Despite being considered by many as a relatively modern field of research, the first descriptions of human-associated microbiota date back to the 1670s–1680s, when Antonie van Leeuwenhoek started using his newly developed, handcrafted microscopes. In this Foreword, we highlight the foundations of the field.Read more
Research into human-associated microbiota has come a long way since Antonie van Leeuwenhoek first began to study microorganisms back in the 17th century. What advances allowed researchers to move from seeing single cells to studying complex microbial communities? In this audio, we hear from microbiologist David Relman, who spoke with Anand Jagatia.
In a 1944 study of cellulose-degrading microorganisms in the bovine rumen, Robert. E. Hungate’s revolutionary roll-tube approach enabled the successful culture of an anaerobe. This culture method, which is still in use to this day, enabled the first isolation of human-associated anaerobes.Read more
In 1958, a study reported the successful treatment of pseudomembranous enterocolitis using a faecal enema. Since then, faecal microbiota transplantation has become widely accepted as a successful rescue treatment for recurrent Clostridioides difficile infection.Read more
In 1965, a new use for germ-free animals was introduced: the transfer of bacterial cultures to germ-free mice. Such transfer experiments have been essential in studying the effects of the gut microbiota on the host ever since.Read more
By Lucia Brunello
Taren M. Thron, California Institute of Technology
Peppercorn and Goldman demonstrated that the anti-inflammatory drug, salicylazosulfapyridine, could be degraded in conventional rats and when cultured with human gut bacteria, but not in germ-free rats, indicating a role for the gut microbiota in drug transformations. An increasing number of studies have confirmed the role of the microbiota, not limited to the gut, in drug metabolism and highlighted the implications for drug inactivation, efficacy and toxicity.
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Koppel, N., Maini Rekdal, V. & Balskus, E. P. Chemical transformation of xenobiotics by the human gut microbiota. Science356, eaag2770 (2017)
Early studies, dating as far back as 1900, described various aspects of bacterial succession in infants, but in 1981, three studies were reported that set out to quantitatively characterize early acquisition of gut commensals and to study how feeding shapes our initial microbiota.Read more
By Ashley York
S. Bradbrook / Springer Nature Limited
The microbes that live with us from cradle to grave
Inside your body there are trillions of microscopic organisms: bacteria, viruses, fungi and archaea - collectively known as the microbiota. Over the past decade, we’ve learnt that these communities help to shape our physiology and contribute to our wellbeing. But there are still many questions: When do we acquire our first microbes? How does our microbiota change throughout our lives and how do these changes differ between people or contribute to disease?
In 1996, human-associated microbiota was characterized using sequencing-based methods. The study analyzed the diversity of cultivated and noncultivated bacteria within a human faecal sample using 16S ribosomal RNA sequencing.Read more
In 1998, a study used 16S ribosomal RNA gene amplification and temperature gradient gel electrophoresis (TGGE) to visualize the diversity of faecal bacteria in 16 adults, revealing that each individual has their own unique microbial community. By monitoring two individuals over time, the researchers showed that their TGGE profiles were stable over a period of at least six months. Subsequent studies have investigated microbial stability over longer time periods.Read more
Viruses, fungi and archaea are also important members of our microbiota, with potential effects on human health. In 2003, the first metagenomics analysis of an uncultured viral community from human faeces was reported.Read more
Two studies revealed how the immune system senses our microbiota and how bacteria modulate immune system development under normal conditions. These findings opened a new perspective on immune response to microorganisms not as host defence, but as a symbiotic physiological process.Read more
Our gut microbiome harbour thousands of genes involved in breaking down dietary substrates from which they obtain energy. In 2005, a study showed that a change in diet alters the degradative activity of the colonic microbiota.Read more
Researchers found that human phenotypes could be reproduced in mice by faecal microbiota transplantation. This first study using faeces from obese and lean humans paved the way for investigating mechanistic links between the microbiota and human phenotypes.Read more
From 2006, numerous studies have highlighted the crucial impact that diet can have on the gut microbiota and host metabolism, the resulting implications for human health, and how we can use our knowledge of these interactions to develop nutrition-based treatments.Read more
Colonization resistance (the process by which our microbiota prevents the establishment of pathogens) had been observed in earlier studies, but in 2007, three key papers provided initial insights into the mechanistic basis of this process.Read more
Eline Klaassens and colleagues applied a metaproteomics approach to uncultured faecal microbiota, providing the first insights beyond taxonomic identification. This was followed by numerous studies using ‘omics methods, such as metabolomics and metatranscriptomics, as well as the development of multi-omics pipelines; methods that are still uncovering the functions of the microbiota today.
