Mechanisms of Microbe-Immune System Dialogue Within the Skin

Introduction

The crucial role of the skin microbiome in aiding the development and maintenance of host cutaneous health and immunity has been gaining gradual recognition in the field of skin microbiome science (Liu et al., 2023). From establishing immune tolerance in early life, to producing antimicrobial compounds to combat infection, and driving wound healing to prevent entry of unwanted pathogens past the skin barrier and into the body, it is becoming increasingly clear that these skin-associated microorganisms have a direct role in impacting host cell behaviour and function during immune development. 

This is further revealed through the disruption of this balance between the two symbionts triggering infection and the development of skin disorders detrimental to host skin health. Recent studies have noted a rapid increase in the incidence of chronic inflammatory disorders like that of atopic dermatitis (AD) in recent years, with much of this through to be brought about as a result of modern lifestyle changes (i.e., increased hygiene and less exposure to microbes that enrich the microbiome) that fail to provide sufficient training for the immune system in developing these tolerogenic responses against inflammation (Alkotob et al., 2020).

Therefore, understanding and filling in our existing gaps in knowledge regarding the specifics of this immune-microbiome dialogue will be key to advancing the development of effective microbe-based treatments and therapies to address these problem areas and disorders.

Study No. 1: Mechanisms of microbe-immune system dialogue within the skin (Lunjani et al., 2021)

This review article set out to outline the mechanisms through which microbes on the skin interact with each other, as well as discussing the systems that drive communication between the cutaneous microbiome and host immune system, in order to understand the role of such host-microbiome interactions in maintaining skin health (Lunjani et al., 2021).

Results

Resident microbes were found to overproduce antimicrobial compounds in response to an overabundance of Staphylococcus aureus, a bacterial pathogen commonly associated with the skin disorder atopic dermatitis (AD), with beneficial, protective strains of staphylococci, such as S. epidermidis and S. hominis, producing bacteriocin peptides to inhibit their growth by disrupting normal cell function.

These species are also capable of producing other types of antimicrobial peptide that achieve similar results. The secretion of phenol-soluble modulins (PSMs) and proteases by S. Epidermidis work by disrupting the cell membrane of these bacteria and inhibiting S. aureus biofilm formation, respectively. On the other hand, S. hominis is capable of producing lantibiotics that are also capable of disrupting cellular membranes and preventing cell wall biosynthesis (Chakraborty, Gangopadhyay and Datta, 2019), while species such as S. lugdunensis releases the peptide lugdunin to interrupt the usual bioelectrical activity of the cell membrane, preventing functions such as energy generation and communication (Benarroch and Asally, 2020) that allow S. aureus to survive.

Furthermore, the authors note S. aureus has developed a complex system of communication that allows individual bacterial cells to detect and respond to changes in their local environment known as quorum sensing (Moreno-Gámez, Hochberg and van Doorn, 2023). In response, several species of commensal microbes are able to produce inhibitory molecules that block this signalling through quorum quenching, which is then able to block subsequent biofilm formation and enhance host immune response to infection.

In addition to describing the complex ecological interactions mediating population control within these microbial communities on the skin, the authors of the paper also explored the mechanism of modulation of the host immune system by the cutaneous microbiome.

Groups of specialised immune receptors present on the surface of skin cells of the epidermis (i.e., keratinocytes) are able to detect and distinguish between different microbe-identifying components such as proteins or genetic material, which allows the host immune system to regulate microbial density and community composition by preventing unwanted growth of potential pathogens through triggering the release of antimicrobials upon detection.

Commensals on the skin are also capable of engaging in complex forms of communication with these keratinocytes to alert the host to any unwanted strains and triggering their defences. For example, the PSMs secreted by S. epidermidis can also induce the production of keratinocyte-derived antimicrobial peptides and specific inflammatory molecules by activating some of the immune receptors present on these cells. However, these bacteria are just as capable of inhibiting a pro-inflammatory response by synthesising lipoteichoic acid following epithelial injury, which instructs these skin cells to increase the function of immune cells expressing immunoregulatory and tissue repair genes that block infection and repair the wounded skin.

The authors also highlighted the role of other types of antimicrobial produced by resident skin commensals. Sapienic Acid is a type of fatty acid generated upon the metabolising of sebum by groups of bacteria, with deficient production of this compound associated with atopic dermatitis, possibly owing to its action against S. aureus, which is believed to be a risk factor for this condition. Cathelicidin, a peptide that works to disrupt the cell membranes of fungal and bacterial pathogens, as well as damaging the envelope of any infecting viral agents (Currie et al., 2016). Anti-microbial histones, a component of neutrophil immune cells that can target and kill bacteria, as well as modulating the inflammatory immune response during infection both within the cell and outside in the extracellular environment. They are able to act against specific microorganisms like S. aureus, E. coli, and C. acnes by inducing damage to their cellular membranes (Muñoz-Camargo and Cruz, 2024).

