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MILESTONES Credit: Tetra Images / Alamy Stock Photo Tetra Credit: FOREWORD Koch, Escherich, Kendall and a few others, laid the foundations of how we understand host–microrganism interactions. Pasteur developed the A field is born germ theory of disease, but also thought that non-pathogenic micro- “I then most always saw, with of bacteria (although he called them organisms might have an important great wonder, that in the said animalcules at the time) present in role in normal human physiology; matter there were many very little his own mouth and that of others, Metchnikoff believed that microbiota living animalcules, very prettily and subsequently also compared composition and its interactions a-moving.” his own oral and faecal microbiota, with the host was essential for health; — Antonie van Leeuwenhoek. determining that there are differences and Escherich was convinced that between body sites as well as between understanding the endogenous flora Despite being considered by many as health and disease. Some of the first was essential for understanding a relatively modern field of research, direct observations of bacteria were the physiology of digestion and the the first descriptions of human- of human-associated microbiota. pathology and therapy of intestinal associated microbiota date back to Fast-forward a couple of cen- disease. Sound familiar? The themes the 1670s–1680s, when Antonie van turies and, in 1853, Joseph Leidy we explore in these ‘Milestones in Leeuwenhoek started using his newly published a book entitled A Flora human microbiota research’ largely developed, handcrafted microscopes. and Fauna within Living Animals, brought to bear the hypotheses and In a letter written to the Royal Society which some consider to be the early work of these microbiology of London in 1683, he described origin of microbiota research. Then, giants, on the shoulders of which the and illustrated five different kinds the work of Pasteur, Metchnikoff, field stands today. NATURE MILESTONES | HUMAN MICROBIOTA RESEARCH JUNE 2019 | S3 MILESTONES In 1890, Koch published his numbers of existing cells and how 25 milestones, we want to highlight the field [...] famous postulates, four criteria many could grow in the lab, what particular areas of research — both designed to establish a causative rela- became known as the ‘great plate established and burgeoning — that took off in tionship between a microorganism count anomaly’. This key observa- have contributed to a better under- earnest once and a disease, and during the first tion motivated the development standing of our microbial selves, as methods half of the twentieth century, micro- of sequencing-based approaches well as methodological advances to culture biology became more focused on the to identify unculturable micro- that have propelled the field for- identification of etiological agents of organisms, which were pioneered by ward. We also want to highlight anaerobic disease. This was also likely due to Woese, Pace, Fox and others to study important but lesser known aspects organisms were the fact that most bacterial pathogens environmental microorganisms and of the field, such as the fact that our discovered in can grow in the presence of oxygen, subsequently adapted to the analysis microbiota is not just composed of whereas most members of the gut of human-associated communities, bacteria; that human-associated, the 1940s and microbiota cannot and thus could providing an unprecedented view health-promoting microbial com- 1950s, when not be studied at the time. Alfred into their composition. A key step munities exist on all bodily surfaces, members of Nissle, a German physician, isolated in popularising microbiota research, not only our gut; and, importantly, the microbiota the Escherichia coli Nissle 1917 strain which got it into the mainstream that to have a complete picture — which remains a commonly used news and made it a household con- of the functional capacity of our were grown probiotic — in 1917. During World cept, was the finding by the Gordon microbiota and its roles in human and studied in War I, when the first gut eukaryotic group, in 2006, that reconstituting health, we need to look beyond the the laboratory microorganisms and bacteriophages mice with the microbial communities gut of white, Western populations. were also described, Nissle noticed associated with a human disease state We thank the many researchers that one soldier did not succumb to could transplant the phenotype to from all corners of the field who dysentery and thought he might have the animals. This opened the door have advised on the different aspects a protective microorganism in his to research trying to establish causal of this project, as well as those who gut. He isolated the strain and later relationships between altered micro- have participated in the podcasts. showed that it antagonized other bial communities and disease, which It is, of course, impossible to cover pathogens, establishing the concept has become a cornerstone of the field. everything in a field as broad and of colonization resistance, whereby Although the first use of faecal diverse as this one, but we hope to human-associated microorganisms microbiota transplantation (FMT) in have captured the major steps for- prevent the establishment of patho- Western medicine was published in ward. In our attempt to summarise gens in the same niche. 1958 by Ben Eiseman and colleagues, almost 350 years of research, we will Despite these early insights, the who successfully treated four people have unavoidably missed impor- field only took off in earnest once suffering from pseudomembranous tant contributions and sincerely methods to culture anaerobic organ- colitis (before Clostridioides difficile apologize for any unintended over- isms were discovered in the 1940s was the known cause), FMT was sights. Although we have focussed and 1950s, when members of the already used in ancient Chinese these milestones on the study of microbiota were grown and studied medicine. Fourth-century Chinese human-associated microbiota, other in the laboratory. This is where we medical literature mentions its use, vibrant research communities are have chosen to start our timeline of by Ge Hong among others, to treat trying to understand plant- and milestones, as increasing numbers food poisoning and severe diarrhoea. animal-associated, as well as envi- of researchers became interested in In the sixteenth century, Li Shizhen ronmental, microbial communities. understanding the composition and used oral administration of a ‘soup’ We hope that this journey through function of the microbial communi- containing fresh, dry or fermented history will be inspirational and ties that live on our different surfaces stool to treat abdominal diseases. we look forward to the exciting and how they change throughout In seventeenth century Europe, the developments that are sure to come, our lives. The realization that much Italian Fabrizio and the German ultimately aiming to harness our of the normal physiology of conven- Paullini documented the use of FMT, understanding of microbial commu- tional laboratory mice was missing and the American microbiologist nities to improve not only human in germ-free mice, and could be Stan Falkow candidly recalled his health, but that of plants, animals reconstituted through colonization role in preparing first-generation and ecosystems. with bacteria obtained from faeces, poop pills to reconstitute the gut Nonia Pariente, Nature Microbiology enabled the first in vivo experiments. communities of surgical patients a Comparisons of germ-free and year before Eiseman and colleagues FURTHER READING Savage, D. C. Microbial colonised animals in the 1960s led to published their work. biota of the human intestine: a tribute to some pioneering scientists. Curr. Issues Intest. Microbiol. observations that predicted much of We recognize that an enormous 2, 1–15 (2001) | Finegold, S. M. A century of what has since been discovered using body of work precedes each anaerobes: a look backward and a call to arms. Clin. Infect. Dis. 16, 453–457 (1993) | Falk, P. G., methodologies that enable more milestone that we have selected to Hooper, L. V., Midtvedt, T. & Gordon, J. I. Creating and in-depth analyses. Despite advances highlight progress in this field. This maintaining the gastrointestinal ecosystem: what in culturing microorganisms, it soon foreword aims to pay homage to we know and need to know from gnotobiology. Microbiol. Mol. Biol. Rev. 62, 1157–1170 (1998) | became apparent that there were some of these microbiota pioneers. Leidy, J. A Flora and Fauna Within Living Animals gross discrepancies between the With this project, divided into (Smithsonian Institution, 1853). S4 | JUNE 2019 www.nature.com/collections/microbiota-milestone.