Larazotide acetate induces recovery of ischemia-injured porcine jejunum via repair of tight junctions.

Slifer ZM, Hernandez L, Pridgen TA, Carlson AR, Messenger KM, Madan J, Krishnan BR, Laumas S, Blikslager AT

PloS one22 Apr 2021Cited by 11 (Europe PMC)

PMID33886649PMCIDPMC8061941DOI10.1371/journal.pone.0250165PepBankPUB-33886649

Summary

Intestinal ischemia results in mucosal injury, including paracellular barrier loss due to disruption of tight junctions. Larazotide acetate (LA), a small peptide studied in Phase III clinical trials for treatment of celiac disease, regulates tight junctions (TJs). We hypothesized that LA would dose-dependently hasten recovery of intestinal ischemic injury via modulation of TJs. Ischemia-injured tissue from 6-8-week-old pigs was recovered in Ussing chambers for 240-minutes in the presence of LA. LA (1 μM but not 0.1 μM or 10 μM) significantly enhanced transepithelial electrical resistance (TER) above ischemic injured controls and significantly reduced serosal-to-mucosal flux LPS (P<0.05). LA (1 μM) enhanced localization of the sealing tight junction protein claudin-4 in repairing epithelium. To assess for the possibility of fragmentation of LA, an in vitro enzyme degradation assay using the brush border enzyme aminopeptidase M, revealed generation of peptide fragments. Western blot analysis of total protein isolated from uninjured and ischemia-injured porcine intestine showed aminopeptidase M enzyme presence in both tissue types, and mass spectrometry analysis of samples collected during ex vivo analysis confirmed formation of LA fragments. Treatment of tissues with LA fragments had no effect alone, but treatment with a fragment missing both amino-terminus glycines inhibited barrier recovery stimulated by 1 μM LA. To reduce potential LA inhibition by fragments, a D-amino acid analog of larazotide Analog #6, resulted in a significant recovery response at a 10-fold lower dose (0.1 μM) similar in magnitude to that of 1 μM LA. We conclude that LA stimulates repair of ischemic-injured epithelium at the level of the tight junctions, at an optimal dose of 1 μM LA. Higher doses were less effective because of inhibition by LA fragments, which could be subverted by chirally-modifying the molecule, or microdosing LA.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study9

6 results from studies that gave the peptide. No result from this study comes from people.

