Are microbiomes worth the hype?

A scientist examines petri dishes used for studying microbes

Many types of micro-organisms, including bacteria, make up microbiomes. Via Unsplash

Microbiome research is turning heads. Since the mid-2010s, scientists have been excited about newly discovered links between the human microbiome and health. AgriTech start-ups, such as Solena Ag and Ceragen, are engineering soil and plant microbiomes for increased crop yield and quality. Harnessing the power of the microbiome was even hailed as a potential method to prevent global biodiversity loss in a 2022 article published in Nature. From the medical field to the ecological field, microbiomes are making waves.

What is a microbiome?

The microbiome is the community of microorganisms together with their “theatre of activity” (the surrounding environmental conditions, signalling molecules, and structural elements) present in a specific environment. Bacteria, fungi, unicellular eukaryotes, archaea (prokaryotes which are evolutionarily distinct from bacteria, often found living in extreme conditions), and their associated elements are all included within this definition, although much research focuses primarily on bacteria.

There is exceptional interest in the study and manipulation of microbiomes. This is unsurprising given the abundance of data that can be acquired from a single study on a microbiome. For context, one gram of soil can contain thousands, if not millions, of different microbial species, with each microbe possessing its own repertoire of thousands of genes.

In today’s Information Age, studies which produce this volume of data are exceedingly attractive to not only researchers, but investors, too. Projects that produce a lot of data allow for researchers to flexibly interrogate the datasets depending on what they, or their client, want to know. In this way, projects that produce a lot of data are much more attractive to researchers and investors than those that produce small datasets. The questions you can answer with the magnitude of information supplied by microbiomes is nearly limitless, making findings from this sector highly interesting and applicable.

How can microbiomes be studied?

The genetic material of microbes can be assessed through one of two approaches. The first is marker gene sequencing, which provides the sequence of a specific gene region, and the second is metagenomic sequencing, which facilitates the analysis of all genetic material within a sample. Both methods can be used to identify the composition of the microbial community, sometimes down to a species level. Supplementing these approaches with metatranscriptomics (quantification of actively expressed genes), metabolomics (quantification of small molecules, such as amino acids and signalling compounds), and other ‘omics technologies, you can reveal the microbiome’s functional profile. In short, you can know which microbes are present and what they are doing.

For example, Andrzej Tkacz and colleagues from the University of Oxford have demonstrated that the structure of the plant root microbiome is influenced by plant species. They observed different community compositions between Arabidopsis thaliana, Medicago truncatula, Pisum sativum, and Triticum aestivum. Additionally, soil type and thedistance from the root also influenced the composition of the root-associated microbiome. More simply, the dominant microbes found close to the root (primarily Proteobacteria) differed from the microbes which dominated the surrounding soil (Acidobacteria and Actinobacteria). Furthermore, depending on where the soil is from, these microbes would also differ.

The reason for these differences are thought to be due to the action of the plants themselves. Plants actively assemble their root-associated microbiome by secreting nutrients and signalling compounds, whilst also utilising their immune system to prevent unwanted microbes (i.e., pathogens such as Phytophthora infestans or Pseudomonas aeruginosa) from populating the region closest to the roots. However, these differences are equally influenced by the microbes themselves. It is thought that Proteobacteria dominate the soil closest to the roots due to their fast metabolism, allowing them to outcompete other microbes for the nutrients exuded by the plant.

The human gut microbiome is attracting even more attention. Pioneering this research was the Human Microbiome Project (HMP), launched in 2007. This initiative, started by the United States National Institute of Health, characterised the gut, skin, vaginal, nasal, and oral microbiomes of healthy human subjects. Following this, the HMP looked to characterise “unhealthy” microbiomes—those in patients with chronic conditions, such as Crohn’s disease and type 2 diabetes mellitus. Although this project has been criticised for its lack of diversity in human subjects (primarily sampling from patients in the USA and Europe), it is definitely a step in the right direction.

We still don’t know everything

Despite the plethora of microbiome studies conducted in the past two decades, many mysteries and limitations still remain. As Albert Einstein once said, The more I learn, the more I realise how much I don’t know’. If microbiome research is to live up to the hype, these limitations must be overcome.

