Potential for GLP-1 Receptor Agonists in Irritable Bowel Syndrome

Introduction

Irritable bowel syndrome (IBS) is characterized by abdominal pain and altered bowel habit; the prevalence in a recent global survey of 28,771 adults (based on Rome V criteria and data from 15 countries) was 8.5%.¹ Visceral hypersensitivity contributes to abdominal pain in IBS. The effects of glucagon-like peptide-1 (GLP-1) receptor agonists on bowel functions (diarrhea or constipation) are documented in randomized controlled trials (RCTs) in obesity and type 2 diabetes, for which they are licensed treatments. The potential effects on abdominal pain are less well established. The greatest unmet need in IBS is abdominal pain, and targeting GLP-1 receptors on the first order neurons² has potential to reduce pain in IBS.

Obesity remains a disease of epidemic proportions, with more than 40% of the United States population affected and prevalence rates worldwide doubling between 1990 and 2022. Yearly prescription rates for seven anti-obesity medications billed through Medicaid between 1999 and 2023 show a 6,674% increase.³

The aims of this review are to summarize the elements of gut sensation, review the evidence that GLP-1 receptor agonists modify gut motor and sensory functions that may ameliorate or aggravate symptoms or may be leveraged to benefit patients with IBS, and to discuss future research needs. The article was informed by a PUBMED literature search using the terms: GLP-1, GLP-1 receptor agonist, GLP-1 analog, motility, transit, hypersensitivity, abdominal pain, and adverse effects.

The Elements of Gut Sensation

Afferent nerves that mediate sensation from visceral organs follow the vagus or spinal nerves; the latter have cell bodies in the dorsal root ganglion (DRG). These first order afferent nerves synapse in the superficial dorsal horn lamina I and III, intermediolateral cell column, and sacral parasympathetic nucleus in the spinal cord. The second order neurons in the dorsal columns and the lateral spinothalamic tract convey proprioception, pain, and temperature to the third order neurons which arise in the thalamus and project to the cerebral cortex for conscious sensation. Spinal second order neurons receive convergent input from other visceral organs, contributing to cross-organ sensitization, and descending modulation from brainstem centers. This three-neuron chain also connects visceral sensation to autonomic (e.g., cardiovascular) responses to the stimuli. The predominant mediators involved in visceral sensation are serotonin, substance P, calcitonin gene-related peptide, norepinephrine, κ-opiate, and others, including GLP-1.²

Effects of Glucagon-like Peptide-1 on Gut Motility and Sensation

The adverse effects associated with GLP-1 receptor agonists include diarrhea and constipation; the prevalence of adverse gastrointestinal effects with each of the several GLP-1 receptor agonists are similar.⁴ Effects of GLP-1 receptor agonists on motility have been evaluated chiefly in human studies of patients with type 2 diabetes, obesity, or IBS with constipation (IBS-C), and animal studies,^5–13 and are summarized in Table 1. Relative to the details in Table 1, it is noteworthy that colonic transit should be measured at 48 or 72 hours to confirm slow colonic transit or should be based on the difference in colonic transit profile between 24 and 48 hours.¹⁴

Table 1.

