With an estimated incidence reaching up to 70%, hypertrophic scar stands as one of the prevalent complications in burn patients, characterized by abnormal, elevated, and thickened tissue growth at the site of healed skin lesions (Bombaro et al., 2003). Various factors contribute to the development and progression of hypertrophic scar, with local risk variables such as wound or scar stress, systemic factors like hypertension, genetic factors including single-nucleotide polymorphisms, and lifestyle choices all playing a role. To address hypertrophic scar volume and alleviate discomfort and itch of patients, a suitable approach is crucial. Clinical available interventions include surgery, radiotherapy, and conservative treatments such as gel sheets, tape fixation, and the application of topical or injectable external medications, should be utilized on an individual basis (Ogawa, 2022), as their improper use can potentially lead to adverse effects such as skin shrinkage, telangiectasia, pigmentation issues, skin ulcers, and other imperfections (Lee and Jang, 2018). The impact of hypertrophic scars places a considerable psychological and financial burden on affected patients. Consequently, it is imperative to delve into a comprehensive understanding of the modifiable risk factors and the potential ramifications associated with hypertrophic scarring.

The human gut microbiota is characterized by a rich diversity of bacteria, comprising up to 1,000 different microbial species (Li et al., 2022). This intricate microbial community plays a pivotal role in a myriad of physiological functions, exerting a profound influence on human health. Dysbiosis of the gut microbiota, including both compositional and functional imbalances, is associated with a spectrum of diseases ranging from local gastrointestinal conditions to neurological, metabolic, hepatic, and cardiovascular diseases (Lynch and Pedersen, 2016). Actually, due to the heterogeneity in experimental procedures and study designs, it is currently challenging to identify distinct microbiome signatures for most human diseases, including some intestinal diseases such as pediatric celiac disease (where environmental factors during childhood may not be as significant as in adulthood; Abdukhakimova et al., 2021). However, certain specific bacteria within the microbiota may warrant further investigation to understand their potential applications as probiotic therapies, diagnostic tools, or prognostic biomarkers. The emerging concept of the gut–skin axis outlines the interaction between gut microbiota and skin (Saarialho-Kere, 2004; Salem et al., 2018; Mahmud et al., 2022). More specifically, the health and balance of gut microbiota can influence the condition and function of skin, and vice versa. The effects induced by microbiota on specific inflammatory skin disorders are thought to originate from factors such as a compromised intestinal barrier, elevated levels of inflammatory mediators, and the release of metabolites by microbes (Mahmud et al., 2022). Nevertheless, the presence of a causal relationship between gut microbiota and hypertrophic scarring remains uncertain. Therefore, it is crucial to thoroughly explore this potential causal link.

Mendelian randomization (MR) is a statistical technique employed to assess causal relationships between a risk factor or biomarker (exposure) and a disease (outcome) by leveraging genetic variations as instrumental variables. The fundamental principle underlying MR is to utilize the random assortment of genetic material during meiosis, the process of gamete formation, to simulate a randomized controlled trial and draw inferences regarding causation (Burgess et al., 2015). MR presents distinct advantages over conventional observational research by providing more robust evidence for causal relationships. This strength arises from the fact that genetic variations are established at conception, thereby minimizing susceptibility to confounding or reverse causation (Abdellaoui et al., 2023).

In this work, we aim to explore the causal connections between gut microbiota and hypertrophic scarring and identify specific gut microbiota through a bidirectional MR analysis. The findings of this study may provide valuable insights for future research on the genetic underpinnings and biological therapies related to the intricate features associated with gut microbiota and hypertrophic scar.

Hypertrophic scar, as a fibroproliferative condition in the reticular dermis layer, is characterized by persistent inflammation, heightened angiogenesis, and excessive collagen deposition (Berman et al., 2017; Ogawa, 2017). Nutritional deficiencies, systemic diseases like diabetes, and autoimmune disorders involving chronic inflammation not only impede the intricate cascade of healing but also foster an environment conducive to the aberrant proliferation of fibroblasts, thereby contributing to the development of hypertrophic scars (Ogawa, 2022; Faour et al., 2023). In fact, the relationship between gut microbiota and skin-associated disorders has been a central focus of extensive investigation in recent years, encompassing conditions like hidradenitis suppurativa, rosacea, acne vulgaris, and atopic dermatitis (Mahmud et al., 2022). Our study unveiled the broadly applicable microbial signatures associated with hypertrophic scarring through performing a bidirectional two-sample MR analysis. Seven causal associations between gut microbiome and hypertrophic scarring were identified, involving Intestinimonas, Ruminococcus2, Barnesiella, Dorea, Desulfovibrio piger, Eubacterium rectale, and Ruminococcus torques.

