Irritable bowel syndrome through the lens of systems biology

Polina Zimmerman/Pexels

Practitioners should rethink about how they view irritable bowel syndrome (IBS) and how they treat patients with the disease, said Robert Rountree, MD, at the 2022 Integrative Healthcare Symposium in New York City.

Rountree who is the founder of the private healthcare consulting practice, Boulder Wellcare, in Boulder, Colo., defined irritable bowel syndrome (IBS) not as a disease, but constellation of clinical symptoms. He said these symptoms include abdominal pain and discomfort, bloating, and distension and are accompanied by altered bowel habits. These bowel problems can take the form of diarrhea, known as IBS-D, constipation, known as IBS-C or a combination of both, IBS-M. 

According to a review published in The New England Journal of Medicine, IBS patients would be willing to give up 10 to 15 years of their life for an instant cure.

“That is really profound, don’t you think?” commented Rountree.

He explained that IBS is the most commonly diagnosed functional gastrointestinal disorder (FGID), affecting 10 to 20 percent of people worldwide and affecting females at much higher rates.

A functional medicine approach to IBS treatments, explained Rountree, requires applying the syndrome to a systems biology model by identifying antecedents, triggers, and biological mediators.


Studies have clearly indicated that there is a genetic component to IBS, Rountree said. He cited a Swedish nationwide study, published in Molecular and Cellular Pediatrics, that found that IBS risk was increased among first, second, and third-degree relatives of those with the condition.

Rountree explained that the genetic background of most IBS patients includes a large amount of common genetic variants, each contributing a small part to their overall risk. Scientists have studied over 60 candidate genes. These genes contribute to, serotonin synthesis and reuptake, mucosal immune activation and inflammation, neuropeptide signaling, nociception, bile acid synthesis, and intestinal secretion.

Of the researched genes, two appeared to be associated with IBS including KDELR2, which assists in the retrograde transport of proteins to the endoplasmic reticulum, and TNF SF15, which strengthens T cell activation and immune response that may contribute to IBS related inflammation, according to Rountree.

Rountree then explained that personalized medicine may pave the way for genetically complex diseases such as IBS to one day identify patients with well-defined genetic abnormalities. This would allow scientists to pinpoint specific genetic variants that increase the risk of IBS, allowing for more personalized treatment options.


According to a study published in the Current Opinion Gastroenterology, the main trigger for IBS patients is food.

“Duh,” Rountree said. “The question is, what foods? There lies the rub.”

Rountree identified wheat and gluten as two major food triggers for those with IBS. He explained the gluten has been found to alter barrier function in animal studies, sometimes resulting in immune activation. Wheat, he said, contains s α‐amylase/trypsin inhibitors (ATIs) and wheat lectin agglutinin, proteins that induce immune pathways. It also contains fructans, sugars which are difficult for the body to absorb. They also increase bacterial fermentation and gas production.

Rountree said a gluten and wheat free diet may prove effective in many IBS patients, particularly in those who carry celiac susceptibility genes including, HLA‐DQA1, HLA‐DQB1 because they may show mind slight responses and gut dysfunction to gluten.

Another method to avoid IBS triggers, according to Rountree is to follow a low FODMAP diet. FODMAPs include, oligosaccharides, disaccharides, monosaccharides (fructans, galacto‐oligosaccharides, lactose, fructose), and polyols. Studies show more than 50 percent of IBS patients benefit from a low FODMAP diet and that symptom relief can be shown as early as 48 hours after starting the diet.

Rountree’s FOPMAPs systems biology treatment strategy involved:

  • Short term avoidance
  • Reintroduction
  • Gut microbiome analysis
  • Enzyme supplements

Biological Mediators

Originally, IBS was considered to be a “functional” disorder.

“What does functional mean?” asked Rountree. “In the past it meant there’s nothing really wrong.”

However, according to Rountree, evidence suggests a link between a lack of diversity in gut bacterial communities, activation of the gut immune system, and low-grade inflammation in patients with IBS. He said the microbiota may be a predominant factor in IBS pathophysiology.

Testing for IBS has proven to be difficult. One test Rountree discussed was a breath test for small intestinal bacterial overgrowth (SIBO). He said those with IBS are more likely to have an abnormal breath test for SIBO than healthy volunteers, suggesting the two conditions may be related.

In addition, Rountree explained that stool microbiome testing through shotgun metagenics has potential for identifying dysbiosis, presence of fermenting organisms, and ruling out inflammatory pathogens. Rountree laid out a list of questions to ask while testing the gut microbiome including:

  • Which microorganisms are present or absent?
  • What is the relative percentage of each microbe? How do these percentages compare to the “normal”population?
  • What metabolic tasks is the individual microbiome capable of performing?

Then, Rountree listed IFM’s “Five ‘R’ Strategy for Healing IBS” which instructs physicians to:

  • Remove: Potential pathogens, triggering foods (lactose,wheat/gluten, FODMAPs), excess bile
  • Replace: enzymes (pancreatic and plant‐based), betaine
  • Reinoculate: prebiotics, probiotics, fecal transplants
  • Repair: gut lining/reduce hyperpermeability, decrease
  • Rebalance: liberalize diet; stress management

Rountree concluded his presentation with a list of interventions. He said although low FODMAP diets are effective in some patients, they are not sustainable in the long term. He also said both wheat and dairy-free diets should be prescribed to all IBS patients. Finally, he said digestive enzymes, particularly those containing alpha‐galactosidase as well as some probiotic strains can be effective in managing IBS.

“I just gave you a tour of systems biology and what happens when you start looking at the star and trying to connect the dots based on the principles,” concluded Rountree.