Host and its Microbial Ecosystem: Exploring the Intricate Relationship

Introduction

The human microbiome is a significant driver of human health and disease, composed of trillions of microorganisms that contribute to supporting host health and development. While various factors play a role in influencing the overall diversity and composition of these communities, little remains known regarding the driving factors determining their inheritance and establishment (Benga et al., 2024).

Two main competing hypotheses exist to explain this: either the human microbiome is actively shaped by (1) host genetics, or (2) maternal transmission. Many studies seeking to resolve them have achieved mixed results, making it difficult to conclude on which is the primary driver of microbial inheritance. Regardless, recent findings on the skin and gut microbiomes now suggest that host genotype might play a more important role in the active shaping of certain microbial communities than initially thought (Benga et al., 2024).

Importance of the skin and gut microbiomes

As the largest organ of the human body, the skin employs a variety of chemical, physical, and biological defences to protect the body from external stress or damage by acting as a barrier to infection, promoting thermoregulation, and preventing water loss (Smythe and Wilkinson, 2023). As an extra layer of protection, it has also evolved a specialised community of symbiotic microorganisms to carry out additional functions pertaining to human skin health known as the skin microbiome. With a density of 104 to 106 bacteria per square centimetre of skin surface (Cundell, 2018), it plays an essential role in promoting skin health by preventing growth of pathogens, priming the immune system to differentiate harmful microbes from friendly ones (Lunjani et al., 2021), and even regulating skin growth and development (Meisel et al., 2018). The gut is another key organ that possesses its own highly diverse and interconnected community of microorganisms, reaching densities as high as 1012 cells per gram depending on segment (Sekirov et al., 2010). These microbes line the inner walls of the gastrointestinal tract like the stomach, small, and large intestine, where they aid in carrying out essential functions involving development of the human nervous (Dash, Syed and Khan, 2022) and immune systems, influencing host metabolic activity, fermenting food, and defending against pathogens (Hou et al., 2022).

Influence of host genotype

Several factors influence human microbiome composition over the course of an individual’s life. In most cases, these forces can act to introduce new species, increase or decrease their abundance, or completely wipe them out, which can affect host health in either a positive or negative direction. While we have a fairly comprehensive understanding of the environmental and endogenous factors modulating gut (e.g., immune system, diet) and skin (e.g., cosmetics, hormones) microbiome composition, less is known regarding the key factors influencing the active shaping of these communities in early life. So far two possible hypotheses have been proposed: (1) host genetics actively shape the microbiome, or (2) microbial inheritance occurs through maternal transmission.

Evidence that all humans (to date) share over 50 bacterial species across their gut microbiota despite other compositional differences is taken as evidence that there exists a core human gut metagenome responsible for preserving these groups across the human population (Boccuto et al., 2023). Host-genetics are theorised to influence establishment of the gut microbiome through specific genes. Although the mechanisms of how it does so is not so well understood, some evidence points to these genes influencing certain physiological factors in the host body that affect gut landscape and resulting growth of microbes. For example, one study reported a strong association between the lactase gene and levels of Bifidobacterium, a bacterium that has evolved to digest sugars found in human and cow milk, with lactose-intolerant individuals possessing a higher abundance of this bacteria than lactose-persisters (Qin et al., 2022). This is thought to be because their inability to metabolise lactose makes this sugar more easily available for consumption by bacteria in the gut compared to persisters that can break it down on their own, thus increasing their population (Goodrich et al., 2016).

As with the gut, microbial communities on the skin are thought to be influenced at some level by host genetic factors, albeit if similarly (if not more) understudied, with studies pointing to the influence of these genes on skin architecture (Si et al., 2015) and its associated immune system (Srinivas et al., 2013) affecting the ability of certain species to colonise the skin surface. For example, one study found a significant link between genetic variants related to deficient skin barrier function and an abundance of Corynebacterium jeikeium, a skin bacterium responsible for causing infection in immunocompromised patients, suggesting an impaired skin barrier results in poorer defence against pathogenic bacteria like C. jeikeium that permit it to invade and cause disease more easily (Si et al., 2015).

