Commensal skin bacteria exacerbate inflammation and delay skin healing
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Abstract
The skin microbiome can both trigger beneficial immune stimulation and pose a potential infection threat. Previous studies have shown that colonization of mouse skin with the model human skin commensal Staphylococcus epidermidis is protective against subsequent excisional wound or pathogen challenge. However, less is known about concurrent skin damage and exposure to commensal microbes, despite growing interest in interventional probiotic therapy. Here, we address this open question by applying commensal skin bacteria at a high dose to abraded skin. While depletion of the skin microbiome via antibiotics delayed repair from damage, application of commensals-- including the mouse commensal Staphylococcus xylosus , three distinct isolates of S. epidermidis, and all other tested human skin commensals-- also significantly delayed barrier repair. Increased inflammation was observed within four hours of S. epidermidis exposure and persisted through day four, at which point the skin displayed a chronic-wound-like inflammatory state with increased neutrophil infiltration, increased fibroblast activity, and decreased monocyte differentiation. Transcriptomic analysis suggested that the prolonged upregulation of early canonical proliferative pathways inhibited the progression of barrier repair. These results highlight the nuanced role of members of the skin microbiome in modulating barrier integrity and indicate the need for caution in their development as probiotics.
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This study included a mouse commensal Staphylococcus xylosus isolate which was cultured from the skin of mice housed in the MIT/DCM facility. Although it was not literally isolated and then applied to the same mouse, it was isolated from mice from the same vendor within a short time frame (less than 6 months) and likely was very similar to S. xylosus natively present on mice purchased from Taconic and housed in MIT/DCM.
I am not aware of any studies that directly compared ‘self-microbiome’ (or autologous) probiotics to other probiotics- in this JAMA study (Nakatsuji et al, 2021, https://jamanetwork.com/journals/jamadermatology/article-abstract/2781297) authors compare treatment with autologous commensal coagulase-negative Staphylococci to saline vehicle application and observe a significant improvement in atopic dermatitis symptoms in …
This study included a mouse commensal Staphylococcus xylosus isolate which was cultured from the skin of mice housed in the MIT/DCM facility. Although it was not literally isolated and then applied to the same mouse, it was isolated from mice from the same vendor within a short time frame (less than 6 months) and likely was very similar to S. xylosus natively present on mice purchased from Taconic and housed in MIT/DCM.
I am not aware of any studies that directly compared ‘self-microbiome’ (or autologous) probiotics to other probiotics- in this JAMA study (Nakatsuji et al, 2021, https://jamanetwork.com/journals/jamadermatology/article-abstract/2781297) authors compare treatment with autologous commensal coagulase-negative Staphylococci to saline vehicle application and observe a significant improvement in atopic dermatitis symptoms in patients that receive the autologous Staphylococci.
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It would be interesting to observe the effect of a skin microbiota consortium, we did not test it in our study. Given that Staphylococcus epidermidis grows rapidly and survives well on the aerobic skin surface, it is possible that the negative impact of S. epidermidis we observed would dominate any effects of other likely consortium members based on the human skin microbiome (Cutibacterium acnes, various Corynebacterium species).
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We were not able to quantify specific microbial load for many tested species at the experimental endpoint by CFU plating because colony morphologies of applied bacteria and common skin commensals are similar. It is worth noting that we applied a high CFU (10^9) of washed bacterial cells to the mouse skin daily (at tapestripping and 24hr thereafter), for all tested strains. As such, mice in each microbial condition were repeatedly exposed to a similar CFU.
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Our results show that, despite their beneficial role during health, the application of native human and mouse skin commensals to damaged skin delays healing by exacerbating inflammation and prolonging proliferation.
While these results have been observed for native human and mouse skin commensals, I wonder if people expect the same results if the damaged skin was treated with 'self-microbiome' (microbiome or single species formerly isolated from the wounded animal itself) ? Is there any precedent of such study? I wonder if somebody's immune system adapts to its own microbiome and vice-versa. Thus, introducing bacterial species, even if commensal but non from the host, could lead to specific immune response and /or bacterial adaptation to a new environment leading to inflammation and delayed healing.
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all tested human skin commensal microbes significantly delayed healing relative to controls
I am curious to know if the authors had considered using combinations of different species in addition to single species. While single species don't seem to improve healing, do they expect that combination of species would yield a similar output? Because microbial communities phenotypes are rarely the sum of individual phenotypes thanks to microbial interactions, I wonder if healing would be improved or at least no delayed when using a mix of commensal species.
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These results show that the detrimental effect of microbial exposure on barrier repair is not common to all bacteria applied to damaged skin and appears to be limited to skin commensals and opportunistic pathogens.
I am curious to know if the authors have measured, for all the tested strains, the growth and survival at wound site. Did E. coli grow well and did not delay the healing, or is it just because it did not grow, or not as much as the other species?
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