The Hidden Hormone Sabotaging Your Gut: What INSL5 Reveals About Chronic Diarrhea

How INSL5 Hormone Could Revolutionize Diagnosis and Treatment of Bile Acid Diarrhea

"Microscopic visualization of enteroendocrine L-cells releasing INSL5 in response to bile acids in the colon, linked to chronic diarrhea symptoms.

INSL5 hormone released by gut cells may drive chronic diarrhea in bile acid malabsorption./Freepik

Chronic diarrhea affects millions worldwide. One under‑recognized cause is bile acid diarrhea (also known as bile acid malabsorption, or BAD). A groundbreaking 2025 study from the University of Cambridge has identified a hormone—Insulin‑Like Peptide 5 (INSL5)—as a major contributor in up to 40% of diarrhea‑predominant irritable bowel syndrome (IBS‑D) cases, promising new diagnostic and therapeutic approaches.

What Is Bile Acid Diarrhea (BAD)?

Bile acid malabsorption occurs when bile acids (released by the liver to digest fats) are not properly reabsorbed in the terminal ileum, leading them to enter the colon where they stimulate water secretion and intestinal motility. This results in watery stools, urgency, and sometimes fecal incontinence. BAD can be primary (idiopathic) or secondary to surgery, Crohn’s disease, celiac disease, or bacterial overgrowth .

Despite affecting roughly 1 in 100 adults, BAD is often misdiagnosed as IBS‑D—studies show that SeHCAT tests reveal up to ~32% of IBS‑D patients actually have bile acid retention below 10%, with ~80% responding to bile acid sequestrants like cholestyramine .

New Findings: INSL5 as a Key Player

Published in Gut in July 2025, research led by Cambridge scientists reports that INSL5—a hormone produced by enteroendocrine L‑cells in the distal colon and rectum—is released in response to bile acids in the colon, and correlates with diarrhea severity .

Key elements of the study:

An enema of taurocholic acid in healthy volunteers sharply elevated INSL5 levels, and higher INSL5 correlated with faster time to defecation 4.
INSL5 levels were minimal (< 100 pg/mL) in healthy people but much higher in patients with BAD.
Among IBS‑D patients, ~42% had elevated INSL5—these responded significantly better to the anti‑nausea drug ondansetron compared to placebo (p < 0.05) 5.

These findings suggest INSL5 both as a potential biomarker for diagnosing BAD via blood testing and as a therapeutic target.

Mechanisms: How INSL5 Promotes Chronic Diarrhea

INSL5 is secreted from L‑cells when bile acids irritate the distal colon. It appears to trigger colonic pro-motility effects, accelerating transit and triggering loose stools. In animal models, INSL5 analogues increased colonic motility, supporting its physiological role in diarrhea beyond GLP‑1 and PYY pathways .

Traditionally, low levels of FGF19 (a liver‑derived feedback hormone) were implicated in bile acid overproduction. Reduced FGF19 leads to excess bile acids entering the colon, contributing to BAD—even when ileal absorption is normal .

This new research positions INSL5 downstream: bile acids reach the colon, trigger INSL5 secretion, resulting in colonic hypermotility and diarrhea.

Clinical Implications: Diagnosis & Treatment

Diagnosis

Currently, BAD is diagnosed via:

SeHCAT test (nuclear medicine, retention < 15% suggests severity), but not widely available in many countries 8.
Serum assay of 7α‑Hydroxy‑4‑cholesten‑3‑one (C4) as a marker of bile acid synthesis.

The identification of elevated INSL5 in blood offers potential for a simple blood-based diagnostic to distinguish BAD from IBS‑D earlier and more easily.

Treatments

Standard treatment employs bile acid sequestrants (e.g. cholestyramine, colesevelam), effective in ~60–80% of cases but with tolerability issues for some patients .

The INSL5 study suggests that a subgroup of IBS‑D or BAD patients may benefit from ondansetron, a 5‑HT3 receptor antagonist shown to block INSL5-mediated colonic effects in mice and improve stool consistency in elevated-INSL5 patients .

Future therapies targeting INSL5 directly or modulating its receptor or release may offer novel treatments for recalcitrant chronic diarrhea.

Why This Article Remains Evergreen

This content is evergreen because:

Bile acid diarrhea remains a persistent clinical challenge.
INSL5 provides a fundamental mechanistic insight and holds long-term relevance for diagnostics and therapies.
The integration of hormones, bile acids, and gut motility is a stable framework for future innovations.

Frequently Asked Questions (FAQ)

What percentage of IBS‑D cases are actually BAD?: SeHCAT studies show ~32% of IBS‑D patients have severe bile acid retention (<10 1="" bad="" consistent="" dd="" of="" population="" with="">
Does INSL5 rise in all BAD patients?: Yes — the Cambridge study observed elevated INSL5 throughout patients with confirmed BAD.
Can INSL5 be used as a diagnostic blood test today?: Not yet—it requires validation in larger cohorts and commercial assay development. But the study’s new immunoassay showed clear differences between patients and healthy controls 12.
How does ondansetron help in elevated‑INSL5 cases?: Ondansetron blocks 5‑HT3 receptors and, in mice, inhibits INSL5‑driven motility. Patients with elevated INSL5 responded significantly better in trials (>40% showed improvement) 13.
What other tests exist for BAD?: SeHCAT retention scan and serum C4 assay are established tests. FGF19 levels can also be informative due to their feedback role in bile acid synthesis 14.
Could microbiome or diet affect INSL5?: Microbiome and bile acid metabolism influence colonic irritation; studies show microbiome differences in BAD, though direct impact on INSL5 remains under study 15.

Chronic diarrhea due to bile acid malabsorption is common yet under‑diagnosed. The discovery of elevated INSL5 in many BAD and IBS‑D patients provides a promising biomarker and potential target for treatment. Future developments may include INSL5-based blood tests, receptor modulators, or repurposed therapy like ondansetron for specific patient subgroups. This work shines a light on the critical role of gut hormones in gastrointestinal disease.

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