Limosilactobacillus reuteri alleviates psoriasis via aryl hydrocarbon receptor-mediated regulation of Interkeukin-17A.

Both topical and oral administration of heat-killed NCHBL-005 significantly alleviated clinical and histological features of psoriasis in an imiquimod-induced mouse model.

• Therapeutic effects included reduced epidermal thickness, improved Psoriasis Area and Severity Index (PASI) scores, and diminished inflammatory cell infiltration.
• The model used was an imiquimod-induced psoriasis-like mouse model.
• Both routes of administration (topical and oral) were evaluated and found effective.

NCHBL-005 suppressed interleukin-1β and interleukin-17A expression in psoriatic lesions and decreased IL-17A-positive RORγt-positive T-cells while maintaining regulatory T-cell balance.

• IL-17A-positive RAR-related orphan receptor gamma t-positive (RORγt+) T-cells were decreased following NCHBL-005 treatment.
• Regulatory T-cell balance was maintained, suggesting selective immunomodulation rather than broad immune suppression.
• Both interleukin-1β and interleukin-17A expression were reduced in psoriatic lesions.

The therapeutic effects of NCHBL-005 were abolished in aryl hydrocarbon receptor (AhR)-deficient mice but retained in Toll-like receptor 2- and NOD2-deficient mice.

• AhR-deficient mice showed loss of NCHBL-005 therapeutic efficacy, identifying AhR signaling as essential.
• TLR2-deficient mice retained the therapeutic effects of NCHBL-005.
• NOD2 (nucleotide-binding oligomerization domain-containing protein 2)-deficient mice also retained the therapeutic effects.
• These results indicate that the mechanism of action is AhR-dependent and TLR2/NOD2-independent.

NCHBL-005 directly attenuated inflammatory responses in keratinocytes by suppressing IL-1β, IL-17A, and TNF-α expression and inhibiting NF-κB activation.

• Nuclear factor kappa-light-chain-enhancer (NF-κB) activation was inhibited in keratinocytes.
• Expression of interleukin-1β, interleukin-17A, and tumor necrosis factor-alpha were all suppressed.
• These effects were observed directly in keratinocytes, indicating a direct cellular mechanism.

LC-MS/MS profiling identified indole-3-acetaldehyde, indole-3-carbinol, and indole-3-lactic acid as major aryl hydrocarbon receptor ligands derived from NCHBL-005.

• Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to profile AhR ligands produced by NCHBL-005.
• Three major AhR ligands were identified: indole-3-acetaldehyde (I3A), indole-3-carbinol (I3C), and indole-3-lactic acid (ILA).
• These compounds are indole derivatives produced by the bacterial strain.

Among the identified AhR ligands, indole-3-acetaldehyde most effectively reproduced the therapeutic effects of NCHBL-005.

• Indole-3-acetaldehyde reduced IL-17A-positive cells, epidermal hyperplasia, and NF-κB activation.
• Indole-3-acetaldehyde was identified as the most potent of the three identified AhR ligands in reproducing therapeutic effects.
• Its effects paralleled those of the parent heat-killed bacterial preparation NCHBL-005.

Psoriasis is characterized by keratinocyte hyperproliferation and interleukin-17A-driven inflammation, and growing evidence highlights the contribution of microbiome-derived factors to cutaneous immune regulation.

• Psoriasis is described as a chronic immune-mediated skin disorder.
• IL-17A is identified as a key driver of psoriatic inflammation.
• Microbiome-derived postbiotic factors are implicated in cutaneous immune regulation, motivating the study of bacterial metabolites.