Strengths and challenges of current microbiome research

While it is clear that the human microbiome is nowadays recognized as an ‘organ’ for its contribution to digestive, metabolic, and immunological health, its complexity is not fully understood. While there is no defined universal signature of a healthy microbiome, the concept of ‘dysbiosis’ is being used in the media and among some providers to refer to an altered microbiome or a disruption of the equilibrium state between the microbiome and the host. However, the reality is that it is a vague and oversimplistic term with limited clinical applicability. A new perspective in Nature Reviews Microbiology, part of the EU Horizon 2020 funded Human Microbiome Action project, updates the healthy human microbiome concept1.

Joël Doré, microbial ecologist, director of research at INRAE, and coordinator of the Human Microbiome Action project, acknowledges that the strengths of microbiome research today stem from the depth and resolution of microbiome assessment tools used that allow fine mapping of all genes and functional potential of the microbiome and to gain insight into factors that impact the microbiome as well as alterations linked to disease or risk and response to treatments.

However, limitations come from the recent availability and still non-systematic use of standardized tools for microbiome assessment that hinder robust comparative assessments. The EU-funded Human Microbiome Action project did establish recommendations on the scientific consensus on analytical tools to ensure coherence in the way microbiome research is performed and the creation of a FAIR (Findable, Accessible, Interoperable, Reusable) compliant database for the handling and storage of human microbiome and host-associated data.

 

Features of a ‘healthy’ microbiome

The definition of a ‘healthy’ human microbiome has depended mainly on small-scale case-control studies that have distinguished disease-related ‘dysbiotic’ or ‘healthy’ microbiomes based on the health status of participants at recruitment. However, these studies usually use small sample sets of healthy subjects, focus on Western populations, apply narrow inclusion criteria, often include healthy subjects with pre-clinical conditions, and do not always account for confounders (e.g., colonic transit time) that influence the microbiomes. In addition, while sequence-based methods have been paramount in microbiome research, some species are still only recovered using traditional culture-based methods and conversely not all sequenced microorganisms can be cultured yet.

Gut microbiome taxonomy alone is not a predictor of a ‘healthy’ microbiome due to large variations in microbiome composition within an individual and across geography. In contrast, microbial metabolic functionality is associated with more cross-individual stability – a notion often called functional redundancy (numerous species may contribute to similar functions exerted by the microbiome). This explains that inter-individual variability is much higher at the level of taxonomic composition than functional profiling3. In addition, to consider the microbiome as a reporter and predictor of health, the combination of independent measures of both the host and the microbial community health is required1.

Raphaela Joos, from University College Cork, explained to GMFH editors that a microbial community is considered ‘healthy’ if it harbors a wide variety of functionally efficient microbes that promote metabolic activity, resilience, and resistance to disturbances. However, such a community may not always benefit its human host. For instance, antibiotic-resistance genes that enhance microbes’ resistance against perturbation improve the resilience of the microbiome but are detrimental to the host.

The new consensus of the healthy microbiome introduces the concept of the “healthy functional core”, which refers to a subset of essential metabolic and physiologic functions of the microbiome, irrespective of their individual taxonomic composition. Therefore, such a ‘functional core’ allows the comparison of individuals with potentially different microbial make-ups and the longitudinal follow-up of the same individual and its microbiota functionality across different ecological sites of the body.

 

 

Next steps for integrating microbiome biomarkers for personalized medicine

Instead of relying on cross-sectional case-control studies for identifying features of healthy microbiomes, following a large population over time without any pre-defined ‘healthy’ criteria can better show how host and microbiome health co-evolve and recover from or even predict future disease. This approach will also better identify the influences of diet and other environmental factors on the microbiome to finally integrate microbiome-based biomarkers into established clinical biomarkers.

Regarding how understanding what constitutes a ‘healthy’ microbiome will contribute to the next 10 years of microbiome research, Joos states that “with big data and AI technologies at the forefront, we will be able to analyze vast microbial genetic data more effectively, enabling the identification and metabolic categorization of an increasing number of microbes. We also anticipate new, technology-driven insights that will reveal more detailed mechanistic roles of microbes in human health and disease. Ultimately, these advancements will help define standards for “healthy” microbiomes, driving personalized diagnostics and therapies.”

The definition of a healthy microbiome may also host implications for the pharmaceutical industries. However, Doré acknowledged the field of microbial medicine is still in its infancy. An example of a potential clinical translational application of the microbiome can be given in cancer therapy, where features of the microbiome profile can predict with good sensitivity and accuracy the potential of a patient to respond to immunotherapy, to which often less than 50% of patients are responders. “In this context, the microbiome could be a predictive biomarker and also pint at strategic microbiotherapy measures to promote a status of a responder among patients receiving immunotherapy”, explained Doré. Other conditions with unmet medical needs in which predictive microbiome-based biomarkers would be most helpful include for example graft versus host disease and amyotrophic lateral sclerosis.

The microbiome is also a relevant player in the One Health approach that recognizes that the health of people is closely connected to the health of animals and our shared environment. “Because the human is microbial, in a microbial world, microbiome functionalities, relevant at interfaces with food, between microbes or with the host, will clearly provide an insight towards the One Health concept and will be a central piece of information for health-care professionals”, said Doré.

 

References:

  1. Joos R, Boucher K, Lavelle A, et al. Examining the healthy human microbiome concept. Nat Rev Microbiol. 2024. doi: 10.1038/s41579-024-01107-0.
  2. Walker AW, Hoyles L. Human microbiome myths and misconceptions. Nat Microbiol. 2023; 8(8):1392-1396. doi: 10.1038/s41564-023-01426-7.
  3. Konopka A. What is microbial community ecology? ISME J. 2009; 3(11):1223-1230. doi: 10.1038/ismej.2009.88.