Temper the hype of human microbiome studies

As biotechnology has evolved, especially with the reduced cost of sequencing and the rapid development of accessible bioinformatic pipeline analysis tools, our understanding of the microbiome has also increased. We can now not only exploit the bacterial composition in great resolution, but this has also opened the potential for translation of microbiome data into a wide range of therapeutic applications. However, there are still many unknowns and prevailing misconceptions awaiting further exploration.

It is a consensus that the human microbiome significantly impacts our health. The human body is a great host for many microorganisms including fungi, viruses, and other microbes. The diversity of the microbiota is key to maintaining a homeostatic environment and plays an instrumental role in bodily health. Sometimes microbes become pathogenic and temperamental when dysbiosis occurs, as many (and fast accumulating) studies have uncovered. We are also beginning to appreciate the contribution of the microbiota to many aspects of our lives, such as how we digest and modulate mood, respond to pathogen attacks, and even how it impacts our mental health. Most importantly, many studies have found that certain cancers, inflammatory diseases, and even brain developmental disorders are associated with pathogenic bacteria. Overall, the human microbiome closely correlates with health, and we should look after it well.

The gut microbiota has been extensively investigated due to its prominent abundance in the gastrointestinal tract, its role in nutrient uptake, the immune response, metabolism, and associated health implications. The gut microbiota has typically been in the spotlight of the research, yet other parts of the body should not be neglected. For example, the skin is the largest human organ. The commensal skin microbiota has evolved with the immune system, and acts as an important barrier to protect against invading pathogens when inflamed or wounded. The oral microbiota is equally diverse and complex, and is associated with many oral diseases such as oral cancer, dental caries and periodontal disease.

Not surprisingly, oral microbiota dysbiosis has also been linked to a plethora of diseases such as obesity, diabetes, crevicular diseases, inflammatory bowel diseases, rheumatoid arthritis, and other neurodegenerative diseases (Alzheimer’s disease). The most plausible mechanism is that oral bacteria can directly translocate in the bloodstream, and some periodontal pathogens also indirectly affect distal sites. In addition, tantalizing headlines about the vaginal microbiome have arrested public attention. A study found that C-section babies lack key microbial species, but abound in harmful microbes commonly found in hospitals. Lactobacillus spp. are abundant microbial species in the vaginal microenvironment and impart many health-promoting benefits. Generally, they are important in maintaining a healthy body and mind.

Fecal microbiota transportation (FMT) has proved to be effective in treating intricate colonic diseases caused by recurrent Clostridioides difficile infection. This success story, and the concept of transplanting a microbiome from a healthy donor into a patient, have galvanized other researchers to use the microbiota as a biomarker to develop targeted therapeutics or practices, such as “vaginal seeding”. We are elated by these exhilarating research outcomes, but at the same time, we should be cautious about the limitations and drawbacks of the current microbiome studies, not least as we should be wary of the safety and efficacy of potential treatments. Still, several points need to be addressed before we become ‘over-hyped’ about microbiome studies.

There is no fixed composition of the healthy microbiome

We have a better understanding of what a ‘healthy microbiome’ may look like now, but a concrete picture of what healthy microbiomes consist of is still a million-dollar question. Multiple factors still impend to define this equivocal question. For example, ever-burgeoning microbiome studies predominate in developed countries, mainly due to funding and technical support. On top of that, most microbiota research has been conducted in Caucasian ethnic groups. Most underdeveloped or developing countries and minority groups tend to be overlooked in the long term, by projects such as the National Institute of Health (NIH) Common Fund’s Human Microbiome Project (HMP) program, and the Human Microbiome Project. Therefore, the implications and findings of population-based microbiome studies cannot be over-generalized. Many variables and limitations could help to compound our understanding of the healthy microbiome, other than rectifying geographic and socioeconomic bias. The taxonomic profiling of microbial species is preliminary and necessary, but we also need more sophisticated approaches to grasp the intricate interaction between the microbiome and host.

Many microbiome studies are correlation, not causation

In looking at conclusions from many epidemiological and observational studies, we spot that the microbiome shows stark differences in healthy conditions compared to disease conditions. We believe in the strong association between changes in the microbiota and our health conditions, but it cannot explicitly explain whether changes in the microbiome are the culprit of numerous diseases or cancers, or whether in contrast, host physiology alters the microbiota when inflamed. The delicate relationship between host physiology and the microbiota remains to be disentangled. Therefore, experiments are paramount to unlock the many attributes of microbes in a reductionist manner, such as their function, potential, and responses to other stimuli. Unfortunately, most human gut microbes are anaerobic and unculturable in lab conditions. The strain level resolution of microbial characterization could help to facilitate our mechanistic understanding of the etiology of pathogenic microbes across different body sites.

The reproducibility of many microbiome studies is limited

Several factors might contribute to poor reproducibility, such as limited reference genomes, incomplete databases, and a lack of standardized protocols for genomic DNA extraction and analysis. In addition, as most of the human gut microbiome data is generated from feces samples, those results might not fully capture the dynamic changes of the microbiome in different regions of the gastrointestinal tract. Insights from mouse microbiome studies are pivotal, but there is still a gap when these are translated into humans. The composition of mouse gastrointestinal bacteria is less than 3% shared with humans, which also impedes translational practice in the clinical setting.

Without any doubt, with updated databases and techniques we are getting closer to revealing the dark matter of human microbiomes. In the meantime, we would do well to take good care of the gut flora. The good news is that, unlike genetics, microbiota is an amendable and dynamic factor if we are willing to make positive lifestyle changes, such as dietary intervention and exercise.

Further reading

1. Eisenstein, M. The hunt for a healthy microbiome. Nature 577, (2020).

2. Gilbert, J. A. et al. Current understanding of the human microbiome. Nat. Med. 24, 392–400 (2018).

3. Byrd, A. L., Belkaid, Y. & Segre, J. A. The human skin microbiome. Nat. Rev. Microbiol. 16, 143–155 (2018).

4. France, M., Alizadeh, M., Brown, S., Ma, B. & Ravel, J. Towards a deeper understanding of the vaginal microbiota. Nat. Microbiol. 7, 367–378 (2022).

5. Beresford-Jones, B. S. et al. The Mouse Gastrointestinal Bacteria Catalogue enables translation between the mouse and human gut microbiotas via functional mapping. Cell Host Microbe 30, 124-138.e8 (2022).

6. Walker, A. W. & Hoyles, L. Human microbiome myths and misconceptions. Nat. Microbiol. 8, 1392–1396 (2023).