Reference
Chojnacki C, Poplawski T, Blonska A, Konrad P, Chojnacki J, Blasiak J. The usefulness of the low-FODMAP diet with limited tryptophan intake in the treatment of diarrhea-predominant irritable bowel syndrome. Nutrients. 2023;15(8):1837.
Study Objective
To determine if low-tryptophan (TRP) foods, in addition to a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet, would lead to improved clinical outcomes in irritable bowel syndrome–diarrhea subtype (IBS-D)
Key Takeaway
A low-tryptophan diet may improve global symptoms of IBS-D, including symptoms related to the microbiota-gut-brain axis; however, long-term implications are unclear.
Design
Open-label, cross-sectional clinical trial
Participants
The study included 3 comparator groups. Group I consisted of 40 healthy people without IBS who served as the control. The intervention groups consisted of 80 patients with confirmed IBS-D, divided into Group IIA and Group IIB.
Inclusion criteria for Group II: Those who met the criteria of Rome IV for IBS-D and had loose or watery stools at least 25% of the time for the last 6 months.
They all had an intensity of pain with bowel movements of above 4 on the Gastrointestinal Symptom Rating Scale (GSRS), along with Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Depression Rating Scale (HAM-D) scores above 11 points.
Exclusionary criteria for Group II: Investigators excluded participants from the trial if endoscopic and histological examination revealed pathology of gastric, duodenal, small intestinal, and colonic mucosa. Small intestinal bacterial overgrowth (SIBO) was ruled out via lactulose hydrogen breath test (LHBT). Participants were excluded if diagnosed with colitis, celiac disease, Crohn's disease, allergy, food intolerance, parasitic and bacterial disease, liver and renal disease, diabetes, severe anxiety, or depression. Patients were excluded if they used antibiotics, probiotics, or psychotropics in the month before the enrollment study.
Group II was divided into 2 arms based on nutritional intervention. Group IIA followed a low-FODMAP diet, and Group IIB followed the same low-FODMAP diet, except it was also low tryptophan.
Interventions
Group I was the control group, consisting of healthy participants consuming their usual diets, which investigators tracked for overall nutrient comparisons.
The interventional groups were randomly divided into 2 groups of 40 participants each: Group IIA consisted of IBS-D participants assigned to the FODMAP diet for 8 weeks after educational instruction.
Investigators directed Group IIB, also consisting of 40 IBS-D participants, to follow a low-TRP, low-FODMAP diet. Low TRP was defined as a reduction of tryptophan intake by at least 25% for 8 weeks. The recommended diet maintained optimal amounts of protein, carbohydrates, and fats, and it achieved a reduction in TRP by excluding or drastically reducing products high in TRP, such as wheat bread, sweets, hard cheeses, light and dark meats, and fish, as well as raw fruits and vegetables.
Study Parameters Assessed
Investigators used the GSRS-IBS, the HAM-A, and the HAM-D to analyze abdominal symptoms and the mental state of subjects. At the start and end of the trial, investigators also obtained routine blood tests, along with measurements of C-reactive protein (CRP), fecal calprotectin (FC), and urinary levels of TRP and its metabolites: 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QUIN-A).
Primary Outcome
IBS symptom improvement, including improvements in GSRS-IBS, HAM-A, and HAM-D
Key Findings
Both IBS-D groups (Group IIA and IIB) had a significant reduction in somatic and mental symptoms after dietary treatment with the FODMAP restriction diet. When participants restricted TRP in addition to FODMAP foods (Group IIB), there was a greater improvement in symptomatology. Results for group IIB vs Group IIA:
- GSRS score: 49.8% vs 38.1% (P<0.001)
- HAM-A score: 49.9% vs 38.7 % (P<0.001)
- HAM-D score: 35% vs 13.8% (P<0.001)
There was a greater percentage of improvement in abdominal pain (40.5% vs 63.2%; P= 0.044) and diarrhea (34.3% vs 64.7%; P= 0.012) when comparing Group IIA to Group IIB.
Group IIA had no significant changes in the urinary excretion of TRP metabolites from baseline to the study’s end (8 weeks).
Group IIB had lower levels of 5-H1AA, KYN, and QA and higher levels of KYNA (P<0.001) from baseline to study end.
In both groups, the greater the TRP intake, the greater the GSRS symptom score, which shows a correlation of the intensity of abdominal symptoms with TRP intake (P<0.05).
Transparency
The authors noted no conflicts and made no mention of funding source.