01LabEx vivo tissueEfficacy outcome
In ischemia-injured porcine jejunum, larazotide at 1 μM significantly increased TER versus injured controls.
In plain wordsIn lab tests of injured pig intestine, larazotide at 1 μM increased electrical barrier resistance versus injured controls.
Peptide
Larazotide
Outcome
IncreaseTransepithelial electrical resistance
Study
pign: not reported in source
Ischemia-injured porcine jejunum in Ussing chambers
Comparator
Ischemic injured controls
Outcome group
Gastrointestinal protection · Gastrointestinal
Studied dose
1 μM · 240 minutesAs given in this study (pig).
Source sentences
Summary
LA (1 μM but not 0.1 μM or 10 μM) significantly enhanced transepithelial electrical resistance (TER) above ischemic injured controls and significantly reduced serosal-to-mucosal flux LPS (P<0.05).
1 context sentence(design, population, supporting numbers)
Summary · context
Ischemia-injured tissue from 6-8-week-old pigs was recovered in Ussing chambers for 240-minutes in the presence of LA.
Show in the study text Report a problemFND-3388664901
02LabEx vivo tissueEfficacy outcome
In ischemia-injured porcine jejunum, larazotide at 0.1 μM did not significantly enhance TER versus injured controls.
In plain wordsIn lab tests of injured pig intestine, larazotide at 0.1 μM did not significantly increase barrier resistance versus injured controls.
Peptide
Larazotide
Outcome
No significant changeTransepithelial electrical resistance
Study
pign: not reported in source
Ischemia-injured porcine jejunum in Ussing chambers
Comparator
Ischemic injured controls
Outcome group
Gastrointestinal protection · Gastrointestinal
Studied dose
0.1 μM · 240 minutesAs given in this study (pig).
Source sentences
Summary
LA (1 μM but not 0.1 μM or 10 μM) significantly enhanced transepithelial electrical resistance (TER) above ischemic injured controls and significantly reduced serosal-to-mucosal flux LPS (P<0.05).
1 context sentence(design, population, supporting numbers)
Summary · context
Ischemia-injured tissue from 6-8-week-old pigs was recovered in Ussing chambers for 240-minutes in the presence of LA.
Show in the study text Report a problemFND-3388664902
03LabEx vivo tissueEfficacy outcome
In ischemia-injured porcine jejunum, larazotide at 10 μM did not significantly enhance TER versus injured controls.
In plain wordsIn lab tests of injured pig intestine, larazotide at 10 μM did not significantly increase barrier resistance versus injured controls.
Peptide
Larazotide
Outcome
No significant changeTransepithelial electrical resistance
Study
pign: not reported in source
Ischemia-injured porcine jejunum in Ussing chambers
Comparator
Ischemic injured controls
Outcome group
Gastrointestinal protection · Gastrointestinal
Studied dose
10 μM · 240 minutesAs given in this study (pig).
Source sentences
Summary
LA (1 μM but not 0.1 μM or 10 μM) significantly enhanced transepithelial electrical resistance (TER) above ischemic injured controls and significantly reduced serosal-to-mucosal flux LPS (P<0.05).
1 context sentence(design, population, supporting numbers)
Summary · context
Ischemia-injured tissue from 6-8-week-old pigs was recovered in Ussing chambers for 240-minutes in the presence of LA.
Show in the study text Report a problemFND-3388664903
04LabEx vivo tissueEfficacy outcome
In ischemia-injured porcine jejunum, larazotide at 1 μM significantly reduced serosal-to-mucosal LPS flux versus injured controls.
In plain wordsIn lab tests of injured pig intestine, larazotide at 1 μM reduced LPS movement compared with injured controls.
Peptide
Larazotide
Outcome
DecreaseSerosal-to-mucosal LPS flux
Study
pign: not reported in source
Ischemia-injured porcine jejunum in Ussing chambers
Comparator
Ischemic injured controls
Outcome group
Gastrointestinal protection · Gastrointestinal
Studied dose
1 μM · 240 minutesAs given in this study (pig).
Source sentences
Summary
LA (1 μM but not 0.1 μM or 10 μM) significantly enhanced transepithelial electrical resistance (TER) above ischemic injured controls and significantly reduced serosal-to-mucosal flux LPS (P<0.05).
1 context sentence(design, population, supporting numbers)
Summary · context
Ischemia-injured tissue from 6-8-week-old pigs was recovered in Ussing chambers for 240-minutes in the presence of LA.
Show in the study text Report a problemFND-3388664904
05LabEx vivo tissueMechanism
In repairing porcine epithelium, larazotide at 1 μM enhanced claudin-4 localization.
In plain wordsIn lab tests of pig intestine, larazotide at 1 μM increased claudin-4 localization in repairing tissue.
Peptide
Larazotide
Outcome
IncreaseClaudin-4 localization
Study
pign: not reported in source
Ischemia-injured porcine jejunum in Ussing chambers
Outcome group
Gastrointestinal protection · Gastrointestinal
Studied dose
1 μM · 240 minutesAs given in this study (pig).
Source sentences
Summary
LA (1 μM) enhanced localization of the sealing tight junction protein claudin-4 in repairing epithelium.
1 context sentence(design, population, supporting numbers)
Summary · context
Ischemia-injured tissue from 6-8-week-old pigs was recovered in Ussing chambers for 240-minutes in the presence of LA.
Show in the study text Report a problemFND-3388664905
06LabEx vivo tissueEfficacy outcome
In porcine intestinal tissue, recovery with 1 μM larazotide was similar in magnitude to recovery with Analog #6 at 0.1 μM.
In plain wordsIn lab tests of pig intestine, recovery with 1 μM larazotide was similar to recovery with Analog #6 at 0.1 μM.
Peptide
Larazotide
Outcome
Not applicableRecovery response versus analog
Study
pign: not reported in source
Ischemia-injured porcine jejunum in Ussing chambers
Comparator
Analog #6 at 0.1 μM
Outcome group
Gastrointestinal protection · Gastrointestinal
Studied dose
1 μM · 240 minutesAs given in this study (pig).
Source sentences
Summary
To reduce potential LA inhibition by fragments, a D-amino acid analog of larazotide Analog #6, resulted in a significant recovery response at a 10-fold lower dose (0.1 μM) similar in magnitude to that of 1 μM LA.
1 context sentence(design, population, supporting numbers)
Summary · context
Ischemia-injured tissue from 6-8-week-old pigs was recovered in Ussing chambers for 240-minutes in the presence of LA.
Show in the study text Report a problemFND-3388664909