Effects of GLP-1 and agonists/analogs on motor mechanisms

Study Design	Measurement of Motility	Effect of GLP-1, or GLP-1 Receptor Agonist (RA) or Analog	Ref.
RETARDATION OF INTESTINAL OR COLONIC TRANSIT OR MOTILITY
Retrospective case series in patients undergoing clinically-indicated assessment of whole gut transit	Wireless motility capsule	Prolonged whole gut transit time in more than 40% of patients treated with GLP-1 RA	5
	Radioscintigraphy over 24 hours	No significant differences in colonic transit at 24 hours in those receiving GLP-1 RA compared with patients not receiving these drugs	6
Retrospective cohort study with propensity score-weighted assessment of whole gut transit	Radioscintigraphy over 48 hours	Delayed colonic transit in ~30% of individuals vs. 20% in controls not on GLP-1 RA at the time of scintigraphy	7
RCT with GLP-1 infused over 4 hours (dose range 0.7 to 2.5 pmol.kg−1.min−1) in healthy subjects and patients with IBS	Gastrointestinal motility by manometry	GLP-1 suppressed gastrointestinal motility and inhibited the migrating motor complex in both healthy subjects and patients with IBS	8
RCT with infusions of GLP-1 or ROSE-010 in healthy subjects	Antroduodenal manometry or muscle strips from humans undergoing bypass surgery for obesity	GLP-1 inhibited gastrointestinal motility and migrating motor complexes; muscle strip research showed inhibition mediated by myenteric neuronal mechanisms involving nitrergic and cAMP-dependent mechanisms by GLP-1 and its analog ROSE-010	9
4-week cross-over RCT with daily SQ liraglutide (dose escalated from 0.6mg to 1.8mg SQ daily) in patients with colectomy and ileal pouch anal anastomosis	Bowel movement frequency	Liraglutide reduced bowel movement frequency	10
STIMULATION OF INTESTINAL OR COLONIC TRANSIT OF MOTILITY
26-week RCT of liraglutide 1.8 mg/day vs placebo for 26 weeks in patients with type 1 diabetes and polyneuropathy	Wireless motility capsule	Liraglutide reduced large bowel transit time (31.7%, p = 0.04) and decreased motility index (6.1%, p = 0.04) compared with placebo	11
Animal study with GLP-1 applied to the colon of conscious rats	Colonic transit	GLP-1 accelerated colonic transit, via central corticotropin-releasing factor and peripheral vagal pathways	12
RCT of ROSE-010 in patients with IBS-C	Radioscintigraphy over 48 hours	ROSE-010 accelerated overall colonic transit compared with placebo	13

GLP-1 has effects on sensory mechanisms, especially in DRG neurons, and on multiple pain syndromes as summarized in Table 2.² GLP-1 receptor agonists also relieve pain in diverse organ systems,¹⁵ in both animal and human studies, through their neuroprotective and metabolic regulatory properties, for example by inhibiting inflammation and oxidative stress and promoting β-endorphin release.¹⁵

Table 2. Effects of Glucagon-like Peptide-1 on Sensory Mechanisms.

Adapted from ref. 2, Camilleri M. Clin Gastroenterol Hepatol 2026;24:2348–2358.

Experimental Model	Effects of GLP-1 or GLP-1 Receptor Agonists
Cell viability in DRG neurons exposed to H2O2	GLP-1 receptor agonists (exendin-4 and GLP-1) prevent reduction of cell viability and apoptosis
Chemotherapy (paclitaxel)-induced peripheral neuropathy	The GLP-1 receptor agonist exenatide reduced the increase in oxidative stress and inflammatory signals, increased β-endorphin and μ-opioid receptors through IL-10, increased neurite length, promoted neuroregeneration, and reduced the increased expression of the TRP family
Mechanisms in reducing neuropathic pain by GLP-1 RA	Literature review documents that the GLP-1 receptor agonists liraglutide and exenatide mitigated the inflammatory processes, decreased cytokines TNF-α and IL-1β in mouse models of diabetic neuropathy, and induced IL-10 (an inhibitor of pro-inflammatory cytokines) expression in chronic pain models
Colonic-sensitized rat models	The GLP-1 receptor agonist exendin-4 reduced visceral hypersensitivity by upregulating SERT and downregulating TPH- 1 expression in a dose-dependent manner
Lipopolysaccharide or water-avoiding stress hypersensitivity in rats	The GLP-1 receptor agonist liraglutide reduced visceral allodynia by suppressing pro-inflammatory cytokine production and improving colonic barrier integrity

Currently approved GLP-1 receptor agonists cross the blood-brain barrier and can, therefore, modulate central inflammatory pathways which sustain neuropathic pain in rodent models of both diabetic neuropathy and chronic pain.

Human studies of the analgesic effects of GLP-1 receptor agonists in headache and chronic pain disorders have been performed,¹⁵ including two RCTs of the effect of ROSE-010 for acute pain episodes in IBS.^16,17 It has also been shown that treatment of IBS with a low FODMAP diet, which may lead to improvements in abdominal pain in IBS, is associated with increased circulating levels of GLP-1.¹⁸

Pivotal Points Regarding GLP-1 Receptor Agonists and IBS

1. Effects of GLP-1 Receptor Agonists in the Gastrointestinal Tract and Potential to Aggravate Symptoms in Patients with IBS

