LL-37 is the only human cathelicidin, an antimicrobial peptide of innate immune defense. It is released by epithelial cells, including those in the gut, and attacks bacteria directly.

How does Campylobacter jejuni neutralize LL-37?

Resistant strains use the serine protease HtrA, which cleaves LL-37 between Isoleucine 20 and Valine 21. The cleaved peptide loses its antibacterial activity.

What is the I20M/V21R variant?

A lab-engineered LL-37 variant with two amino acid substitutions at the cleavage site. It resists HtrA cleavage and showed better antibacterial activity in a mouse model.

Was this studied in humans?

No. The study is based on cell and mouse models. It describes a mechanism, not a use in humans.

Where was the study published?

In Science Advances (AAAS), on 22 May 2026, DOI 10.1126/sciadv.aee1996. The work is titled on the HtrA-mediated degradation of LL-37 by Campylobacter jejuni.

LL-37 in the Gut: How Campylobacter jejuni Cleaves the Antimicrobial Peptide, and a Cleavage-Resistant Variant (Science Advances, May 2026)

Important note: This article is provided exclusively for scientific information and research purposes. LL-37 is a research peptide and is not intended for human consumption. The findings described come from cell and mouse models, not from human use.

TL;DR: What the study shows

Date: 22 May 2026, published in Science Advances (AAAS). Key finding: The gut bacterium Campylobacter jejuni uses the serine protease HtrA to selectively cleave and neutralize the human antimicrobial peptide LL-37, which promotes intestinal colonization. Cleavage site: between the amino acids Isoleucine 20 and Valine 21. LL-37 itself upregulates htrA production via the regulator NssR. Counter-strategy: The researchers engineered a cleavage-resistant LL-37 variant (I20M/V21R) with improved antibacterial activity and pathogen clearance in a mouse model.

LL-37regeneration

Cathelicidin-derived antimicrobial peptide (37 amino acids). Researched for innate immunity, antimicrobial activity, and wound-healing pathways. ≥98% HPLC purity with Janoshik CoA.

LL-37: the body's antimicrobial front line

LL-37 is the only human cathelicidin and a central molecule of innate immune defense. Epithelial cells, including those in the gut, release LL-37 to directly attack invading bacteria. The peptide can destabilize bacterial membranes and also acts as an immunomodulator. At mucosal surfaces in particular, LL-37 is a first chemical barrier against pathogens.

This very barrier is at the heart of the new work in Science Advances. The study shows that successful pathogens do not merely evade LL-37, they actively neutralize it.

The bacterial counterattack: HtrA cleaves LL-37

Campylobacter jejuni is one of the most common causes of bacterial gut infections. The researchers showed that resistant strains deploy the serine protease HtrA to cut LL-37 apart. The decisive mechanistic finding is the precise cleavage site: HtrA splits LL-37 between Isoleucine 20 and Valine 21. The cleaved peptide loses its antibacterial activity, and the bacterium can colonize the gut.

A feedback loop that favors the pathogen

Particularly elegant and unfavorable for host defense: contact with LL-37 upregulates htrA production via the bacterial regulator NssR. In other words, the host's defense peptide indirectly triggers the production of the very protease that destroys it. The pathogen turns the defense signal into the cue for its counterattack.

Protein engineering as the answer: the I20M/V21R variant

A concrete counter-strategy follows from this mechanistic understanding. Because cleavage occurs at a defined site, the peptide can be redesigned so that HtrA can no longer act there. The researchers engineered a cleavage-resistant LL-37 variant with the substitutions I20M/V21R (Isoleucine 20 to Methionine, Valine 21 to Arginine).

This variant resisted HtrA cleavage and showed improved antibacterial activity and better clearance of the pathogen in a mouse model. It is a fine example of how precise knowledge of a resistance mechanism gives rise to a deliberately optimized molecule.

Important: cell and mouse model

The findings come from in vitro experiments and a mouse model. This is basic research on the mechanism, not a clinical trial in humans. No therapeutic or usage conclusions can be drawn from it.

Why this matters for LL-37 research

Antimicrobial peptides are seen as one of the hopes for dealing with antibiotic-resistant pathogens. The new work, however, also shows why natural antimicrobial peptides are not automatically clinically robust: pathogens evolve specific proteases to inactivate them. Anyone researching LL-37 has to factor in this arms race between host defense and bacterial counter-defense.

The engineering approach (a resistant variant altered at the cleavage site) is therefore interesting well beyond Campylobacter. It provides a blueprint for how cathelicidin-based strategies can be hardened against protease-armed pathogens. For basic research on LL-37, this is a significant mechanistic building block.