May 2018 Issue

FODMAPs: Overview of the Emerging Science
By Kate Scarlata, RDN, LDN
Today's Dietitian
Vol. 20, No. 5, P. 14

Best known for its effect on symptom reduction in patients with irritable bowel syndrome (IBS), the low-FODMAP (fermentable oligo-, di-, and monosaccharides and polyols) diet is revealing new information about itself in the literature. Although the osmotic and fermentative effects of FODMAPs in the gut are likely factors in symptom induction, emerging science is broadening the scope of the pathophysiology of FODMAP metabolism.

A low-FODMAP diet has been shown to manage symptoms in 50% to 70% of people with IBS; however, more recent research shows it improves mood, reduces inflammatory markers, and alters the gut microbial signature.1-6 The significance of gut microbiome and metabolome shifts in relation to the low-FODMAP diet for long-term health remains unknown.

Mood and Quality of Life
In the first US-based randomized controlled trial on the low-FODMAP diet, University of Michigan researchers found that a reduction in FODMAPs not only decreased symptoms of pain and bloating compared with a standard IBS diet approach (a modified version of the United Kingdom's NICE [National Institute for Health and Care Excellence] guidelines for treatment of IBS) but also improved anxiety and quality of life measures.2 Principal investigator of this study Shanti Eswaran, MD, a gastroenterologist at the University of Michigan, says, "It's now understood that a low-FODMAP diet not only helps IBS symptoms but [also] translates to improved functioning and improved mental health as well. In our study, patients on a low-FODMAP diet were more than twice as likely to report a significant improvement in IBS-related quality of life than patients who adopted usual dietary recommendations for IBS. There was also a significant improvement in anxiety symptoms on the low-FODMAP diet, which wasn't seen with usual IBS dietary recommendations."

FODMAPs and Immune Activation
Given the fact FODMAPs are, in essence, fast foods for our gut microbiota (ie, their small size allows for rapid consumption), it seems plausible that a reduction in FODMAPs would have an impact on gut microbial metabolites beyond gas and short-chain fatty acid production. Could changes in the gut metabolome from the decrease in FODMAPs play a role in how a low-FODMAP diet improves gastrointestinal (GI) symptoms? In a novel study published in the July 2017 issue of Gut, the low-FODMAP diet in IBS patients resulted in an eight-fold reduction of histamine, a measure of immune activation.3 Stephen Vanner, director of the gastrointestinal diseases research unit at Queen's University, Kingston General Hospital, in Ontario, Canada, and a researcher for this study, says, "Histamine is known to be elevated in the intestinal tissues of IBS patients and can sensitize pain-sensing nerves. Several studies suggest that blocking histamine signaling decreases pain sensations in a subset of IBS patients. Lowering FODMAPs in the diet appears to be another means of decreasing histamine signaling."

The mechanism for how the low-FODMAP diet reduces histamine remains unknown. "It's possible that metabolites resulting from fermentation of FODMAPs can cause the release of histamine and other mediators from mast cells and/or they could be stimulating the microbiota in susceptible patients to produce histamine," Vanner says. Mast cells line the intestine and can release several inflammatory chemical mediators including histamine into the gut inducing GI symptoms, notably pain. Mast cell degranulation may occur due to many triggers, including infections, stress, as well as luminal distention, to name a few.

"The most intriguing finding in our study was that a subset of patients had elevated histamine levels at baseline and that these increased or decreased depending on the diet," Vanner says. "This suggests that FODMAPs could be a trigger of immune activation by signaling to either the immune compartment and/or the microbiota to increase histamine signaling to nerves. This could lead to the discovery of biomarkers to determine who might best benefit from diet intervention (ie, mechanistic insights), and therefore new targets for treatment in IBS."

Intestinal Permeability and Inflammation
In an innovative study from the University of Michigan, gut microbiome researchers also noted a reduction in the gut microbial endotoxin lipopolysaccharides (LPS) with the low-FODMAP diet vs a high-FODMAP diet in diarrhea predominant IBS (IBS-D) patients.4 LPS are found on the outer membrane of most gram-negative bacteria. Elevation in LPS is linked with intestinal permeability and gut inflammation and may compromise the tight junctions in the gut, allowing toxic constituents to cross the intestinal wall. In a rat study, the researchers examined the effects of fecal supernatant from human subjects with IBS-D before and after a low-FODMAP diet; they found rats injected with fecal supernatant that contained elevated LPS were more susceptible to rectal stimuli. In other words, LPS found to be elevated in individuals with IBS-D on a high-FODMAP diet may play a role in the visceral hypersensitivity present in IBS patients.

