Deciphering the causes of Hidradenitis Suppurativa – Deci-Verneuil

Hidradenitis Suppurativa (HS), also known as Verneuil’s disease, is an incurable skin disease manifesting as recurrent, painful abscesses leading to significant scarring. The estimated worldwide prevalence of HS is around 1%, with highest rates in Europe (1-4%) and a more than 2-fold higher incidence in women. In addition to causing intense pain, HS is commonly associated with disability, depression and anxiety. The aetiology of the disease remains unknown. The sustained production of pro-inflammatory cytokines in skin lesions suggests a defective regulation of inflammation. Moreover, a distinctive anaerobic microbiota was identified in HS skin lesions, the expansion of which correlates with lesion severity. While unable to systematically cure, immunomodulatory drugs and antibiotics correcting the uncontrolled inflammation and cutaneous dysbiosis that are associated with HS skin lesions are effective at reducing the disease’s symptoms, showing that immune and microbial components are both involved in lesion development. In order to better treat HS, it is essential to understand what triggers and connects its diverse clinical manifestations.

To gain new insight into the causes of HS, we recently conducted an integrated metabolomic and transcriptomic analysis of patient skin. Our study revealed a dysregulation of tryptophan catabolism by host cells and local microbiota in HS skin lesions, correlating with defects in bacterial production of tryptophan-derived agonists of the immunoregulatory Aryl Hydrocarbon Receptor (AHR). We also identified a systemic tryptophan depletion in HS patients, likely accounting for the perturbed metabolism of this essential amino acid in HS skin lesions. In the present project, our consortium of immunologists and biophysicist with complementary expertise in bacterial skin infections, host-microbiota cross-talk and metabolomics proposes to establish causal relationships between systemic tryptophan depletion, defective AHR activation, uncontrolled inflammation and dysbiosis in the skin, as well as depressive symptoms. Specifically, our objectives will be to:

- Determine whether and how systemic tryptophan depletion impacts the metabolism, microbiota composition and immune status of the skin
- Delineate the potential role of AHR deficiency, alone or combined with tryptophan deprivation, in cutaneous dysbiosis and immune dysregulation
- Test the impact of AHR deficiency, combined or not with tryptophan deprivation, on brain concentrations of tryptophan-derived neurotransmitters and induction of depression-like behaviour
- Mine the skin microbiota for AHR ligand-producing species and evaluate the therapeutic potential of an AHR agonist-based topical treatment in HS

Together, these inter-related mouse studies will test the new concept that dysregulation of the tryptophan metabolism/AHR signalling axis contributes to HS pathogenesis. In addition to improving our knowledge of HS pathophysiology, this research programme may lead to the identification of novel microbiota- or host-targeted therapies for HS, and provide pre-clinical proof of the therapeutic potential of AHR agonists in HS. More generally and beyond HS, it will generate a new understanding of skin immunity and biology of depression, based on the metabolism of tryptophan.