- Setting the Stage for a Successful Launch Into the Microbiome Space
- The Skin Microbiome in Relation to the Clothing Microbiome
- Microbiome host interaction: Influence of FLG Loss-Of-Function Mutations in Host-Microbe Interactions During Atopic Skin Inflammation
- Developing Beneficial Bacteria as Topical Therapeutics to Treat Skin Diseases
- How Phage Capsids Can Be Engineered for Gene Therapy of the Microbiome
- Restoring Healthy Skin Ecology with Microbial Ensembles
- Biofilm Production & Inflammatory Skin Molecules Support the Growth & Persistence of Cutibacterium acnes in Acne Vulgaris
Microbiome host interaction: Influence of FLG Loss-Of-Function Mutations in Host-Microbe Interactions During Atopic Skin Inflammation
Bernhard Homey, Dpet. of Dermatology, University Hospital Düsseldorf
Allergy and autoimmunity are a growing problem in societies around the world. We have detailed information on genetic risk factors, as well as on the molecular and cellular players in AD and PSO, but we know very little about how the host-microbe interaction triggers and regulates the inflammatory cascade that leads to the allergic or autoimmune reaction.
We propose that environmental and genetic factors, characteristic of a particular disease, initiate a cascade of inflammatory events through the modulation of antimicrobial defense. Dysregulation of innate and adaptive immune responses leads to inadequate responses to physical, microbial or allergenic stimuli, eventually manifesting itself in the clinical symptoms of AD or PSO.
High-throughput analysis of the whole microbiome and transcriptomic analysis with bioinformatics and systems biology are able to unravel the pathways during host-pathogen interactions that can trigger an allergic or autoimmune reaction, allowing to the identification of the key microbes and molecular targets to develop new intervention strategies to reduce and prevent allergies and autoimmunity.
In general, it has been observed that in AD there is a more marked reduction in microbial diversity than in psoriasis. In AD there is an increase in S. aureus, responsible for the decrease of all the other components, while in psoriasis an increase in Corynebacterium. In AD, but also simply in dry skin sufferers, the ecological niche of anaerobes is almost completely destroyed.
On the other hand, transcriptomic analysis has shown that beyond a “core set” of genes that change in both diseases, in psoriasis there are more transcriptomic changes than in AD. In AD, there are transcriptomic modifications that identify patients with high S. aureus versus those with low S. aureus as a non-random signature. In particular, genes related to kynureninase (KYNU) and to the tryptophan degradation pathway are up-regulated and DA lesions are 75% colonized by S. aureus strains capable of synthesizing tryptophan and therefore not dependent on it. These observations led to the “tryptophan” hypothesis according to which the initial colonization of strains capable of degrading tryptophan would lead to an increase in inflammatory metabolites and at the same time create a hostile environment for the growth of trp-dependent strains, favoring, in a vicious cycle, that of trp-independent strains.
From the point of view of host-microbe interaction, it was then investigated how a genetic mutation of filaggrin (common to atopic dermatitis and ichthyosis vulgaris) and the consequent barrier defects affect the characteristics of the microbiota. The mutation of filaggrin is associated with alterations in the natural moisturizing factor (NMF), ceramides, pH and TEWL. The loss of function of the skin barrier leads to greater penetration of allergens and irritants which triggers an inflammatory reaction.
Transcriptomic analysis showed that, although Staphylococcus aureus dominates the microbiome in both “wildtype” and “mutated” AD patients, the lesional skin of “mutated” patients demonstrated significantly greater transcriptomic dysregulation than in “wildtype” patients. The integrative approach demonstrated loss-of-function mutations in filaggrin to be a “genetic shortcut” for atopic dermatitis and revealed the complexity of the relationships between genotype, transcriptome and microbiome. Another observation is the negative correlation between S. aureus and WNT1, already known for its “negative” modulating action on antigen-carrying DCs cells in asthma models.
These data lead to the conclusion that the genetic “niche” is very important and that in patients without the mutation the path to atopic dermatitis is much longer and requires the presence of more inflammatory signals.