Changes in the Gut Microbiome
A growing number of studies have evaluated the impact of the low-FODMAP diet on the gut microbiome, suggesting some potentially deleterious changes. Vanner's recent study showed that the low-FODMAP diet results in a decrease in probiotic bifidobacteria but overall a higher bacterial richness and diversity in the fecal samples of IBS patients.3 Kevin Whelan, PhD, RD, a professor of dietetics and head of the department of nutritional sciences at King's College London, United Kingdom, weighs in on the microbial changes that ensue after completing the low-FODMAP elimination diet: "My research career has always focused on the beneficial effects of prebiotic carbohydrates on the microbiome, so I was initially reluctant for IBS patients to adopt the low-FODMAP diet. In 2012, we published the first randomized controlled trial of the low-FODMAP diet, confirming that although it did improve symptoms in IBS it also modified the microbiome—in particular reducing bifidobacteria.5 This has been confirmed in many subsequent studies, and, indeed, other changes in the microbiome also occur. Bifidobacteria generally are considered beneficial for the gut microbiome. However, the two unanswered questions are whether these changes to the microbiome are harmful or not and what happens when FODMAPs are reintroduced." In other words, are the bifidobacteria restored when the low-FODMAP diet is liberalized in the personalized stage of the diet? This area requires more research.

Not for a Lifetime
The gut microbial environment can undergo alterations in just one day of dietary change. Learning how the gut microbiome changes after patients have completed the three phases of the low-FODMAP diet may provide a better understanding of the impact of following this diet therapy. Most of the data evaluating the impact of the low-FODMAP diet on the gut microbiome centers around the elimination phase. It's important for dietitians to know that patients aren't supposed to follow the low-FODMAP elimination diet for a lifetime. Whelan agrees, adding, "[The low-FODMAP diet] consists of three stages: FODMAP restriction (when a strict low-FODMAP diet is followed), FODMAP reintroduction (when specific FODMAPs are sequentially challenged), and FODMAP personalization (when FODMAPs shown to be well tolerated in that patient can be consumed). The goal is to follow the personalized low-FODMAP diet in the longer term so that patients with IBS can have a balanced and varied diet. We hope that the diverse fibers and fermentable carbohydrates will mean there will be less impact on the microbiome."7

On the Horizon
Currently, researchers are evaluating other compounds, such as volatile organic compounds (VOC), via stool samples to better gauge which patients may benefit from the low-FODMAP diet. VOCs are metabolites produced by the gut flora. Whelan says, "There are hundreds of different types of VOCs, and the number, type, and amount of each VOC produced will be impacted by a wide range of factors such as gut disease and the type of diet we eat. Our research published in Clinical Gastroenterology and Hepatology in 2018 has shown that the amounts of 15 VOCs in stool predicted whether patients with IBS responded to the low-FODMAP diet (or not) with an accuracy of 97%.8 VOCs are measured by taking a small stool sample and analyzing it in a machine that's currently only a research tool—but in the long term could be available widely in dietetic and gastroenterology clinics." Having a biomarker to help determine which IBS patients will benefit from the low-FODMAP diet will help minimize unnecessary diet modifications in those who won't benefit from the diet.

There's increasing interest in the role fermentable carbohydrates play in gut health. Because people have their own gut microbial fingerprint and genetic makeup, it's likely nutrition professionals will see an emergence of personalized diets based on a better understanding of these individual characteristics and an improved understanding of how the gut microbial community and diet impacts health.

— Kate Scarlata, RDN, LDN, is a Boston-based dietitian and New York Times best-selling author with 30 years of experience. She's well known for her expertise in the low-FODMAP diet and gastrointestinal nutrition. She's an advisor for FODY Foods and author of the iOS FODMAP Grocery Guide app.

Disclosure: Kevin Whelan, PhD, RD, a professor of dietetics and head of the department of nutritional sciences at King's College London, United Kingdom, has received research funding from the National Institute for Health Research (UK), Medical Research Council (UK), and Clasado Ltd, and he's the coinventor of an app for people following the low-FODMAP diet (FODMAP by FoodMaestro).


References
1. Halmos EP, Power VA, Shepherd SJ, Gibson PR, Muir JG, A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Gastroenterology. 2014;146(1):67-75.

2. Eswaran S, Chey WD, Jackson K, Pillai S, Chey SW, Han-Markey T. A diet low in fermentable oligo-, di-, and monosaccharides and polyols improves quality of life and reduces activity impairment in patients with irritable bowel syndrome and diarrhea. Clin Gastroenterol Hepatol. 2017;15(12):1890-1899.

3. McIntosh K, Reed DE, Schneider T, et al. FODMAPs alter symptoms and the metabolome of patients with IBS: a randomised controlled trial. Gut. 2017;66(7):1241-1251.

4. Zhou SY, Gillilland M 3rd, Wu X, et al. FODMAP diet modulates visceral nociception by lipopolysaccharide-mediated intestinal inflammation and barrier dysfunction. J Clin Invest. 2018;128(1):267-280.

5. Staudacher HM, Lomer MC, Anderson JL, et al. Fermentable carbohydrate restriction reduces luminal bifidobacteria and gastrointestinal symptoms in patients with irritable bowel syndrome. J Nutr. 2012;142(8):1510-1518.

6. Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Gibson PR, Muir JG. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut. 2015;64(1):93-100.

7. Whelan K, Martin LD, Staudacher HM, Lomer MCE. The low FODMAP diet in the management of irritable bowel syndrome: an evidence-based review of FODMAP restriction, reintroduction and personalization in clinical practice. J Hum Nutr Diet. 2018;31(2):239-255.

8. Rossi M, Aggio R, Staudacher HM, et al. Volatile organic compounds in feces associate with response to dietary intervention in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2018;16(3):385-391.e1.

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