ORIGINAL ARTICLE Klaassens, E. S., de Vos, W. M. & Vaughan, E. E. Metaproteomics approach to study the functionality of the microbiota in the human infant gastrointestinal tract. Appl. Environ. Microbiol.73, 1388–1392 (2007).
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Antibiotics not only act on bacteria that cause infections but also affect the resident microbiota. In 2008, a study revealed that treatment of healthy individuals with ciprofloxacin influenced the abundance of approximately one third of bacterial taxa in faecal samples.Read more
The software pipeline QIIME, which stands for ‘quantitative insights into microbial ecology’, enables the analysis and interpretation of the increasingly large datasets generated by microbiome sequencing.
ORIGINAL ARTICLE Caporaso, J. G. et al. QIIME allows analysis of high-throughput community sequencing data. Nat. Methods7, 335–336 (2010).
Advances in metagenomics and high-throughput sequencing in the early 2000s inspired projects aimed at capturing microbiome diversity in large human populations. Large population studies have greatly advanced our understanding of microbiome diversity and have identified numerous potential links to health and disease, inspiring many new research avenues.Read more
In 2011, several experimental findings in mice shed light on how a lack of conventional microbiota affects behaviour, gene expression in the brain and the development of the nervous system. More recent studies in humans are revealing potential links between the microbiota and our nervous system.Read more
High-throughput anaerobic culturing enabled the recovery of a large part of the diverse human gut microbiota and the creation of individual culture collections.
ORIGINAL ARTICLE Goodman, A. L. et al. Extensive personal human gut microbiota culture collections characterized and manipulated in gnotobiotic mice. Proc. Natl Acad. Sci. USA108, 6252–6257 (2011).
Genetic variation occurs between human populations living in different places, but little was known about variation in microbiomes. To investigate how gut microbiomes differ among human populations, Yatsunenko et al. characterized bacterial species in faecal samples from cohorts living in different regions, including the Amazonas of Venezuela, rural Malawi and US metropolitan areas. The authors found pronounced differences in the composition and functions in the gut microbiomes between these geographically distinct cohorts.
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Nayfach, S., Shi, Z. J., Seshadri, R., Pollard, K. S. & Kyrpides, N. Novel insights from uncultivated genomes of the global human gut microbiome. Nature https://doi.org/10.1038/s41586-019-1058-x (2019)
Regulatory T cells (Tregs) are crucial in maintenance of immune homeostasis. In 2013, three studies found that microbiota-derived short-chain fatty acids promote the expansion and differentiation of Tregs, revealing a form of chemical-mediated communication between the commensal microbiota and the immune system that affects immune mechanisms.
ORIGINAL ARTICLES
Smith, P.M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science341, 569–573 (2013)
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Identification of biosynthetic gene clusters for antibiotics in the genomes of the human microbiota, suggests new sources of antimicrobial drugs whose species-specific production has the potential to modulate the local microbial community structure.
ORIGINAL ARTICLE Donia, M. S. et al. A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics. Cell158, 1402–1414 (2014).
Commonly used medications affect gastrointestinal microbial abundances and bacterial gene expression, which may both positively and negatively contribute to the effects on human health associated with drug treatment.
ORIGINAL ARTICLES
Tsuda A et al. Influence of proton-pump inhibitors on the luminal microbiota in the gastrointestinal tract. Clin. Transl. Gastroenterol.6, e89 (2015)
Freedberg, D. E. et al. Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial. Gastroenterology149, 883–885 (2015)
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Following earlier studies in mouse models, gut microbiota composition was shown to affect the response of melanoma patients, and those suffering from advanced lung or kidney cancer, to immune checkpoint therapy, as well as tumour control.
ORIGINAL ARTICLES
Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science359, 91–97 (2018)
Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients Science359, 97–103 (2018)
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Advances in computational methods, recently pioneered in the environmental microbiology field, enable the reconstruction of bacterial genomes from metagenomic datasets. This approach was used to identify thousands of new uncultured candidate bacterial species from the gut and other body sites, of global populations from rural and urban settings, substantially expanding the known phylogenetic diversity and improving classification of understudied, non-Western populations.
ORIGINAL ARTICLES
Pasolli, E. et al. Extensive unexplored human microbiome diversity revealed by over 150,000 genomes from metagenomes spanning age, geography, and lifestyle. Cell176, 649–662 (2019)
Almeida, A. et al. A new genomic blueprint of the human gut microbiota. Nature568, 499–504 (2019)
Nayfach, S. et al. New insights from uncultivated genomes of the global human gut microbiome. Nature568, 505–510 (2019)
Where is microbiota research headed? What needs to be done for this field to live up to its promise? In a roundtable discussion, Anand Jagatia puts these questions to Rochellys Heijtz, Jennifer Wargo and Eran Elinav, three researchers at the cutting-edge of the discipline.