Male Pattern Hair Loss (MPHL) and Female Pattern Hair Loss (FPHL) also referred to as Androgenetic alopecia (AGA) stand out as the most prevalent form of hair loss, impacting a substantial portion of the population. It is estimated that by the age of 70, at least 80% of men and 50% of women experience AGA (Devjani et al., 2023). AGA is marked by the gradual miniaturization of hair follicles, resulting in hair loss (Trüeb, 2002). Dealing with alopecia is a challenging and time-consuming process. Individuals experiencing hair loss often suffer from a diminished quality of life, including reduced self-confidence and heightened feelings of depression (Lee et al., 2002; Yeo et al., 2014; Marks et al., 2019). Consequently, the effective management of hair loss plays a crucial role in improving people’s overall wellbeing. To enhance our ability to prevent and treat AGA effectively, it is essential to acquire a more comprehensive understanding of the underlying mechanisms that contribute to its development. Nevertheless, the precise cause behind the escalating incidence rate of AGA has yet to be fully elucidated.

Numerous factors influence the initiation and progression of AGA, the interaction of endocrine factors and genetic predisposition is one of the primary factors (Lolli et al., 2017). Studies have confirmed that a range of external factors, such as metabolism, psychological changes, environmental exposure, dietary intake, and microorganisms, can have adverse effects on the lifespan of hair (Lai et al., 2013; Phillips et al., 2017; Ho et al., 2019; Suzuki et al., 2021). Recently, there is a study has shown that gut microbiota also is an essential factor in the development of AGA (Jung et al., 2022). However, in research related to AGA, there is a relatively limited study on the specific role of the gut microbiome in AGA. The conventional observational study is susceptible to the impact of numerous potential factors, including lifestyle and socioeconomic status, during the implementation process, rendering it prone to biases. Hence, we examined existing summary data from the results of genome-wide association studies (GWAS) to investigate the influence of gut microbiota on AGA.

Genome-wide association studies with large sample sizes has revealed some single nucleotide polymorphisms (SNPs) correlated with both AGA and gut microbiota (Wang et al., 2019). Mendelian randomization (MR) is a method that employs genetic variants linked to a hypothesized risk factor as proxies to ascertain the causal impact of that exposure on a specific outcome (Birney, 2022). In this study, we evaluated the causal effects of gut microbiota and AGA using a two-sample MR study design. Our results demonstrated a potential causal association between specific gut microbiota and AGA.

Androgenetic alopecia is characterized by a progressive thinning of hair in specific areas, influenced by genetic and hormonal factors (Kwack et al., 2023). Prior research has hinted at a connection between AGA and the microbiome (Jung et al., 2022), but much remains unknown about the genetic factors driving this relationship. We employed a bidirectional two-sample MR analytical method, drawing data from GWAS databases encompassing both gut microbiota and AGA. Our inquiry delved into the intricate action of gut microbiota on AGA, unearthing significant insights into how gut microbiota influences AGA. Specifically, our findings spotlight the protective role of certain microbial—such as family Acidaminococcaceae, genus Anaerofilum, and genus Ruminiclostridium 9—in AGA. Conversely, genera like genus Olsenella, genus Ruminococcaceae UCG-004, and genus Ruminococcaceae UCG-010 were identified as risk factors associated with AGA.

The human microbiota has evolved in tandem with its host and serves as an essential component of the human body. Acquired at birth, the microbiota matures alongside the host and maintains significance throughout life, impacting various bodily functions from infancy to old age (Adak and Khan, 2019). Earlier investigations have indicated that in individuals with AGA, both the scalp and gut microbiomes exhibit greater complexity and density, as reflected by elevated values of network topological statistics such as degree centrality, vertices, and edges (Jung et al., 2022). Two patients with alopecia universalis experienced hair regrowth after undergoing fecal microbiota transplantation as a treatment for recurrent Clostridioides difficile infections (Rebello et al., 2017). Imbalanced gut microbiota, notably the proliferation of Lactobacillus murinus, followed by biotin deficiency, constitutes crucial factors contributing to the onset of alopecia (Hayashi et al., 2017). The transplantation of fecal microbiota or the use of a specific probiotic (Bifidobacterium longum HK003) obtained from the feces of healthy individuals could potentially stimulate hair regrowth (Lam et al., 2022). Concerning Ruminiclostridium 9, it has demonstrated its regulatory effects on lipid metabolism, inflammation reduction, enhancement of intestinal barrier function, weight gain reduction, and improved insulin sensitivity in mice, effectively countering obesity development (Wang et al., 2020). However, its specific role in AGA remains unstudied. Further research on the effect of the family Acidaminococcaceae, genus Anaerofilum, and genus Ruminiclostridium 9 on AGA may guide targeted probiotic applications. Our findings suggest that modulating the gut microbiota through probiotics could offer new avenues for the prevention and treatment of AGA.