Influence of maternal transmission

Other sources point to the early establishment of an individual’s gut microbiota being primarily driven by maternal inheritance, with mode of delivery (vaginal or caesarean) being the main mechanism through which this occurs, however, the extent of its influence over the gut microbiome remains controversial. Some studies state vaginally-delivered infants possess more species characteristic of the mother’s vaginal (Lactobacillus + Bacteroides) and fecal microbiota (Bifidobacterium), while those delivered via C-section have a greater abundance of skin microbes such as Staphylococcus (Wang et al., 2024). However, these findings are inconsistent across studies, and some even suggest these effects are short-lived, with compositional differences between the two groups dropping to <2% within 5 years of an infant’s life (Bogaert et al., 2023). Other proposed means by which maternal legacy shapes the gut microbiome is through breastfeeding, which transfers essential nutrients and beneficial microbes from the mother’s milk microbiome to the infant gut (Tian et al., 2023), or placental transmission (Miko et al., 2022) of microbes and microbial metabolites from the mother’s gut to the infant’s to seed the gut and prime the fetus’s primitive immune system to distinguish between friendly and harmful microbe strains.

Similarly, mode of delivery has also been found to play a role in influencing the establishment of bacterial and fungal communities present on the infant skin, with one study reporting vaginally-born children possess more vagina-associated fungal groups (Candida and Rhodotorula) than caesarean-delivered children that possess more skin-associated and airborne fungal genera (Malassezia and Alternaria) (Wang et al., 2022). Other studies have also reported differences in the bacterial composition of vaginally and caesarean-delivered children, with the former possessing more vaginal bacteria like Lactobacillus, and latter a greater abundance of skin bacteria, like Staphylococcus, Corynebacterium, and Cutibacterium, indicating some level of influence in delivery mode in influencing skin microbiome abundance for the first 10 years of life (Dominguez-Bello et al., 2010). Other studies however, have noted that microbial richness, diversity, or taxonomic profiles do not significantly differ between the cutaneous microbiomes of the two infant groups in the four weeks after birth (Pammi et al., 2017), or even between vaginally and caesarean-delivered infants aged 1–3 months (Capone et al., 2011). These observations are believed to be attributed to the highly dynamic nature of the newborn skin microbiome that resolves these differences over time, and also highlight the inconclusive nature of this data.

Study: The host genotype actively shapes its microbiome across generations in laboratory mice (Benga et al., 2024)

Existing literature regarding the effects of maternal legacy (i.e., passage through the birth canal, weaning, coprophagy, and grooming) and host genotype on human microbiomes remain inconclusive. This study set out to determine which of the two factors plays a more important role in actively shaping host microbiome composition over several generations within a controlled setting, being one of the first studies to both look at host genotype effects on skin-based communities, and maternal effects across multiple generations, providing greater insight into its longer-term influences (Benga et al., 2024).

Results

The team collected early-stage embryos from two different mice strains, and by carefully controlling the environment to minimise its effect on the mice, bred them for six generations. The first generation of offspring were exposed to a common initial microbiome to observe how the effects of host genetics and maternal legacy would go on to alter composition over the next five generations, and disentangle these factors (Benga et al., 2024).

As illustrated in Figure 1, maternal legacy had a strong effect in shaping microbiome composition within the first generation of offspring, particularly for gut-based communities. However, its influence over both skin and gut microbiome composition weakened over time and was gradually overpowered by host genotype across subsequent generations. By F3 to F5, genetic factors became the dominant force in determining microbiome structure, as represented by the shifting balance in the schematic diagram. The study identified 33 microbial species that preferentially colonized hosts of specific genetic backgrounds, indicating genotype-specific enrichment of particular taxa. Furthermore, quantification of blood serum metabolites revealed significant differences in microbial metabolite abundance between host genotypes, suggesting an interaction between host genetics and microbiome function (Benga et al., 2024).

Conclusion

The study suggests that under controlled environments, host genetic traits far outweigh any maternal impact on the gut microbiome, with genotype driving the active shaping of the host microbiome over several generations under controlled environmental factors. These effects could also possibly extend to the metabolic activity of the microbiome being modulated by host genetic factors, thus further shaping its behaviour and function. The study resolves the debate by showing that maternal legacy does not persist beyond the initial offspring generation in stable environments.