Practice Implications & Limitations
Irritable bowel syndrome (IBS) is now understood as a disorder of the microbiota-gut-brain axis. IBS features peripheral and central sensitization, known as visceral hypersensitivity (VH), mediated by both gut microbiota metabolites and neurotransmitters. Researchers and clinicians must think through multiple angles and dimensions when investigating IBS.
IBS presents with dysregulation of intestinal motility (dysmotility). Consequently, IBS can lead to malabsorption, maldigestion, and increased intestinal permeability due to microbiota imbalances (dysbiosis). These imbalances can result in symptoms such as abdominal pain, constipation, diarrhea, bloating, gas, depression, and anxiety.
IBS is not one unifying disorder. A patient may be diagnosed with IBS-diarrhea subtype (IBS-D), IBS-constipation subtype (IBS-C), post-infectious IBS (PI-IBS) subtype, or even IBS-mixed subtype (IBS-M). Further, we can diagnose IBS with or without small intestinal bacterial overgrowth (IBS-SIBO) or IBS with intestinal methanogen overgrowth (IBS-IMO). Now, we even can detect IBS with overgrowth of hydrogen sulfide–producing microbes. Each of these subtypes requires a unique treatment approach.
One of the main treatments for IBS addresses serotonergic (5-HT) pathways in the enteric nervous system (ENS) and central nervous system. These include 5-HT4 agonists, which promote motility; 5-HT3 antagonists, which reduce motility; and selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, which modulate serotonin and norepinephrine in the gut and brain. While these treatments are effective in helping manage certain clinical patterns, they may come with other unwanted side effects, such as nausea and dry mouth. So, there is an ongoing pursuit of less invasive and more holistic therapies to address IBS.
There are concerns about the long-term impact of the low-FODMAP diet on the microbiome, as well as concerns about restrictive diets contributing to the development of avoidant/restrictive food intake disorder (ARFID).
Two approaches have emerged as holistic treatments for IBS. One is the low-FODMAP diet, a specialized diet featuring the reduction of rapidly fermentable carbohydrates (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) in the diet. The low-FODMAP diet has been demonstrated to reduce IBS symptoms in patients with visceral hypersensitivity at a 75% success rate.1
The other emerging treatment is gut-directed hypnotherapy (GDH). Trials lasting over 6 weeks have been completed comparing GDH in combination with or without the low-FODMAP diet. One significant trial showed GDH to be as effective in benefiting patients as the low-FODMAP diet for endpoints such as global abdominal symptoms, anxiety, and depression.2
The low-FODMAP diet is far from a cure for IBS, but rather it’s a management aid useful in stabilizing patients with IBS. There are concerns about the long-term impact of the low-FODMAP diet on the microbiome,3 as well as concerns about restrictive diets contributing to the development of avoidant/restrictive food intake disorder (ARFID).4
These observations lead the clinician and researcher to consider how we can best understand the mechanisms of the microbiota-gut-brain axis. Currently, there are 2 distinct philosophical arms. One side is focused on IBS as a disease of brain-gut interaction; the other side emphasizes IBS as a disorder of microbiota-mediated imbalance.
Interestingly, the tryptophan-kynurenine pathway explores commonalities between both camps. In the paper currently under review, the authors explore the effectiveness of lowering tryptophan levels to influence IBS-D symptoms.
Why lower tryptophan? Tryptophan is involved with core pathways concerning intestinal, immune, and brain function. Tryptophan is a substrate for the production of serotonin (5-HT), and excessive intestinal serotonin is linked to diarrhea, visceral hypersensitivity, and anxiety, making reduction of TRP availability a hypothetical strategy in IBS-D. In general, the low-FODMAP diet is higher in tryptophan-containing foods, including hard cheeses, light and dark meats, fish, raw fruits, and vegetables. So an intervention lowering tryptophan consumption, in combination with the low-FODMAP diet, should theoretically further the benefits for IBS-D sufferers.
Biochemically, TRP has 3 fates in the gastrointestinal tract.5 First, it may follow the serotonin pathway in enterochromaffin cells and produce 5-HT. Second, TRP may follow the kynurenine pathway (KP) in epithelial, immune cells, and the liver. Finally, the indole pathway occurs largely through interfacing with the gut microbiota. In the indole pathway, Lactobacillus spp, Clostridium spp, and Bacteroides spp can all produce indoles. Indoles are important as they bind to aryl hydrocarbon receptors (AHRs), a main immune-regulating component subject to much research in the world of autoimmunity and oncology.