The human gut microbiota is composed of four main phyla, which are collectively known as Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria (Arumugam et al., 2011). Genus Barnesiella from phyla Bacteroidetes and genus Desulfovibrio piger from phyla Proteobacteria exhibited correlations with various immunoregulatory cells, indicating their potential to create a gut environment less susceptible to inflammation (Loubinoux et al., 2002; Weiss et al., 2014). Moreover, in a previous investigation utilizing 16S rRNA gene sequencing, participants with pathological scars exhibited a relative higher abundance of Firmicutes (Li M et al., 2023). Similarly, we observed that specific gut microbiota from phyla Firmicutes act as protective factors against hypertrophic scarring, including Intestinimonas, Ruminococcus2, Dorea, and Ruminococcus torques. Regarding the modified species, Ruminococcus torques was reported to be associated with the alleviation of inflammation through regulating bile acid compositions (Zhang M et al., 2023). At the genus level, both Intestinimonas and Ruminococcus2 are butyric acid-producing bacteria, deemed potential probiotics for alleviating and treating inflammatory diseases due to their capacity to regulate T regulatory cells and inhibit Histone Deacetylase (HDAC) (Gao et al., 2023). Additionally, it has been revealed that Dorea, a commensal bacterium, functions as immune sentinels within tissues (Zhang et al., 2023b). Moreover, Ruminococcus have also been reported to possess the ability to ferment glucose, xylose, and indigestible dietary fiber (Crost et al., 2013; Ghanbari Maman et al., 2020), obtaining energy and nutrients from otherwise complex and difficult-to-digest substrates. Overall, the deficiency of the aforementioned six gut microbiota may contribute to the occurrence of inflammation, representing a potential factor in the onset of hypertrophic scars. On the other hand, the findings concerning the species Eubacterium rectale from phylum Firmicutes suggested a potential role as a risk factor for hypertrophic scars. This aligns with a prior study indicating that Eubacterium rectale contributes to promoting colitis by activating the transcription factor NF-κΒ (Wang et al., 2021). Nevertheless, definitive evidence is necessary to confirm how Eubacterium rectale elevates the risk of hypertrophic scarring, given its role as a butyrate-producing flora that generally provides advantages in specific disorders (Lu et al., 2022). To sum up, our study suggested that the mentioned gut microbiota may play a crucial role in the development of hypertrophic scars by modulating the systemic inflammatory response.

In this study, MR analysis was employed to establish the causal relationship between gut microbiota and the development of hypertrophic scar. This approach helped eliminate the impact of confounding variables and minimized the potential for reverse causation, thereby enhancing the ability to infer the causality. Notably, compared to other research (Li Y et al., 2023; Xia et al., 2023; Yang et al., 2023) (211 gut microbiota from MiBioGen consortium), a larger dataset (418 gut microbiota) was employed here through combing GWAS summary statistics from MiBioGen consortium and Dutch Microbiome Project. As a result, a higher statistical power can be achieved and is better at detecting smaller causal effects, providing a more accurate reflection of the likely range of the true causal effect. Furthermore, we identified seven crucial gut microbiotas, from which extracellular vesicles should need further investigation to be a potential nanobiotechnology therapy for hypertrophic scars and wound healing (Han et al., 2023). However, there are several limitations in this study. One notable aspect is that the GWAS summary statistics predominantly stem from European populations, which may affect the generalizability of the findings to other ethnic groups. Besides, while MR analysis demonstrated statistical causality and supported a link between gut microbiota and hypertrophic scarring, further functional experimental research is necessary to validate these results and clarify plausible genetic pathways.

The potential association between a distinct microbiome environment and a disease impacting a disparate physiological tract may be considered plausible. For instance, oral dysbiosis has been linked to an increased risk of cardiovascular diseases. Bacteria associated with periodontal disease can enter the bloodstream, potentially contributing to inflammation and atherosclerosis in blood vessels (Leishman et al., 2010; Teles and Wang, 2011). Besides, emerging research suggested a connection between the gut microbiome and neurodegenerative conditions like Parkinson’s disease. Changes in the gut microbiome composition might influence the development and progression of neurodegenerative diseases through the gut-brain axis (Zhu et al., 2021; Zhang et al., 2023a). From a similar perspective, this study analyzed the impact of the non-cutaneous microbial environment on hypertrophic scarring. However, the evidence about this microbiome influence is still unclear or inconsistent. On the contrary, the evidence supporting the influence of local microbiota on the skin is continually growing. Changes in the skin microbiome have been implicated in various skin conditions, such as seborrheic dermatitis and acne (Ferček et al., 2021). It has also been found that the dysbiosis of the microbiota occurring in hypertrophic scars is primarily associated with S. aureus colonization (Yu et al., 2023). Currently, there is a lack of research on the influence of gut microbiota on skin microbiota and the impact of skin microbiota on hypertrophic scars. Further research is needed to explore these aspects.

In this study, we conducted a comprehensive assessment of the causal connections between gut microbiota and the development of hypertrophic scar. Through MR analysis, six bacterial taxa were identified as protective factors, while one was identified as a risk factor for hypertrophic scar. In particular, the reverse MR study failed to demonstrate a reverse causal relationship between gut microbiota and hypertrophic scarring. Our study contributed additional supportive evidence and valuable insights into the causal relationship between gut microbiota and the development of hypertrophic scar, providing avenues for mechanistic exploration and the identification of potential therapeutic targets.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

KX: Conceptualization, Methodology, Software, Validation, Writing – original draft, Writing – review & editing. GZ: Data curation, Formal analysis, Investigation, Resources, Writing – original draft. ZihL: Data curation, Formal analysis, Investigation, Resources, Writing – original draft. XZe: Data curation, Formal analysis, Investigation, Resources, Writing – review & editing. ZiL: Visualization, Writing – review & editing. FW: Visualization, Writing – review & editing. XZh: Visualization, Writing – review & editing. CL: Supervision, Validation, Visualization, Writing – review & editing. CM: Supervision, Validation, Visualization, Writing – review & editing.