This study by Benga et al. (2024) stands out as one of the few researches to explore both the effects of host genotype and the maternal influences on the microbiome. However, it is essential to acknowledge that findings from mice models may not fully translate to human physiology. Therefore, future studies should aim to replicate this research in human populations to better understand how host genotype and maternal effects interact to shape the microbiome.

Strengths and limitations

Strengths:

Improving our understanding of the factors modulating the composition and behaviour of the human microbiome has important implications for the identification of host disease markers and abnormal species growth that can interfere with microbiome function to cause disease, allowing the development of measures that mitigate against these host genotype-driven effects (Benga et al., 2024)

Understanding the factors influencing infant microbiomes and their role in the subsequent development of early immunity can catalyse the development of novel prebiotic/probiotic therapies that prevent pathogen colonisation and infection in vulnerable infant populations (Pammi et al., 2017)

Developing multi omic platforms that can analyse the metagenomic composition of individuals in relation to other components such as proteomics and metabolomics can help identify any genetic markers that could be associated with a dysbiotic microbiota and offer personalised solutions to help counteract and balance these effects

Limitations:

Many of the studies looking into disentangling the effects of maternal and host genetic influence on microbiome composition remain inconclusive regarding the effects of either, with many studies concluding on the influence of host genotype being performed on immune defective or highly inbred mice, or lacking natural process of microbiome colonisation, instead relying on artificial methods not representative of actual microbial exposure in human infants (Benga et al., 2024)

These studies also fail to consider sites other than the gut microbiome, leaving a scarcity of information regarding the influence of maternal and host-specific factors on other communities in the body such as the skin, thus preventing any meaningful conclusions being drawn from gut-specific studies

More longitudinal studies are needed to establish a stronger long-term link between these factors and their influence on human microbiomes, with most host genotype studies using murine models that may not accurately reflect human physiology, behaviours, and life history processes/child-rearing practices

Implications & Applications

Development of therapies to maintain the health of the microbiome in susceptible populations or reverse the dysbiotic effect of faulty genetics

Knowledge of how maternal influence can affect microbiome and resulting infant health can empower caregivers to practice microbiome-friendly child rearing where possible, or encourage the development of similarly beneficial alternatives if not

Combining genetics and microbiome screening approaches can allow for more accurate models to be drawn to predict individual therapeutic drug responses when treating dysbiotic microbiomes (Sanna et al., 2022)

Related Research and Future Directions

Application of experiments seeking to establish a more causal relationship between host genotype and microbiome composition via studies implementing controlled interventions (e.g., genetic knock-outs, germ-free hosts) to better understand the genetic mechanisms controlling microbiome composition (Bubier, Chesler and Weinstock, 2021)

Expanding upon the respective roles of maternal legacy and host genotype in influencing microbiome composition and shaping at other body sites such as the vaginal and oral microbiomes to understand how these can influence overall health and disease progression

Extend this to see how host genotype can influence the relationship between microbiome dysbiosis and psychological health by studying the relationship between host genetics, microbiome composition, and any psychiatric disorder-associated phenotypes or endophenotypes

Conclusion

The skin and gut both harbour trillions of microbes that play a crucial role in the maintenance of health and regular bodily function, with numerous factors contributing to their composition. Host genotype is likely to prevail over the effects of maternal legacy when determining the initial formation and establishment of these microbial communities in early life, with maternal legacy effects only persisting in a single generation, after which they are overpowered and persisted by the host’s own genetic factors. Expanding these studies to other bodily sites, and more longitudinal ones, can help elucidate the extent to which these factors persist in their influence, as well as how they interact with or drive disease phenotypes (Benga et al., 2024).

At Sequential, we are at the forefront of microbiome research, revolutionizing the field through its innovative Multi-Omic Studies, which integrate human and microbiome analysis to uncover deeper insights into biological interactions. By employing state-of-the-art technologies, including genetic and metabolic profiling alongside advanced microbial sequencing, we provide a comprehensive understanding of how host genetics and the microbiome shape health outcomes. This multi-layered approach enables the development of science-baked formulations, enhances product efficacy, and advances personalized skincare solutions. With an extensive microbiome database and expertise in clinical testing, we are driving scientific progress in human-microbiome research.

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