Married to the Microbiome
Feb 20, 2019 Diane Krieger
She’s an endocrinologist. He’s a gastroenterologist. Together, their bi-disciplinary research has yielded startling discoveries.
Maybe it was destiny. The paths of Mark Pimentel, MD, and Ruchi Mathur, MD, first crossed as toddlers in remote Thunder Bay, Ontario. “We might have met on a sandlot,” says Pimentel, who was born and raised in the Canadian town.
Mathur lived there only a year before her Indian-immigrant parents moved to Winnipeg. But Pimentel and Mathur would meet up again in medical school.
“It was the classic cadaver romance,” she says. “His corpse was across from my corpse.”
“You could say we met corpse-side,” he wisecracks. “It took time to warm up.”
Today, not only are they married, but they’ve also successfully united their two fields of research.
Pimentel is a pioneer in the diagnosis and treatment of irritable bowel syndrome (IBS), a common gut disorder that can cause cramping, bloating, pain, and diarrhea or constipation. He’s responsible for the paradigm-shifting insight that microbes are behind the condition, which had previously been thought to be caused by stress.
Mathur discovered the junction between metabolic disorders and the gut microbiome, finding potential links between gas-producing bugs and diabetes, obesity, and polycystic ovary syndrome (PCOS).
Here, they retrace the evolution of their unlikely partnership as medical investigators.
Dr. Pimentel, how did you become interested in IBS?
Pimentel: I was interested in motility and the esophagus. Everyone said: “Why? You’re going to see all IBS patients, and they’re crazy.” But as soon as I started seeing IBS patients, I knew they were 100 percent not crazy. This notion that IBS was all in your head—it just didn’t compute.
Dr. Mathur, what drew you to diabetes?
Mathur: In the late ’90s, so many new medications were coming out for diabetes, yet incidence was going up. Same thing with obesity. I thought, “There’s got to be a missing piece.”
Dr. Pimentel, was there an “ah-ha” moment for you?
Pimentel: The first epiphany was realizing bloating is the key to IBS. The human body cannot make methane, so any methane present must be produced by microorganisms. Researchers used to think this fermentation gas was basically inert—doing nothing. Now we know it’s contributing to disease. Methane can change the physiology of the nerves and muscles of the gut.
Dr. Mathur, how did your research converge with your husband’s?
Mathur: When I started my Cedars-Sinai fellowship, the person I was supposed to work under in diabetes epidemiology had left the division. So I was orphaned, wandering the halls, and Mark’s mentor took me under his wing.
Pimentel: A second link came after Ruchi started helping a senior Cedars-Sinai researcher studying PCOS, a hormonal disorder in women where they have infrequent or overly long periods, or an excess of male hormones.
And how does PCOS relate to the gut?
Mathur: PCOS has many symptoms: weight gain, irregular periods, hirsutism, acne, male-pattern balding, insulin resistance, and infertility. But I was also seeing IBS-like symptoms in these patients. I thought: “Well, Mark studies bloating distention. Let’s just see if there’s any overlap.” We found women with PCOS tested higher for both bacterial overgrowth and methane than the normal population. In another study, we looked at patients awaiting bariatric surgery and also found methane. The higher their BMI, the higher the methane. So Mark’s work dovetailed with my other line of inquiry: obesity and metabolic disease.
Dr. Pimentel, for years you got pushback from the academic community.
Pimentel: Yes. My team was shamed and humiliated at meetings, literally trashed on the podium. The notion that bacteria could cause IBS or contribute to PCOS or obesity, back in 2001, was heresy. The turning point came when the National Institutes of Health’s Human Microbiome Project started in 2007 to investigate the microorganisms that influence human health and disease.
So where are we now?
Pimentel: Today, IBS is the most-evolved, best-understood disease related to the microbiome. That’s because our work started so early. It’s been 15 years since my mentor [Henry Lin, MD] and I discovered that the antibiotic rifaximin is a very effective treatment for IBS. It was finally FDA-approved in 2015. We’re seeing 30 percent less diarrhea-predominant IBS. We’re curing this. We’ve also shown how IBS develops. A toxin in food poisoning triggers the nerve damage and creates an immune response. Now we can measure that response and diagnose IBS with the first-ever blood test.