Of note, patients with IBS-D have increased postprandial 5-HT, and those with IBS-C have reduced postprandial 5-HT levels.6 5-HT is responsible for motility, secretion and absorption, intestinal transit, and colonic tone. 5-HT mediates feelings of nausea by stimulating 5-HT3 receptors along vagal afferents and can stimulate vomiting via the nucleus tractus solitarius (NTS).7
The kynurenine pathway accounts for 90% or more of tryptophan metabolism.8 Measurable metabolites of this pathway include kynurenine acid, kynurenine, and quinolinic acid. Of note, IBS patients have increased kynurenine concentrations compared to controls. 5 Kynurenic acid (KYN-A) is an antagonist of N-methyl-D-aspartate receptor (NMDAR) and alpha7 nicotinic acetylcholine receptors in the enteric nervous system and central nervous system (CNS). KYN-A is also an agonist to G protein–coupled receptor 35 (GPR35) in the ENS.7
NMDAR is a specific glutamate receptor and has links to excitatory, neurotoxic, and neuroinflammatory effects on the brain and gut when glutamate binds to it. GPR35 receptors facilitate gut-barrier regulation and gut inflammation. In contrast, alpha7 nicotinic acetylcholine receptors mediate the effect of acetylcholine on the brain and other tissues.
In the CNS and ENS, KYN-A has been considered potentially neuroprotective and gut-stabilizing by antagonizing NDMA receptors and agonizing GPR35, while also possibly dampening acetylcholine transmission. In the paper under review here, tryptophan reduction raised its metabolite KYN-A, possibly explaining why the low-tryptophan plus low-FODMAP diet performed better than the low-FODMAP diet alone for improvement of anxiety, depression, and global symptoms.
Quinolinic acid (QUIN-A), another metabolite of the kynurenine pathway, is an NDMA receptor agonist and is considered neurotoxic and excitotoxic, so it may contribute to gut-brain axis issues through its neurologic effects (anxiety) and gut effects (dysmotility), as it may potentiate the effects of glutamate. In the paper under review, lowering TRP intake decreased QUIN-A.
Kynurenine, on the other hand, is what is called an aryl hydrocarbon receptor ligand (AHR). As part of our immune-system regulatory function, as well as an environmental sensor, AHR plays a critical role in stabilizing the immune system, promoting tolerance, and reducing oxidative stress. In fact, AHR is a major area of study for autoimmunity management, along with being manipulated to help fight cancers. In the study reviewed here, kynurenine levels decreased with low-TRP intake in addition to a low-FODMAP diet. The implications of affecting AHR binding over the long term are unknown.
Research shows mucosal kynurenic acid and 5-HT (serotonin) levels correlated with self-reported anxiety and depression scores in patients with IBS. Acute tryptophan depletion, a common clinical method, has resulted in increased KYN-A levels in females with IBS.7
Other mechanisms may explain why TRP reduction may have benefited patients with IBS-D. Systemic tryptophan competes with other large, neutral amino acids like valine, leucine, isoleucine, methionine, phenylalanine, and tyrosine for transport across the blood-brain barrier (BBB). By depleting plasma TRP, there is a reduction in the ratio of plasma TRP to large, neutral amino acids. The rate of tryptophan crossing the BBB for further metabolism is reduced, allowing for other important neurotransmitter precursors to cross more efficiently.7 Perhaps, without competition with TRP, CNS production of other molecules, including norepinephrine, epinephrine, and dopamine, could improve due to more bioavailability in the CNS of other amino acids, especially methionine, phenylalanine, and tyrosine.
Further mechanisms to explore are the role of tryptophan reduction on the levels of indole-producing bacteria. Perhaps lowering tryptophan is dampening bacterial overgrowth by removing the availability of this nutrient for their growth.
This study highlights how the central nervous system and enteric nervous system are interwoven. It helps establish a strategy for dampening QUIN-A and elevating KYN-A in IBS-D sufferers. It helps validate the use of commercially available liquid chromatography with tandem mass spectrometry (LC-MS-MS) to look at the kynurenine pathway and metabolites of tryptophan as a management tool in IBS. In addition, the low-TRP diet in combination with the low-FODMAP diet might be a good temporary intervention to help stabilize symptom flares in those with IBS-D.
As we learn what diets, nutrients, herbs, and supplements can support the central nervous system and enteric nervous system, we can continue to offer more successful treatments for the IBS sufferer and truly treat the microbiota-gut-brain axis.