Studies that did not test the peptide alone3

In this study, Larazotide was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Larazotide.

07LabNot a test of Larazotide aloneEx vivo tissueOther
Mass spectrometry confirmed larazotide fragment formation during ex vivo porcine intestinal analysis.
In plain wordsIn lab tests of pig intestine, mass spectrometry confirmed that larazotide fragments formed.
Peptide
Larazotide
Outcome
Not applicableEx vivo fragmentation
Study
pign: not reported in source
Ischemia-injured porcine jejunum in Ussing chambers
Outcome group
Pharmacokinetics · Pharmacology
Source sentences
Summary
and mass spectrometry analysis of samples collected during ex vivo analysis confirmed formation of LA fragments.
1 context sentence(design, population, supporting numbers)
Summary · context
Ischemia-injured tissue from 6-8-week-old pigs was recovered in Ussing chambers for 240-minutes in the presence of LA.
In this study, Larazotide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Larazotide.
Show in the study text Report a problemFND-3388664907
08LabNot a test of Larazotide aloneEx vivo tissueMechanism
In porcine intestinal tissue, a fragment missing both amino-terminus glycines inhibited barrier recovery stimulated by 1 μM larazotide.
In plain wordsIn lab tests of pig intestine, a larazotide fragment reduced barrier recovery stimulated by 1 μM larazotide alone.
Peptide
Larazotide
Outcome
DecreaseFragment inhibition of barrier recovery
Study
pign: not reported in source
Ischemia-injured porcine jejunum in Ussing chambers
Comparator
1 μM LA alone
Outcome group
Gastrointestinal protection · Gastrointestinal
Source sentences
Summary
Treatment of tissues with LA fragments had no effect alone, but treatment with a fragment missing both amino-terminus glycines inhibited barrier recovery stimulated by 1 μM LA.
1 context sentence(design, population, supporting numbers)
Summary · context
Ischemia-injured tissue from 6-8-week-old pigs was recovered in Ussing chambers for 240-minutes in the presence of LA.
In this study, Larazotide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Larazotide.
Show in the study text Report a problemFND-3388664908
09LabNot a test of Larazotide aloneIn vitro (cell-free)Other
In an enzyme degradation assay, aminopeptidase M generated fragments of larazotide.
In plain wordsIn lab tests, aminopeptidase M broke larazotide into fragments.
Peptide
Larazotide
Outcome
Not applicableEnzymatic fragmentation
Study
n: not reported in source
Aminopeptidase M enzyme degradation assay
Outcome group
Pharmacokinetics · Pharmacology
Source sentences
Summary
To assess for the possibility of fragmentation of LA, an in vitro enzyme degradation assay using the brush border enzyme aminopeptidase M, revealed generation of peptide fragments.
1 context sentence(design, population, supporting numbers)
Summary · context
Ischemia-injured tissue from 6-8-week-old pigs was recovered in Ussing chambers for 240-minutes in the presence of LA.
In this study, Larazotide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Larazotide.
Show in the study text Report a problemFND-3388664906

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
22 Oct 2026, 02:26 UTC
Study results updated
Version 1
21 Oct 2026, 18:59 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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MeSH terms

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