair?
As far back as 1996, epidemiologists had noticed and started to study the way that inflammatory bowel diseases run in families.4,5 But, inheriting genes that make a person vulnerable to Crohn’s disease isn’t as simple as inheriting the genes for eye colour. So while it’s true that Crohn’s disease has a genetic element, not everyone with the Crohn’s causing genes actually develops the disorder.
Why does one brother develop Crohn’s and another, with very similar genes, not? Your risk of developing Crohn’s disease depends on how your unique genetic makeup interacts with your environment—and microbes are part of this environment. Researchers led by Kenneth Croitoru, Professor of Medicine and Immunology at University of Toronto, say the solution to untying this complicated knot may lie in our gut flora.
An International Investigation
The Crohns and Colitis Canada GEM Project Research Consortium program recently presented the results of a huge study over twelve years in the making.1 Published in the journal Gastroenterology, the international team of researchers reports that microbiological markers can predict your risk of developing Crohn’s Disease. Thirty-four researchers across 48 institutions followed over 3,000 participants for up to a decade to figure out how combinations of belly bacteria affect the onset of Crohn’s.
The team suspected that a key difference between people who have Crohn’s disease and their healthy family members, was their gut microbiota. To test this idea, from 2008 to 2017 they recruited 3,500 healthy people between the ages of 6 and 35 years old, who had a close relative (brother, sister, mother, father) with Crohn’s disease. The test subjects lived in Canada, the United States, Israel, the United Kingdom, Ireland and New Zealand. Using stool samples, the researchers inspected the gut microbiomes of the participants. Over the next ten years, they would track which participants would go on to develop Crohn’s disease. None of the researchers were allowed to know both the results of the stool sample tests and whether the donor had developed Crohn’s.
Researchers purified DNA from the stool samples and carefully isolated DNA that belonged only to bacteria. They then sequenced the genome of every bacteria found in the feces sample. Once they had the DNA sequences, the researchers matched them to known bacterial DNA sequences recorded in the NCBI databases. They compiled bacterial composition profiles for every participant.
Another set of researchers called participants every six months until 2020 to ask whether they had symptoms of inflammatory bowel disease or had received a Crohn’s diagnosis.
Crohn’s has a Bacterial Calling Card
At the end of the data collection, the scientists divided the participants at random into two groups. They took the first group and looked for a difference in the mix of bacteria from subjects who would develop Crohn’s and those who didn’t. They also looked to see which of the bacteria people who developed Crohn’s had in common.
This revealed the dominance of specific microbial species—R. torquest, Colidextribacter, and subsets from Oscilloscpiraceae and Blautia. I contrast they noticed that patients who went on to develop Crohn’s disease had far fewer Rosburia species of bacteria in their samples.
The researchers used the patterns of bacterial combinations they had uncovered to build a set of microbial signatures. They noticed that these signatures corresponded to how close a subject had been to developing Crohn’s when they donated their sample.
The question was, could they use these microbiological DNA signatures to predict who was vulnerable to Crohn’s disease?
Predicting who was vulnerable to Crohn’s disease
The researchers turned to the second group of participants and used the reverse approach. They inspected the bacterial signatures and to each patient, assigned a likelihood of whether or not they would develop Crohn’s. They found that their predictions from the first group were pretty accurate. Indeed, they could look at a set of bacterial signatures and identify who would develop Crohn’s within five years of their sample being taken!
This study is the first to demonstrate that a person’s gut microbiome composition can predict future onset of Crohn’s Disease. It suggests that in addition to genetics, the gut microbiome could be a involved in the pathogenesis of Crohn’s Disease.
So what does this mean for people who have a family history of Crohn’s disease? Nearly half of the participants in the study were kids under 18. For those who went on to develop Crohn’s, the average time from joining the study to a diagnosis was around 3 years. The short time between appearing healthy with no signs of inflammatory bowel disease and being diagnosed with Crohn’s disease, underlines just how important it is to have tools that can spot early indicators that something isn’t right. Fingers crossed new diagnostic tools might catch this illness earlier before inflammation sets in.
What’s Next?
Could the understanding of gut bacteria serve as both a diagnostic tool and a remedy for Crohn’s Disease?
The authors of the paper speculated that R. Torques and Blautia might trigger inflammatory bowel disease by depleting mucin from the gut epithelium, decreasing its protection. Conversely, the Roseburia species were observed less in patients who developed Crohn’s Disease, suggesting a possible protective function. However, while it’s tempting to assume that getting rid of the “bacterial perpetrators” of Crohn’s will fix the problem, reality is far from that simple. For instance, we don’t know whether the bacterial combinations cause the inflammation, or the inflammation/anti-inflammatory drugs cause those bacterial combinations to flourish.
Despite the complexities, this research gives us reasons to be cheerful! Altered gut microbiota could be a useful diagnostic tool, offering a glimpse into an individual’s risk even before symptoms surface. In the future, doctors could use stool samples as a risk indicator for someone developing Crohn’s disease within a few years. This would give patients a headstart on treatment and preventative care. While the road to predicting and understanding Crohn’s through gut bacteria might be winding, it’s a crucial step toward more effective intervention and support for those affected by this chronic condition.
References
1.Raygoza Garay JA, Turpin W, Lee SH, et al. Gut Microbiome Composition Is Associated With Future Onset of Crohn’s Disease in Healthy First-Degree Relatives. Gastroenterology. 2023;165(3):670-681. doi:10.1053/j.gastro.2023.05.032
2. Ward CW, Thomas DT. Crohn’s Disease with Acute Obstruction. Br Med J. 1941;2(4217):613-614. doi:10.1136/bmj.2.4217.613
3. What are Crohn’s and colitis? – What are Crohn’s and Colitis – Crohn’s and Colitis Canada. Accessed February 1, 2024. https://crohnsandcolitis.ca/About-Crohn-s-Colitis/What-are-Crohns-and-Colitis
4. Van Limbergen J, Wilson DC, Satsangi J. The Genetics of Crohn’s Disease. Annual Review of Genomics and Human Genetics. 2009;10(1):89-116. doi:10.1146/annurev-genom-082908-150013
5.Tsianos EV, Katsanos KH, Tsianos VE. Role of genetics in the diagnosis and prognosis of Crohn’s disease. World J Gastroenterol. 2012;18(2):105-118. doi:10.3748/wjg.v18.i2.105