Firstly, although ‘omics studies facilitate the identification of microbial taxa, genes, and metabolites in a sample, most microbes found in microbiomes are “unculturable”. In other words, they cannot be isolated and studied under standard laboratory conditions, as they may require unknown nutrients, or even several other microbes, to grow. One example of this is Bacteroides forsythus, a bacteria found in the oral microbiome, which requires N-acetyl muramic acid. This means that analyses can suggest that a specific species or microbial composition is correlated with a particular function, but establishing a causal link is often near impossible.

The gut-brain axis: does correlation equal causation?

The composition of the gut microbiome has been repeatedly correlated with brain and behavioural disorders such as depression, anxiety, and Parkinson’s disease. This connection—dubbed the “gut-brain axis”—was initially met with surprise: do microorganisms in our gut influence our brain, or vice-versa?

The ensuing race to find the answer to these questions is still ongoing. Many studies hint at  potential bidirectional links. However, there are very few convincing arguments for causality, in part due to the inability to isolate and study candidate microbes. Lactobacillus is an exception to this rule. Javier Bravo and colleagues reported that Lactobacillus present in the gut can stimulate the vagus nerve—two bundles of neurons that lead from the gut to the brain. The researchers found that mice treated with a Lactobacillus probiotic (live bacteria administered orally to improve health) had reduced receptor levels in some parts of the brain (the prefrontal cortex and amygdala), but increased neurotransmitter receptor levels in others (the hippocampus).

Additionally, the mice exhibited reduced depressive activity, measured with a forced swim test (FST). Here, mice are placed into a water tank, and the time spent immobile (i.e., not attempting to escape) is measured. This immobility reflects a measure of behavioural despair and is used extensively in evaluations of antidepressant drugs. Not only did the mice behave differently when given the probiotic, but the researchers also reported lower levels of the stress hormone corticosterone. However, in mice whose vagus nerve was severed, no biochemical or behavioural changes were observed. These findings indicate that this neural connection is likely the main route of communication between the gut bacteria and the brain. Although, it should be noted that other routes of communication are possible, such as through metabolic, immune, or endocrine pathways.

Overcoming challenges: Less is not always more

A study similar to the one detailed above would be difficult to conduct with “unculturable” microbes. To overcome this, several methods to culture the “unculturable” are being developed. Synthetic communities (SynComs)—custom-designed communities comprised of a minimal number of microbial taxa (containing only 30–100 species instead of thousands)—are also being utilised for the study of microbial interactions.

This reductionist approach is alluring to those aiming to harness the microbiome’s potential. By examining only a small subset of a larger microbial community, efforts to discover the functions of specific microbes, and harness their benefits, can be streamlined. Possessing the ability to treat brain and behavioural disorders using probiotics is an incredibly appealing scenario. Similarly, what if farmers could improve the nutrient uptake of their crops by inoculating their soil with a precisely designed SynCom?

But what this approach fails to accommodate is the inherent complexity of microbiomes. This leads to the second main limitation of this research field. Microbes interact with one another, with their environment, and with their host (if they have one). By reducing the microbiome down to a small community, or by focusing on one specific microbe (such as a species of Lactobacillus), this strips away many taxa and biological processes that could be crucial. Instead, there is increasing recognition that microbiomes should be investigated in their entirety to understand their function.

Indeed, studies have shown that microbiome dysbiosis—the disruption of a “healthy” microbiome—correlates with altered microbiome functionality. This disruption can be due to perturbations such as tillage of agricultural fields, or the use of broad-spectrum antibiotics in animals.

Importantly, it is often not the presence or absence of any one microbe, but the balance of the entire microbiome that maintains a commensal and stable relationship with a host. However, investigating something of this complexity, and then attempting to harness it for human benefit, is an enormous task. Nevertheless, the Human Microbiome Project, in addition to the plethora of companies focused on microbiomes, are certainly doing their best to achieve this amid the buzz of excitement from both academic spheres and the popular press.

The future looks promising

If microbiome research is to live up to the hype, it needs to start pinpointing more causal links. To do this, we need to develop methods to culture all microbes of interest, and a balance between reductionist and holistic approaches needs to be struck. Nevertheless, this field of research looks set to remain in the spotlight for a little while longer, and rightly so. Microbiome research lies at the intersection between microbiology, ecology, medicine, and bioinformatics. A unification of research fields on this scale is rare, and in itself is a reason to be hopeful for what is to come.