Mathur: This could translate into significant healthcare savings, as fewer expensive diagnostic procedures like barium swallows, colonoscopies, or MRIs are done. Pimentel: And we know from Ruchi’s work that methane bugs are associated with high blood sugar, constipation, and obesity. She recently presented a paper showing that if you give antibiotics to obese prediabetic patients, their glucose, insulin, and cholesterol levels drop.
How do you discover the convergences? Over dinner?
Mathur: Well, yes, actually; we often discuss our projects over dinner. But now, through the MAST program, we collaborate every day and continually find crossovers.
What is MAST?
Pimentel: Cedars-Sinai has backed our research with a new project called the Medically Associated Science Technology program. It’s an incubator that lets us develop and produce drugs, diagnostic tools, and therapeutics for patients with microbiome-based diseases. We already have 18 products in the pipeline.
Mathur: Having a project like this at Cedars-Sinai gives physicians an opportunity to develop new therapies tailored to our patient population and have a real benefit.
Mark Pimentel, MD
Executive Director, Medically Associated Science and Technology (MAST) Program
Ruchi Mathur, MD
Director, Anna and Max Webb and Family Diabetes Outpatient Treatment and Education Center
From Milling to Authoring
Papers Dazzled by the “white lab coats” at the University of Manitoba, Pimentel never imagined he would wear one. The son of a Portuguese-immigrant lumberjack and a Polish-born cafeteria server, he worked summers in a local paper mill to pay for college.
The Hungry Years
On the drive from Winnipeg to start their Cedars-Sinai fellowships, the young couple’s transmission gave out in North Platte, Nebraska. Down to their last $20 when they reached Las Vegas, Mathur risked it all on wild cherries on a slot machine at the Luxor and hit the jackpot. “Vegas helped us survive,” Pimentel says.
Veggies and Apreggios
For relaxation, Pimentel and Mathur enjoy backyard farming and music. He unwinds playing blues guitar. She re-energizes with piano scales and Bach preludes.
All in for the Twins
They never let research get in the way of good parenting. When their kids were young, one of them was always home by 5 p.m. Scientific investigations resumed after their twins’ bedtime. Today, daughter Maya is a pre-med student at the University of Chicago, and son Luis studies business at Boston University.
Pimentel’s and Mathur’s Research Milestones
2000: Small intestinal bacterial overgrowth associated with IBS (Pimentel)
2010: Polycystic ovary syndrome linked to increased risk of IBS (Mathur)
2011: Evidence that rifaximin antibiotic treatment is safe and effective for IBS (Pimentel)
2013: Obesity linked to methane-producing microbe (Mathur)
2014: Developed first blood test for IBS based on history of food poisoning
2015: FDA approves rifaximin for treatment of IBS; first blood tests to definitively confirm IBS developed at Cedars-Sinai (Pimentel); failure to lose weight after bariatric surgery linked to methane-producing microbe (Mathur)
2016: Eliminating methane through rifaximin therapy found to significantly reduce cholesterol and insulin levels in prediabetic patients (Mathur)
2018: Hydrogen sulfide in the gut linked to diarrhea-predominant IBS (Pimentel)
Irritable Bowel Syndrome: A Short History
Irritable bowel syndrome (IBS) is the most common gastroenterological disorder in the United States, affecting one in five Americans. Globally, an estimated 700 million people have the disease.
Once nearly impossible to diagnose, IBS is characterized by a cluster of confounding symptoms: chronic bloating, abdominal pain, gas, and bouts of relentless diarrhea, constipation, or both. The fatigue and the stress of trying to plan one’s life around access to bathrooms can be debilitating.
The concept of bacteria playing a key role in IBS was controversial when Mark Pimentel and his Cedars-Sinai mentor, Henry Lin, MD, first proposed it more than 15 years ago. Pimentel’s research has since confirmed that bacteria in the gut do indeed trigger the symptoms of the chronic condition.
Historically, effective IBS treatment options have been few, and many cause intolerable complications.
Pimentel pioneered the use of an existing antibiotic, rifaximin, for IBS. Absorbed only in the gut, rifaximin provides relief from symptoms for up to 10 weeks after patients stop taking the drug. It also causes far fewer adverse side effects than the two most commonly prescribed old-school IBS therapies: tricyclic antidepressants and alosetron, a drug that slows the movement of stool in the gut.