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The human microbiome – a new frontier

Research and business opportunities in clinical microbiomics

The microbiome is more than bacteria

The vast majority of human-related microbiology focuses on bacteria – the human bacteriome. Frequently, the term “microbiome” is incorrectly confused with “bacteriome”. Advances in DNA sequencing and culturomics have opened the door on the human “mycobiome”, expanding interest beyond bacteria into fungal effects on multiple facets of human health.

The “microbiome” versus the “bacteriome”

Over the past two decades, the human microbiome has exploded into both the public and scientific conscience, generating tens of thousands of publications and patents. However, confusion remains regarding the importance, and even membership, of the human microbiome. 

Technically, the microbiome consists of all microbes; archaea, bacteria, fungi, and viruses. Early researchers focused on bacteria, due to new sequencing tools which broadly identify most known and many previously unknown and uncultivable bacteria, called “16S” sequencing. 

While these new findings catapulted the term “microbiome” into common usage, 16S methods are limited to bacteria. As a matter of fact, so much historical research has been conducted solely on bacteria that the term “microbiome” is now frequently and incorrectly substituted for “bacteriome”. 

The term “microbiome” is intended to describe complex microbial communities including all microbial genomes present in a system. When using 16S methods only the proper term is “bacteriome”. It is also relevant to clarify the difference between “microbiome” and “microbial community”. The microbiome refers to the detectable microbial genomes in a system. When referring to microbes or their activity, one should refer to the “microbial community”, which describes the living microbes contributing biology to the system.

The “mycobiome” and fungi

Development of the fungal-specific ITS (intergenic transcribed spacer) and metagenomic tools have empowered study of a more complete “microbiome”. These methods have empowered expanded interest in “eukaryotic microbes” including fungi. Fungi have been historically difficult, being much more closely related to humans (with a cell nucleus and chromosomes), extremely difficult to grow in culture, and having complex lifestyles involving sexual reproduction. 

Fungi consist of multiple large groups: yeasts such as the famous “Saccharomyces cerevisiae” which makes beer, wine and bread; filamentous fungi such as the mushrooms; moulds such as the dreaded black moulds which contaminate buildings (e.g. Stachybotrys chartarum), the pesky green fluff that grows on your oranges (Penicillium digitatum); and rusts, such as the citrus rusts devastating US citrus groves (Pucciniales species).

Public and research interest has also grown due to newly evolved fungi wiping out entire species, such as the American bat by white-nose syndrome (P. destructans) and many frog species (Batrachochytrium dendrobatidis). These developments have vastly increased research into the mycobiome into greater focus. 

The human mycobiome and skin

Historically, microbial research into human systems was on disease. The common and lethal effects of bacterial infection, coupled with the development of antibiotics (antibacterials), caused research into the effects of bacteria on human health to quickly advance beyond that of fungi. 

Most research on the fungal mediated disease was related to rare disorders until medical advances created a new and more susceptible class: immunocompromised individuals. During the late twentieth century, fungal diseases such as thrush (oral candidiasis), pulmonary aspergillosis, and cryptococcal brain infections became more and more common. 

While these infections spurred an increase in human fungal research, the rarity of the diseases and the research complexity held (and still holds) back research in the area. Interestingly, the majority of fungal research remains in agriculture and focuses on economically important pests including rice blast (Magnaportha) and corn smuts (Ustilago).

A significant chunk of human mycobiome research now focuses on skin, as fungi are a larger percentage of skin than gut microbiomes, at 5-10% of skin microbial genomes versus less than 1% in the gut. Also, the skin mycobiome is less complex and dominated by a single group, with 50-80% of eukaryotic genomes belonging to a single clade named Malassezia. 

It is also critical to note that while it is accepted that 5-10% of the “genomes” on skin represent fungi, Malassezia (at 8-10μg in diameter) are significantly larger than bacteria (at 0.8-1.0μg). Thus, the fungal “active biomass” is likely much greater than 10% of the microbiome. Hence, Malassezia has been an important and under-researched segment of the human microbial community.

Together, advances in fungal research represent a step-change in our ability to assess the functional role of the mycobiome in human disease. We now have tools to better explore the fungi living on/in and contributing to human biological systems. New culture techniques have enabled detailed investigation into fungal biology, and genetic engineering has enabled mechanistic dissection of their role in health and disease. 

This ability to dissect the mechanistic steps in microbe-host interactions should enable a deeper understanding of the fungal/host relationship, faster progress into development of new potential intervention targets, and more effective future treatments.

Future posts will dive into more detail on human skin microbiology, Malassezia, and the role of the mycobiome in human disease.

Thomas Dawson is Senior Principal Investigator at the Institute of Medical Biology, A*STAR, Singapore.

The 7th Microbiome and Probiotics R&D and Business Collaboration Forum will bring together 400+ leaders in industry, research and business to discuss cutting-edge research and commercialisation strategies. Find out more here.

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