The main motility effects of GLP-1 receptor agonists are delayed gastric emptying, increases or decreases in colonic transit, and inhibition of small intestinal migrating motor complexes. All these may result in aggravation of symptoms in patients with IBS. It does not appear that any GLP-1 receptor agonists is more or less likely to lead to gastrointestinal effects, because the spectrum of adverse events across RCTs with currently marketed medications is very similar, with a 10% prevalence of diarrhea and a 15% prevalence of constipation.¹⁹ Another study documented an increased prevalence of constipation among patients with obesity receiving GLP-1 receptor agonists,²⁰ approximately 30% of patients reported constipation, compared with 26% of obese controls receiving bupropion-naltrexone or phentermine-topiramate (P<0.001).²⁰ In contrast, the incidence of constipation with GLP-1 receptor agonist use in these patients was 3.34/100 person years, whereas other anti-obesity medications had a 1-year incidence of 3.73/100 person years, which led to the somewhat confusing conclusion that GLP-1 receptor agonists were associated with a higher rate, but lower incidence, of constipation.²⁰

The diverse and divergent effects of GLP-1, or its receptor agonists and analogs, on colonic transit, in particular, in patients undergoing clinically-indicated colonic transit measurements could support the potential effects of GLP-1 agents on both diarrhea and constipation, as observed in clinical practice and RCTs.

2. Effects of GLP-1 Receptor Agonists Vary by IBS Subtype

Since diarrhea and constipation are adverse events associated with GLP-1 receptor agonists, it is possible that bowel dysfunction in IBS may be either ameliorated or aggravated. For example, a drug that retards colonic transit may improve IBS with diarrhea (IBS-D) but, conversely, aggravate IBS-C.

Three key factors to consider in patients with IBS are the potential for the GLP-1 receptor agonists: To affect colonic transit de novo, to aggravate the underlying bowel dysfunction, and for the retardation of gastric emptying with aggravation of nausea and vomiting thereby impacting the symptoms of functional dyspepsia (FD) that frequently overlap with IBS. In addition, potential analgesic effects of GLP-1 should be considered in patients with IBS.

In addition, in patients with IBS, there is a substantial likelihood of discontinuation or switching of GLP-1 receptor agonists. Among 256 patients with IBS prescribed more than one GLP-1 receptor agonist, 227 (88.7%) patients trialed two or three GLP-1 receptor agonists, and 29 (11.3%) trialed four or more agents.²¹ Patients with IBS with mixed bowel habits (IBS-M) showed the highest rates of switching (22%), followed by IBS-C (12%), and IBS-D (2%) (P=0.02). Semaglutide had more discontinuations within 6 months of starting, compared with liraglutide (63% vs. 43%; P=0.012). Patients with IBS aged ≥65 years were more likely to continue a first agent for >6 months compared with those <65 years (66% vs. 44%, P=0.014). In successive lines of therapy, treatment-related discontinuations, such as injection burden or non-response, remained fairly constant among the subtypes of IBS (17% [IBS-M], 14% [IBS-C], and 14% IBS-D]), but symptom-related discontinuations, including nausea, vomiting, diarrhea, or constipation, increased steadily from the first to the third agent (28%, 30%, and 48%, respectively). Discontinuations are often followed by switching to other GLP-1 receptor agonists; patients with Medicare/Medicaid were more likely to switch ≥3 therapies than those with private/self-pay coverage (23% vs. 7.3%; P=0.006).

3. Clinical Recommendations for Managing Gastrointestinal Adverse Effects of GLP-1 Receptor Agonists in Patients with IBS Undergoing Endoscopy

Patients with IBS are often referred for endoscopic investigation. Available guidelines regarding management of GLP-1 receptor agonists in relation to elective endoscopic procedures should be followed. These management guidelines include possible interruption of therapy, depending upon the half-life of the drug, or point of care ultrasound before the endoscopy to determine whether airway protection is indicated during that procedure. In clinical practice, it is also very helpful to advise patients to have a completely clear liquid diet for the entire day prior to the endoscopy, and also for the endoscopist to query patients as to whether they have symptoms such as nausea, vomiting, early satiety, or upper abdominal bloating, all of which may suggest the presence of impaired gastric emptying, as these would put the patient at higher risk of aspiration. It is, nevertheless, reassuring that most studies that have evaluated the risk of retained gastric content or aspiration during endoscopy found these were not greater in patients receiving GLP-1 receptor agonists compared with those on other antidiabetic medications or to those not receiving either of these classes of medications.²² These observations are consistent with the documented tachyphylaxis in the retardation of gastric emptying with GLP-1 receptor agonists, and the fact that in a prospective 16-week RCT up to 40% of obese non-diabetic patients never experienced any delay in gastric emptying.²³

4. Mitigating the Gastrointestinal Adverse Effects of GLP-1 Receptor Agonists in Patients with IBS

The potential for adverse outcomes, in the form of further bowel dysfunction or development of FD symptoms, should be monitored in patients with IBS receiving GLP-1 receptor agonists, and decisions regarding dosage (escalation and maintenance) or cessation will be important in those patients whose symptoms are aggravated.

