Imagine a bustling metropolis within your mouth—a dynamic community of microorganisms forming biofilms on your teeth and gums. This oral microbiome is not only essential for maintaining oral health, but also plays a pivotal role in shaping your immune system. But there is more: a new, fascinating aspect of this ecosystem is that it differs between females and males, possibly influencing immunity in sex-specific ways.

Now, consider the connections of the oral microbiome with the gut microbial community, host-microbiome reciprocal epigenetics, metabolic and neuroimmunologic associations, and how this shapes health and disease states: the microsexome revolution is underway.

Summary findings

By examining the oral microbiomes of female and male individuals with healthy gums and those with periodontitis, a common inflammatory gum disease, we revealed notable sex-based differences in the microbial composition of oral biofilms. Our research is published in the journal JCI Insight.

Females exhibited a higher abundance of certain pathogenic bacteria in the oral plaque compared to males, a disparity paralleled by reduced bacterial diversity and further exacerbated by smoking.

Regardless of smoking habits, this sex-based divergence was particularly evident during periodontitis at the level of the subgingival niche, a site that actively interfaces with the host immune system. The hypothesis that such microsexome dysbiosis could have an impact on immunity is supported by evidence of disease- and female-specific immune system activation, in terms of the presence of specific antibodies to periodontal bacteria, exclusive to women with periodontitis.

Our study suggests that distinct microbial communities in females and males emerge during disease states and may interact with the host’s immune system differently depending on sex, and potentially contribute to the observed variations in disease phenotype and susceptibility between sexes within and beyond the oral cavity.

The microsexome revolution

The past 15 years have been dominated by an unprecedented growth in microbiome research. Boosted by biotechnological advancements enabling cost-effective microbial profiling and big data analysis as never before, such expanding knowledge has provided insights into the origin and mechanisms of the most disparate health conditions, offering a privileged, yet challenging, perspective on the future of patient-centered care.

Simultaneously, gender medicine has gained traction with the recognition that females and males exhibit different responses to drugs, diseases, and environmental exposures.

Recognition of the importance of understanding and addressing gender-based health disparities has fueled interest in this interdisciplinary field.

Sequencing and bioinformatic advancements have made it feasible to study the microbiome comprehensively, and uncover subtle sex-based differences. The push for personalized and precision-based medicine has subsequently brought gender medicine and microbiome research to the forefront.

It has not yet been a decade since the National Institutes of Health (NIH) mandated the inclusion of sex as a biological variable in preclinical research, pushing scientists to integrate sex-specific insights into tailored health care strategies. So far, high-profile studies have highlighted the interplay between sex, microbiota, and immune function, sparking public and scientific interest.

How is microsexome relevant for health and research?

Microsexome—the sex-based difference in microbiomes—influences not only susceptibility to diseases, but also treatment responses and overall physiological functions.

Many diseases, such as autoimmune disorders, cardiovascular diseases, and certain cancers, show a sex bias. For instance, females are more prone to autoimmune diseases, while males often face higher risks of cardiovascular issues.

Changes in disease susceptibility and phenotypes also occur across life stages in different manners in males versus females, suggesting a role for sex hormones and the microbiome in the underlying pathogenic mechanisms. Understanding how the microbiome interacts differently with the immune system in females compared to males during life stages could shed light on these patterns and enable tailored, sex-specific preventive and management strategies.

Indeed, sex-specific microbial profiles and their related multi-omic connections could serve as biomarkers for disease risk or progression, aiding early diagnosis and targeted intervention.

The host perspective

Understanding the host-microbiome relationship requires delving deeper into the biochemical interactions and functional dynamics between the host and its microbiota.

Metabolomics bridges the functional gap between host and microbiome by providing real-time snapshots of biochemical interactions.

Transcriptomics provides a dynamic functional view of which host or microbial genes are actively expressed over time or in specific niches. Within this interkingdom networking, bidirectionality dominates communications: thus, microbial antigens, signals, and metabolites can influence host gene expression; in turn, host conditions can modulate the activity of microbial pathways.

Genetics, environment, and diet (from Greek diaita or διαιτάω, originally “way of life, regimen,” or “lead one’s life”) might contribute to significant interindividual variability in microbiome-host interactions.

By leveraging metabolomics and transcriptomics alongside metagenomics, researchers can achieve a deeper understanding of the host-microbiome ecosystem and its impact on health and disease, which can be useful for the identification of disease biomarkers, metabolic profiles that predict response to treatment or susceptibility to diseases, as well as novel therapeutic targets involving specific microbial genes or pathways to modulate host health.

Towards patient-centered medical innovations

In conclusion, the intricate relationship between the oral microbiome and the immune system is influenced by sex in significant ways. As research continues to unravel these complexities, it becomes increasingly clear that a one-size-fits-all approach to health care may overlook critical differences.

Embracing the diversity of the human microbiome and its interactions with our bodies will be key to advancing personalized medicine and improving health outcomes for everyone.

Microsexome dimorphism is a vital factor in understanding human health. It bridges the gap between basic microbiome research and practical applications in medicine, offering pathways for personalized treatments, better disease prevention, and inclusive research practices. By embracing these differences, we can enhance health outcomes and move closer to precision-based medicine practices.

The host perspective in the microsexome and microbiome revolution underscores the interplay between host biology and microbial ecosystems, emphasizing sex-specific factors that shape immunity, metabolism, and overall health.

By adopting this perspective, researchers and clinicians can unlock the potential of personalized medicine, improving prevention and treatment strategies for both sexes. This paradigm shift not only enhances our understanding of human biology, but also paves the way for equitable health care innovations.

This story is part of Science X Dialog, where researchers can report findings from their published research articles. Visit this page for information about Science X Dialog and how to participate.

Prof. Rita Del Pinto, MD, PhD is a specialist in Internal Medicine and an Associate Professor at the University of L’Aquila, where she is part of the Center for Hypertension and Cardiovascular Prevention at San Salvatore Hospital. She also serves as an Adjunct Professor at Case Western Reserve University School of Medicine in the Department of Pathology. Her research focuses on cardiovascular risk assessment, gender and precision medicine, and the role of inflammation as a determinant of cardiovascular disease.