Larazotide
A synthetic octapeptide zonulin antagonist that tightens the intestinal barrier by preventing zonulin-mediated disassembly of epithelial tight junctions.
Larazotide acetate (AT-1001) is an orally administered octapeptide that acts locally in the gut to block zonulin receptor signaling, preserving the tight junction proteins (occludin and claudins) that keep the intestinal epithelial barrier sealed. It has been studied most extensively as an adjunctive therapy for celiac disease, aiming to limit the passage of immunogenic gluten peptides across the mucosa during gluten exposure. A Phase 2 trial showed reduced symptom burden in patients on a gluten-free diet, but a Phase 3 trial (ILIT-1) failed its primary endpoint in 2019, and the compound remains investigational with no FDA approval.
Class
Synthetic octapeptide (zonulin antagonist)
Half-life
~30 minutes (acts locally in the gut lumen)
Routes
Oral
Category
Healing & Recovery
Researched benefits
What it's studied for
Tight junction restoration
Larazotide prevents zonulin-mediated opening of intestinal epithelial tight junctions, helping preserve occludin and claudin structure. This maintains the physical seal between epithelial cells that normally excludes large immunogenic molecules.
Intestinal barrier repair
By reducing paracellular permeability, larazotide is studied for supporting a more intact gut barrier. In a mouse model of eosinophilic enteritis it reduced permeability and improved inflammation under stress conditions.
Reduced gluten-triggered symptoms in celiac disease
In a Phase 2 trial, larazotide 0.5 mg three times daily reduced gastrointestinal symptoms in celiac patients already on a gluten-free diet, with 26% fewer symptomatic days and improvements in abdominal pain and fatigue.
Leaky gut prevention
The peptide's core research interest is limiting excessive intestinal permeability ("leaky gut") by blocking the zonulin signaling pathway that drives paracellular leakage of antigens and inflammatory triggers.
Mechanism
How it works
Larazotide acetate is a synthetic octapeptide that functions as a zonulin antagonist. Zonulin is an endogenous protein that reversibly regulates intestinal permeability by triggering the disassembly of tight junctions between epithelial cells. When zonulin signaling is active, the paracellular spaces between cells open, allowing molecules — including immunogenic gluten peptides — to cross the epithelial barrier.
By inhibiting zonulin receptor signaling, larazotide prevents the disruption of tight junction proteins such as occludin and claudins. Keeping these junctions intact blocks the paracellular passage of gluten peptides that would otherwise reach the lamina propria and trigger the CD4+ T-cell-mediated mucosal injury characteristic of active celiac disease.
Because larazotide acts locally at the luminal surface of the gut epithelium and has a short half-life of roughly 30 minutes with minimal systemic absorption, its effects are confined largely to the intestinal barrier. This local mode of action underlies its favorable tolerability profile in research settings and its investigation as an adjunct rather than a systemic drug.
Dosing protocols
Dosing & administration
Dosing reflects protocols reported in research and community literature for educational purposes. It is not medical advice or a recommendation. Most peptides here are not approved for human use.
Clinical (Phase 2)
- Dose
- 0.5 mg
- Frequency
- Three times daily
- Timing
- Before meals
- Duration
- Studied over 12 weeks
- Route
- Oral
Dose used in the 12-week Phase 2 celiac trial that showed reduced symptom days versus placebo; lower doses outperformed higher doses in trials.
Gluten-challenge (dose-ranging)
- Dose
- Low milligram doses
- Frequency
- Divided daily doses
- Timing
- Around gluten exposure
- Duration
- Studied over 14 days
- Route
- Oral
In a dose-ranging RCT, lower doses of larazotide appeared to limit gluten-induced worsening of GI symptoms during a 14-day gluten challenge.
- Larazotide is investigational and not approved; all figures reflect clinical trial protocols, not an established therapeutic regimen.
- Trial data indicate a U-shaped or lower-is-better dose response, with 0.5 mg outperforming higher milligram doses.
- The peptide is taken orally and acts locally in the gut; it is not injected.
- The Phase 3 trial in gluten-free-diet patients did not meet its primary endpoint, so optimal dosing for symptom control remains unproven.
Evidence
Research & clinical studies (3)
Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial
In a 12-week multicenter Phase 2 RCT (n=342), larazotide 0.5 mg three times daily significantly reduced celiac GI symptoms versus placebo, with 26% fewer symptomatic days and improvements in abdominal pain and fatigue.
PMID 25683116A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge
In a dose-ranging RCT (n=86), lower doses of larazotide appeared to limit gluten-induced worsening of GI symptoms during a 14-day gluten challenge, supporting tight junction regulation as a therapeutic target.
PMID 22825365Potassium-Competitive Acid Blocker Increases Ileal Permeability and Exacerbates Ileal Inflammation under Stress Conditions in a Mouse Model of Eosinophilic Enteritis
In stressed mice, larazotide reduced intestinal permeability and improved eosinophilic enteritis inflammation, suggesting zonulin inhibition can reverse stress-dependent barrier damage.
PMID 42008374Combinations
Stacking & blends
KPV + Larazotide: Gut Barrier & Anti-Inflammatory
Support gut barrier integrity while managing mucosal inflammatory signaling
KPV, a C-terminal tripeptide fragment of alpha-MSH, is researched for MC1R-mediated anti-inflammatory action in the gastrointestinal tract, while larazotide reduces intestinal permeability as a tight-junction regulator. The pairing targets both barrier sealing and inflammation.
Safety
Side effects & considerations
Larazotide is generally considered lower risk in research contexts, with no contraindications established in the reviewed sources. It acts locally in the gut with minimal systemic absorption. Individual response varies; consult a qualified healthcare professional before use.
FAQ
Larazotide — common questions
What is Larazotide?
Larazotide acetate (AT-1001) is a synthetic octapeptide zonulin antagonist that reduces intestinal permeability by blocking zonulin-mediated disassembly of epithelial tight junctions. It has been studied mainly as an adjunctive therapy to reduce symptom burden in celiac disease during gluten exposure.
How does Larazotide work?
It inhibits zonulin receptor signaling, preventing the disruption of tight junction proteins such as occludin and claudins. This keeps the intestinal barrier sealed, blocking immunogenic gluten peptides from crossing the epithelium and triggering the CD4+ T-cell-mediated injury seen in celiac disease.
What is Larazotide primarily studied for?
Its main research areas are tight junction restoration, intestinal barrier repair, and leaky gut prevention — most prominently in the context of celiac disease.
Is Larazotide FDA-approved?
No. Larazotide remains investigational. Its Phase 3 ILIT-1 trial failed its primary endpoint in 2019 and no New Drug Application has been filed, though additional Phase 3 work has been discussed. It is research-use only.
What does the research show about Larazotide?
In a 12-week Phase 2 RCT, larazotide 0.5 mg three times daily significantly reduced celiac GI symptoms versus placebo, with 26% fewer symptomatic days and improvements in abdominal pain and fatigue. However, the later Phase 3 trial in gluten-free-diet patients did not meet its primary endpoint.
How is Larazotide administered?
It is taken orally and acts locally within the gut lumen. It has a short half-life of roughly 30 minutes and is not injected.
What are the side effects of Larazotide?
The reviewed sources report no established contraindications and classify it as low risk in research contexts. Individual response varies — consult a qualified healthcare professional before use.
What is Larazotide commonly stacked with?
It is featured in a research stack with KPV — 'KPV + Larazotide: Gut Barrier & Anti-Inflammatory' — combining tight-junction regulation with MC1R-mediated anti-inflammatory action in the gut.
