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Looking beyond the bacterial gut microbiome

Microbiome Futures Roadmap

Most microbiome research to date has focused on the bacterial gut microbiome, and yet microbiomes are comprised of a wide array of microbes – from viruses and archaea to protozoa and yeasts – and colonize nearly every human body site – from the skin and lungs to the urogenital system and breast milk. But, because the predominant group of microbes in human microbiomes is bacteria, the gut hosts the largest microbiome by far of all human body sites, and the gut is viewed as the largest interface between the human immune system and the microbiome, the bacterial gut microbiome has drawn the lion’s share of research and translational attention.

Here, I take a closer look at factors beyond scale that have contributed to this state of affairs, and what is being done to rectify this.

Bacterial Bias

Humans play host to a diverse microbiome that includes trillions of microbes – from viruses, bacteria, and archaea, to eukaryotic organisms such as protozoa, yeasts, and helminth parasites. The study and characterization of this ecosystem, however, has been heavily skewed toward its bacterial component (see The Bacterial Bias in Microbiome Research).

bacterial-bias-microbiome-graph

Database: PubMed.gov; data span: 1/1/2010 to 3/31/2018; search terms: “(microbiome | microbiota | microflora) (human)” and one of the following, “(Bacterium | Bacteria)”, “(Parasite | Parasites)”, “(Protozoan | Protozoa)”, “(Archaeon | Archaea)”, “(Helminth | Helminths)”, “(Virome)”, “(Mycobiome)”, “(Protist | Protista)”, respectively.

A prime reason for this has been the overwhelming natural dominance of bacteria in the human microbiome, which often masks the genetic, physiological and metabolic contributions of other groups. However, two other equally important factors are the prevalent use early on of 16S ribosomal RNA (rRNA) gene sequencing, which limited microbiome characterization to its bacterial and archaeal components, and more recently, inadequate bioinformatic tools to analyze non-bacterial sequence data due to a lack of robust and curated databases cataloguing non-bacterial microbes.

“Microbiome research was bacterio-centric in origin due to a 16S analytical constraint carried over from the microbial ecology field. With the development of next-generation sequencing metagenomic approaches, microbiome research has now become more inclusive of other microbial groups.” says Elodie Ghedin, professor of biology and global public health at New York University and director of the university’s Center for Genomics and Systems Biology. “The caveat is that work on microbiome components such as the virome or the mycobiome is still playing catch up with the bacterial component in terms of basic identification and characterization of the players.”

Indeed, the advent of next-generation shotgun metagenomics approaches that allow the integrated analysis of what some have coined the multibiome – the biodiverse collection of bacteria, archaea, viruses, and eukaryotic microbes that makes up a microbiome – has been instrumental.

But more importantly, it is the development of improved sampling methodologies and of robust genetic markers to optimize the identification of non-bacterial players that is greatly advancing our understanding of how the microbiome operates.

The next challenge will be to integrate microbe group-specific information at different biological levels – genomic, transcriptomic, proteomic, and metabolomic – in ways meaningful to understand basic microbiome biology and to identify potential avenues for translation. According to Ghedin, “the key will be to refine both the sampling and data collection processes as well as the bioinformatics tools to analyze the data to arrive at a robust, consistent and comprehensive picture of relevant intra-microbiome and host-microbiome interactions.”

Gut Bias

At every human body site colonized by a microbiome, a complex set of host-microbe interactions unfolds that helps process and channel environmental cues to the host and regulate the composition and dynamics of the microbiome itself. These host-microbe interactions are mediated by a range of human cells – from epithelial and non-epithelial cells to innate and adaptive immune cells.

Because of size and accessibility, the gut microbiome has been the most well studied human microbiome (see The Gut Bias in Microbiome Research). Yet other sites such as skin or the uterus-cervix-vagina axis are recognized as hosting microbiomes that also play key roles in aspects such as protecting us from infections and establishing an infant’s seed microbiome at birth, respectively.

gut-bias-microbiome-graph

Database: PubMed.gov; data span: 1/1/2010 to 3/31/2018; search terms: “(microbiome | microbiota | microflora) (human)” and one of the following, “(Gut | Colon | Intestinal)”, “(Oral | Mouth | Tongue | Tooth | Subgingival | Supragingival)”, “(Skin | Cutaneous)”, “(Urogenital | Vaginal | Penile)”, “(Airway | Lung)”, “(Breast Milk)”, “(Ocular | Eye)” “(Placenta)”, respectively; adapted and updated from Lloyd-Price et al..

“Microbiome research beyond the gut faces two hurdles: accessibility and density. The gut microbiome can be accessed relatively easily, either directly or through fecal matter analysis, and the amount of biomaterial available is in the tens to hundreds of grams and billions to trillions of cells,” points out Leopoldo Segal, assistant professor at the New York University School of Medicine. “Once you leave the gut, accessibility and/or biomass diminish exponentially.”

Yet, and despite the technical difficulties to study non-gut human microbiomes, we now know that local interactions of those microbiomes with the immune system and other non-immunological processes are of great relevance to understanding health and disease in humans.

The lung, for example, once considered a sterile environment, has now been shown to contain a diverse, low-density microbiome that, in turn, has been implicated in the local and systemic Th17-driven inflammatory response to acute and chronic lung disease.

Moreover, adds Segal, “the complex role the microbiome plays in modulating drug activity in lung, specifically of macrolides in emphysema patients, and in regulating the inflammatory response, is an example of how complex and relevant the interactions between the microbiome and its specific host niche, and between the different microbial groups within the microbiome can be.”

Efforts to better understand the lung microbiome and other non-gut microbiomes include the design of less invasive sampling methodologies, and of comprehensive longitudinal studies that provide the means to decipher the chronology of events in dysbiosis.

And some are already preparing for the next wave of research…

“The first wave of microbiome research consisted of describing the microbial components of the microbiome; a second wave focused on characterizing the intra-microbiome and host-microbiome interactions within specific sites,” observes Ghedin. “But it is a third wave of microbiome research, zooming in on the crosstalk among sites and site-specific microbiomes that is helping us truly understand how the different human microbiomes and their microbial players are interconnected to make a human human.”

The next event in our Microbiome series is the 6th Microbiome R&D and Business Collaboration Forum: USA. Read the agenda here.

Microbiome Futures 2018-Global Engage

Gaspar Taroncher-Oldenburg is Consultant-in-Residence for Global Engage. He was previously Founding and Managing Editor of Nature’s SciBX: Science-Business eXchange (now BioCentury Innovations) and scientific editor of Nature Biotechnology.

2 Responses to “Looking beyond the bacterial gut microbiome”

  1. Bridget Fomenky

    Very intersting observation, microbiome data analysis for other microbes aprt from bacteria using high throughput sequencing is more complicated and expensive(one good reason)

    Reply
    • Gaspar Taroncher-Oldenburg

      Indeed, Bridget, and most of the effort will have to come not from the sequencing effort itself but from the basic characterization of what sequence represents what kind of organism and how to look for it (biomarkers…!)

      Reply

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