Awareness of the possibility of changes in bowel function is critically important and depends upon reports from the patient to their provider. This may result in a joint decision to slow down the dose escalation strategy or to use a lower maintenance dose than would otherwise be used in patients with obesity or type 2 diabetes. A consensus document has made recommendations about how to reach the maintenance dose and how to proceed if gastrointestinal adverse events develop during dose escalation, as well as providing specific directions on how to minimize nausea, vomiting, diarrhea, and constipation.²⁴ The specific recommendations are: first, to extend the dose escalation phase duration (2 to 4 more weeks with the previous dose); second, to avoid dose escalation while gastrointestinal adverse events persist; third, if a gastrointestinal adverse event is experienced when moving to a higher dose, to revert to the lower dose and stay on it for a few days, then increase the dose again gradually; fourth, in the case of persistent gastrointestinal adverse events that limit tolerability, to set a dose lower than the maximum one recommended by the technical data sheet as the maintenance dose; fifth, to withhold treatment temporarily until the resolution of gastrointestinal adverse events and then resume treatment.

5. Leveraging Effects in the Gastrointestinal Tract of GLP-1 Receptor Agonists for the Benefit of Patients with IBS

There are several potential benefits from the effects of GLP-1 receptor agonists in patients with IBS. As mentioned above, there is evidence of slowing small bowel or colonic transit, which may be beneficial in some patients with IBS-D. The example of the effects of liraglutide in patients with ileal pouch anal anastomosis shows the potential benefit in terms of reducing the frequency of bowel movements.¹⁰ Conversely, the observation of acceleration of colonic transit in scintigraphic measurements in patients with IBS-C would suggest there is also potential benefit in those with this subtype.¹³ Equally important is the fact that GLP-1 receptors are located on the DRG cell bodies and mediate visceral sensation as part of the three-order chain of neurons, conveying visceral sensitivity to conscious perception. In the same way that GLP-1 receptor agonists impact the function of the vagus nerve, via effects on the nodose ganglion cell body, there is the potential to modify visceral afferent function through GLP-1 receptors on DRG cell bodies. Indeed, two studies using the GLP-1 analog, ROSE-010, have documented the potential to reduce overall or acute pain in patients with IBS,^16,17 with abdominal pain relief greatest in IBS-C and IBS-M, compared with IBS-D or IBS unclassified.¹⁷

6. Is the Diagnosis IBS-D or Bile Acid Diarrhea?

The clinical manifestations of bile acid diarrhea mimic those of IBS-D. With opportunity to make a positive diagnosis based on 75SeHCAT retention or biochemical measurements such as serum 7αC4 and % primary bile acids in stool, there is also evidence that the GLP-1 receptor agonist, liraglutide, was efficacious in the treatment of bile acid diarrhea in a randomized controlled trial in which it was compared to the bile acid sequestrant, colesevelam.²⁵ GLP-1 receptor agonists may be beneficial in IBS because they prolong small intestinal transit time, whereas they may be effective in BAD because they reduce fecal bile acid concentration.

7. Mechanistic Research Needed to Establish the Potential of GLP-1 Receptor Agonists in IBS

It is essential to pursue further human studies, particularly in patients with IBS-C and IBS-D, that appraise full gastric, small bowel, and colonic transit measurements over at least 48 hours, as well as to assess the effects of GLP-1 receptor agonists on visceral compliance and sensation, e.g. by studying rectal distention. Trials of brenipatide, which is a dual agonist of both GLP-1 and gastric inhibitory polypeptide, in IBS are ongoing.

CONCLUSIONS

Although there is considerable potential for GLP-1 receptor agonists to impact gastrointestinal motor and sensory functions that may be relevant to patients with IBS, there are no published data on the magnitude of transit effects or on the potential for pre-treatment bowel function to ascertain the direction of influence with the GLP-1 receptor agonists. Therefore, there is still scope to conduct proof of concept studies based on their pharmacodynamic effects, as well as their potential effects on patient response outcomes, in the different IBS subtypes before embarking on phase 2B or 3 RCTs. These principles, and the use of biomarkers, have previously proven worthwhile in the development of drugs subsequently approved for IBS or chronic constipation, such as alosetron, lubiprostone, linaclotide, and prucalopride.