Beyond this, the skin itself possesses a group of specialised Langerhans cells that are capable of sampling the environment for any unwanted microbes to trigger an immune response upon the detection of pathogen proteins. This property is also what allows them to produce an effective priming effect upon the host immune system for specific types of microbe such as C. albicans and S. aureus, thus increasing the speed and effectiveness of response upon infection (Lunjani et al., 2021).

Conclusion

The host-microbiome interface employs several molecular and chemical mechanisms to encourage effective communication between the two partners in the context of immune modulation in order to both protect the host from unwanted pathogen colonisation and infection, and defend against microbiome disruption and competition for resources. Such disruptions could lead to unwanted adverse effects, including accelerating the onset of certain dysbiosis-associated skin disorders such as atopic dermatitis, highlighting the importance of this bilateral immune dialogue in protecting the skin (Lunjani et al., 2021).

Study No. 2: Crosstalk between skin microbiota and immune system in health and disease (Liu et al., 2023)

Introduction

This comprehensive meeting report published by Nature summarised the discussions of a workshop held by the US National Institute of Allergy and Infectious Diseases to evaluate the current state of knowledge regarding the interactions between skin microbial communities and the host immune system in health and disease (Liu et al., 2023).

Results

The authors of this report noted microbial colonisation of the skin supports the establishment of immune tolerance in newborns via exposure to bacterial peptides and metabolites that induces the production of commensal-specific immune cells capable of recognising members of the host’s resident microbiota to avoid triggering unwanted immune responses targeting them for removal. Additionally, the presence of lipoteichoic acid in the cell walls of certain groups of bacteria bacteria may act to regulate the function of certain subsets of the host immune system by inducing the recruitment of maturation of immune mast cells into the skin (Wang et al., 2017), while other strains such as S. epidermidis are capable of producing a 6-N-hydroxyaminopurine compound that actively suppresses the growth of tumour cells and subsequent development of melanoma (Nakatsuji et al., 2018).

Several speakers also made mention of the role of certain skin microorganisms in the progression of atopic dermatitis, with some gene products from S. epidermidis such as the enzyme cysteine protease (EcpA), promoting further inflammation and progressing disease severity, suggesting a role of certain species in driving further exacerbation of symptoms associated with certain skin disorders. Other detrimental effects associated with skin microbiome dysbiosis included the presence S. aureus bacteria delaying the resolution of cutaneous lesions caused by infection with parasites belonging to the group Leishmania, hydrolase production by Malassezia correlating with boosted production of proinflammatory cytokines from human skin cells, as well as a possible relationship between fungal dysbiosis and primary immune deficiencies such as STAT3 hyper IgE syndrome, a disorder characterised by eczema and recurrent skin infections (Tsilifis, Freeman and Gennery, 2021; Liu et al., 2023).

Conclusions

Cross-talk between members of the cutaneous microbiome and their associated host are capable of driving both the establishment of immune tolerance, as well as shaping the development of host immune cells in early stages of life. Despite bringing about these beneficial effects, pathogenic behaviours of certain strains can also exacerbate the symptoms of dysbiotic skin disorders like atopic dermatitis, as well as interfering with regular functioning of the immune system, meaning a balance must be struck between the two to ensure skin function and homeostatic immunity (Liu et al., 2023).

Study No. 3: Skin autonomous antibody production regulates host–microbiota interactions (Gribonika et al., 2024)

Introduction

This study sought to investigate the extent to which antibodies are involved in driving host skin immunity by studying the symbiotic mechanisms that trigger their production and mode of action in modulating host–microbiota dialogue and preventing onset of pathogenesis in a series of mouse models exposed to various immune treatments (Gribonika et al., 2025).

Results

The authors of the study reported that topical association and colonisation of the skin by the commensal microbe S. epidermidis was able to trigger the production of specific antibodies targeting this group of bacteria for density control, with signatures of these antibody responses detected within two weeks of administration and persisting for at least 200 days post-exposure, and followed by an increase in the level of S. epidermidis-specific antibody-secreting immune cells in the bone marrow 200 days post-topical association. This represents the development of an immune memory that is capable of producing commensal-specific antibodies targeting this specific species decades after initial exposure (Khodadadi et al., 2019).