Ruminococcaceae is a family of bacteria that belongs to the Bacillota (formerly known as Firmicutes) which is one of the major bacterial phyla observed in the human microbiome. Ruminococcaceae is known to be a significant component of the gut microbiota and plays important roles in various physiological processes (Hou et al., 2022). Ruminococcaceae were good predictors of folliculitis decalvans (Moreno-Arrones et al., 2023). Patients undergoing finasteride treatment exhibited a reduction in Ruminococcaceae levels compared to a healthy control group (Diviccaro et al., 2019; Borgo et al., 2021). The You-gui pill could increasing Ruminococcaceae UCG-007 and Ruminococcaceae UCG-010 in the intestine, thereby aiding in the treatment of kidney-yang deficiency syndrome (Chen et al., 2019). In our research, we identified that genus Ruminococcaceae UCG004 (with a statistical power of 98%) and genus Ruminococcaceae UCG010 (with a statistical power of 100%) are implicated as risk factors in association with AGA. The power levels exceeding 80% for both underscore the reliability of the involvement of genus Ruminococcaceae UCG004 and genus Ruminococcaceae UCG010 in AGA. Additional investigation is required to delve into the role of Ruminococcaceae in AGA.

The gut microbiota comprises a unique blend of various organisms, including bacteria, viruses, archaea, protozoa, and fungi, which interact bidirectionally with the central nervous system, forming what is known as the microbiome-gut-brain axis (Mayer, 2011; Sharon et al., 2016). This axis encompasses immune, neural, endocrine, and metabolic pathways, with steroid hormones playing a significant role. Thus far, the steroidogenic capacity remains incompletely understood. However, microbial species such as Clostridium scindens have the potential to convert glucocorticoids into androgens (Ridlon et al., 2013; Ferreira-Halder et al., 2017), thereby fostering the development of AGA. Additionally, Faecalibacterium spp. is a notable producer of butyrate (Ferreira-Halder et al., 2017), a short-chain fatty acid that plays a crucial role in gut microbiota-brain communication (Dalile et al., 2019) and has recently been proposed to influence sleep modulation (Szentirmai et al., 2019). Consequently, Faecalibacterium spp. may be a potential target for therapy AGA. Interestingly, certain members of the human microbiota (e.g., Bifidobacterium spp. and Lactobacillus spp.) encode genes involved in GABA production, suggesting microbial involvement in the production of this neurotransmitter within the gut (Barrett et al., 2012).

The precise biological mechanisms by which microbiotas influence AGA development remain unclear. The microbiota plays a major role in the endocrine system by interacting with estrogen, androgens, insulin, and other hormones (Qi et al., 2021). The androgens are a critical factor that leads to the gradual conversion of terminal hairs into intermediate and vellus hairs, resulting in the gradual hair thinning and hair loss seen in patients with AGA (Lolli et al., 2017). Different types of gut microbiota can produce enzymes essential for androgen metabolism, facilitating the synthesis and alteration of androgens. The microbial-mediated degradation of testosterone has been witnessed across various environmental contexts. For instance, Actinobacteria and Proteobacteria possess the capability to break down androgens (Qi et al., 2021). Additionally, Clostridium scindens, harboring the 20α-hydroxysteroid dehydrogenase (HSDH) enzyme in its genome, is a human gut microbe with significant potential to convert glucocorticoids into androgens (Ridlon et al., 2013). Meanwhile, microbiota-host communication is primarily facilitated through secreted exosomes (Li Q. et al., 2019). Exosomes, extracellular vesicles involved in cell communication, homeostasis, differentiation, and organogenesis (Li et al., 2018, 2021; Lai et al., 2022), are pivotal in hair morphogenesis and regeneration, holding potential for alopecia treatment (Hu et al., 2020). Plasma exosomes, originating from host cells or gut microbiota, mediate local or remote mutual regulation (Li Y. et al., 2019; Li et al., 2020). Intriguingly, exosomes have been observed carrying Wnt proteins on their surface, inducing β-catenin activation—a crucial signaling pathway in hair morphogenesis and regeneration (Gross et al., 2012). Exosomes from adipose-derived stem cells positively impact hair regrowth by enhancing DPC proliferation via upregulating the Wnt/β-catenin, TNF-α signaling pathways, and vascular endothelial growth factor expression (Hu et al., 2020). Further investigation is required to explore the functions of the six microbiotas mentioned in our article on the composition and decomposition of androgens. Elucidating the potential biological mechanisms at microbiotas that might influence AGA development is crucial.

Our study pioneered a two-sample MR analysis using GWAS summary statistics to probe a potential causal connection between gut microbiota and AGA. This analytical approach not only holds promise for developing effective prevention and intervention strategies for AGA but also offers innovative insights into the underlying mechanisms of AGA through the lens of gut microbiota.

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

HF: Conceptualization, Data curation, Investigation, Methodology, Project administration, Software, Validation, Visualization, Writing – original draft, Writing – review and editing. TX: Methodology, Writing – original draft. WZ: Methodology, Writing – original draft. LJ: Funding acquisition, Resources, Software, Writing – review and editing. SS: Funding acquisition, Resources, Supervision, Writing – review and editing.