Dysregulation of tryptophan catabolism at the host-skin microbiota interface in Hidradenitis Suppurativa

Abstract

Hidradenitis Suppurativa (HS) is a chronic skin disorder of unknown etiology that manifests as recurrent, painful lesions. Cutaneous dysbiosis and unresolved inflammation are hallmarks of active HS, but their origin and interplay remain unclear. Our metabolomic profiling of HS skin revealed an abnormal induction of the kynurenine pathway (KP) of tryptophan catabolism in dermal fibroblasts correlating with the release of KP-inducing cytokines by inflammatory cell infiltrates. Notably, over-activation of the KP in lesional skin was associated with local and systemic depletion in tryptophan. Yet the skin microbiota normally degrades host tryptophan into indoles regulating tissue inflammation via engagement of the Aryl Hydrocarbon Receptor (AHR). In HS skin lesions, we detected contextual defects in AHR activation coinciding with impaired production of bacteria-derived AHR agonists and decreased incidence of AHR ligand-producing bacteria in the resident flora. Dysregulation of tryptophan catabolism at the skin-microbiota interface thus provides a mechanism linking the immunological and microbiological features of HS lesions. In addition to revealing metabolic alterations in HS patients, our study suggests that correcting AHR signaling would help restore immune homeostasis in HS skin.

5‐α reductase inhibition by Epilobioum fleischeri extract modulates facial microbiota structure

“…Lastly, tryptophan degradation appears to be feeding microbial metabolism as evidenced by the connection to NAD biosynthesis. Increased tryptophan degradation is also representative of healthy skin when compared to subjects with atopic dermatitis and lesioned skin from with hidradenitis suppurativa [44, 45]. Geunin‐Macé et al suggest that the metabolism of tryptophan to indoles may reduce inflammation and this may be connected to the effect we see with reduced porphyrins in the active treatment.…”

The aryl hydrocarbon receptor at the forefront of host‐microbe interactions in the skin: A perspective on current knowledge gaps and directions for future research and therapeutic applications

“…Studies addressing the AHR activating potential and downstream effects by skin microbiota are mostly performed by exposure of AHR reporter cells or primary skin cells to whole bacteria, bacterial lysates or purified metabolites, 32 , 33 , 34 , 35 after which known AHR ligands with differences in receptor affinity and turnover times, like TCDD or FICZ are used to substantiate findings. 36 Skin microbiota include a substantial fungal community, which is dominated by Malassezia species.…”

“…Changes in the skin microbiota are characteristic for the disease, with fewer bacteria present known to produce beneficial AHR ligands from tryptophan suggesting a loss of AHR‐mediated host‐microbe communication through altered tryptophan catabolism. 33 Altered tryptophan metabolism is a feature also associated with dysbiosis in atopic dermatitis. 46 , 47 Hence, altered levels or composition of microbial‐derived AHR ligands may contribute to disease pathophysiology.…”

“…To date, only few studies exist addressing AHR signalling in skin investigated patient cohorts 33 , 34 , 48 from a microbiome perspective. Because these had only small sample numbers (<20 per group), there is a need for integrated multi‐omics approaches to investigate and correlate microbiome composition (16S rRNA gene sequencing or ideally metagenomics) with microbial metabolome and host transcriptome/epigenome.…”

Adalimumab therapy is associated with increased faecal short chain fatty acids in hidradenitis suppurativa

“…7 For example, alterations of the gut and skin microbiota metabolic profile in individuals with HS are associated with enrichment of 5-lipooxygenase metabolites 8 and systemic alterations of tryptophan metabolism. 9,10 Particularly relevant examples…”