These antibodies also demonstrated extreme strain-specificity, with no cross-reactions occurring between S. epidermidis-antibodies and other closely related species of skin bacteria such as Staphylococcus aureus. Further inoculating mice with groups of bacteria they had no prior exposure to (i.e., S. aureus or Staphylococcus xylosus) led to the production of antibodies specifically targeting these species, demonstrating the highly precise nature of these commensal-induced antibodies in matching their targets.

Production of these topical microbe-specific antibodies were predicted to be driven by a need for the host to achieve control over the commensal burden by targeting a certain proportion of these bacteria for removal to ensure these microbes remain at a low biomass on the skin surface, as well as a general strategy to prevent infection by pathogens. To verify these claims, the researchers infected a group of mice with S. epidermidis that they had not been previously exposed to and observed the growth of bacteria in these individuals 3 days post infection. In contrast, mice previously exposed to and already associated with this bacteria displayed a much more reduced bacterial presence in their tissues, which lends support to the idea of these commensal-specific antibodies playing a role in regulating population sizes of symbionts, with these effects observed more quickly in hosts already possessing a developed immunity against these commensals due to previous exposure to the same bacteria (Gribonika et al., 2025).

Conclusion

Microbial colonisation and interaction with the skin is capable of priming the host immune system upon exposure into producing commensal-specific antibodies capable of selectively targeting and modulating the population sizes of skin resident species to reduce cutaneous microbiome biomass. These findings also highlight the role of the skin as an “autonomous lymphoid organ” capable of independently mounting an immune defensive response to regulate microbial infection and prevent any uncontrolled growth that could result in pathogenesis or infection (Gribonika et al., 2025).

Strengths & Limitations

Strengths:

Immunodeficient individuals that possess diminished antibody production capabilities have been shown to demonstrate increased susceptibility to skin infections. Further understanding the role of the microbiome in developing the skin’s immune system can have broad implications for the development of new therapies targeting the skin’s microbiome to help improve protection and immune development by leveraging the natural immune-priming properties of the skin microflora alongside its ability to secrete various compounds that protect the skin from disease (Gribonika et al., 2025).

Further research within this field can also foster the development of new technologies for the study of skin immunity such as: germ-free and gnotobiotic mice models, stem cells, and organoids. Not only that, but this might also aid progress in other fields of skin-related research beyond human immune system-skin microbiome interactions, extending to topics like skin physiological development or cutaneous responses to environmental stress (Liu et al., 2023).

Limitations:

Many knowledge gaps still remain in skin microbiome research that must be filled to accelerate progression in developing these immune therapeutic technologies. This includes addressing topics such as the interaction dynamics between the skin microbiome and two major components of the human immune system (innate vs adaptive), how the immune system is capable of identifying and distinguishing between different commensal strains, and what the major cells and signalling pathways involved in this commensal-specific immune response are (Liu et al., 2023).

Other challenges that exist more broadly in the field of skin microbiome research also include developing realistic models that more accurately represent the process of commensal skin colonisation both on the skin and within its various niches (e.g., hair follicles), as well as further studying commensal bacteria-human cell interactions on its surface to better understand the mechanistic process underlying such immune dialogues (Liu et al., 2023).

Related Research and Future Directions

Assessing the potential of topical pre- and probiotics for the treatment of skin disorders can help resolve much of the conflicting information in the current literature regarding the efficacy of such microbiome-based approaches in mitigating the effects of immune disorders of the skin. This can be taken further by investigating novel pre- and probiotic formulations that deviate from traditional ones by incorporating strains of bacteria and isolated metabolites that have not been previously used (Lunjani et al., 2021).

Further identification of new commensals and microbial metabolites that function in the skin microbiome environment could help build a more comprehensive understanding of the specific mechanisms by which the host immune system and cutaneous microbiome modulate each other to accelerate progress in therapeutic development to treat skin-associated disorders, as well as identifying novel targets for these treatments (Liu et al., 2023).

Conclusions

The complex dialogue between the skin and its associated microbial community plays an important role in modulating host immunity and priming the host immune system against pathogen infection, all while promoting the selective recognition of symbiotic commensals through various means such as intercellular communication, antimicrobial peptide secretion, and commensal-specific antibody production. While previous studies offer detailed insight into some of the mechanisms employed during this symbiosis to confer cutaneous immunity, further studies might want to focus on developing knowledge gaps in other aspects of this area like the influence of these microbes over other components of the immune system (and vice-versa) to facilitate the development of novel therapeutics addressing skin health concerns by harnessing the natural immunogenic properties of the skin microbiome.

References

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