Milestone |

Milestones in human microbiota research

The human body is home to trillions of microorganisms that have direct and indirect impacts on health and disease. The microbiota that resides on and within us is a diverse community of bacteria, archaea, viruses, and fungi. This ‘Milestones in Human Microbiota Research’ provides a historical perspective of the breakthroughs in the field as well as future research directions.

This Milestone is editorially independent, produced with financial support from a third party. About this content.

Interactive milestone

Milestone articles and podcasts

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.

Milestones |

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.

Milestones |

Reviews

Culturomics was developed to culture and identify unknown bacteria that inhabit the human gut. In this Review, Raoult and colleagues discuss the development of culturomics and how it has extended our understanding of bacterial diversity, and highlight the potential implications for human health.

Review Article | | Nature Reviews Microbiology

Intestinal regulatory T cells (Tregcells) are distinct from those in other organs and function to maintain tolerance to harmless dietary antigens and commensal microorganisms. The unique features of these cells, as well as the signals involved in their development and maintenance, are discussed in this Review.

Review Article | | Nature Reviews Immunology

Current nutritional approaches to prevent and treat various diseases have limited effectiveness. Here, Zmora et al. review the major principles underlying effects of dietary constituents on the gut microbiota, resolving aspects of the diet–microbiota–host crosstalk, and present the promises and challenges of incorporating microbiome data into dietary planning.

Review Article | | Nature Reviews Gastroenterology & Hepatology

Complex microbial communities shape the dynamics of various environments. In this Review, Knight and colleagues discuss the best practices for performing a microbiome study, including experimental design, choice of molecular analysis technology, methods for data analysis and the integration of multiple omics data sets.

Review Article | | Nature Reviews Microbiology

The microbiota can influence host behaviour through the gut–brain axis. In this Opinion, Johnson and Foster explore the evolution of this relationship and propose that adaptations of competing gut microorganisms may affect behaviour as a by‑product, leading to host dependence.

Perspective | | Nature Reviews Microbiology

Faecal microbiota transplantation (FMT) has emerged as a successful treatment forClostridium difficileinfection (CDI). Here, the authors describe the latest information on the mechanisms of action of FMT in the context of CDI and how it might restore the gut microbial community and structure. They also explore future applications of FMT beyond CDI.

Review Article | | Nature Reviews Gastroenterology & Hepatology

The gut microbiota, traditionally studied in the context of disease, has emerged as a key regulator during normal homeostasis. Here, Sommer and Bäckhed discuss how the gut microbiota promotes the development and homeostasis of the immune system and orchestrates several aspects of human physiology, including tissue morphogenesis, metabolism and even behaviour.

Review Article | | Nature Reviews Microbiology

The resilience of the microbiota can protect us from disease, but a resilient dysbiotic microbiota may also cause disease. This Opinion article discusses the concepts and mechanisms of microbial resilience against dietary, antibiotic or bacteriotherapy-induced perturbations and the implications these have for human health.

Opinion | | Nature Reviews Microbiology

Over ten years, the Human Microbiome Project has provided resources for studying the microbiome and its relationship to disease; this Perspective summarizes the key achievements and findings of the project and its relationship to the broader field.

Perspective | Open Access | | Nature

Research

The human gut microbiome is thought to be shaped by both host diet and genetics. Using a sample set of more than 500 individuals belonging to around 150 families from three different countries, Yatsunenko et al. analyse the impact of both factors on the composition and functional repertoire of the fecal microbiota.

Article | | Nature

Whole-genome shotgun sequencing and sequencing of the gene encoding the 16S rRNA in samples from a variety of body sites in a large cohort of mothers and their infants reveals that, during the 6 weeks after birth, changes in the composition and function of the microbiome are driven by body site but not by the mode of delivery.

Article | | Nature Medicine

Childhood malnutrition is a major health problem in many low-income countries, and although mortality can be reduced by therapeutic food interventions, it is difficult to achieve complete restoration of healthy growth in cases of severe acute malnutrition. Here Jeffrey Gordon and colleagues identify a group of 24 bacterial species whose proportional representation in the microbiota defines how a healthy microbiota assembles over the course of the first two postnatal years in a cohort of healthy children in Bangladesh. They define a 'relative microbiota maturity index' and 'microbiota-for-age Z-score' that allow comparison across individuals and use these indices to demonstrate that severe malnutrition is associated with significant relative microbiota immaturity that is only partially ameliorated by two widely used nutritional interventions. This work suggests that more prolonged food-based interventions and/or addition of gut microbes may be needed to achieve durable repair of microbiota immaturity in childhood malnutrition and improved clinical outcomes.

Letter | | Nature

A collaboration between members of the European MetaHIT and American NIH Human Microbiome projects has led to the development of a framework for metagenomic variation analysis, which is used to analyse single nucleotide polymorphisms, short indels and structural variants in 252 faecal metagenomes of 207 individuals from Europe and North America. Variation patterns suggest that individuals might have unique metagenomic genotypes that could provide data relevant to personalized dietary or drug choices.

Article | | Nature

Microbiologists are beginning to understand how and why mammals are colonized by multitudes of symbiotic bacteria. But what differentiates 'good' from benign or harmful bacteria remains largely unknown. The intestinal microbe Bacteroides fragilis was shown in 2005 to have profound effect on the mammalian immune system, an effect ascribed to a single molecule, capsular polysaccharide A (PSA). Now B. fragilis PSA is shown to protect animals against both bacterial and chemical colitis in a process involving interleukin-10-producing T cells. This suggests that B. fragilis helps maintain human health by suppressing the intestinal inflammatory response, and that symbiosis factors may provide a route to new therapies. In the cover graphic (by Tom DiCesere, Sarkis Mazmanian & Dennis Kasper), In the cover graphic, PSA (yellow) surrounds B. fragilis (green) in the intestine and is taken up by a dendritic cell and processed within the endosomal pathway to a reduced molecular size. The depolymerized PSA is presented by the major histocompatibility complex class II molecule to the CD4+ T cell (green, white, yellow), which becomes activated. Work in this field is being promoted by several major efforts to characterize the human microbiota and determine its role in health and disease, including the Human Microbiome Project. In News Features, Asher Mullard examines the various approaches, and Apoorva Mandavilli reports on a rare opportunity to watch the gut being colonized from scratch after intestinal transplants.

Article | | Nature

The incidence of autoimmune diabetes in NOD (non-obese diabetic) mice, a lab model for type 1 diabetes, varies depending on the conditions in which they are kept. In particular, NOD mice exposed to killed mycobacteria and other microbial products are protected against the development of diabetes, suggesting the involvement of the rapid innate immune response. Experiments in NOD mice deficient in innate immunity — through the absence of the Toll-like receptor signal adaptor protein MyD88 — now show that both innate immunity and intestinal microbiota influence predisposition to diabetes. Germ-free MyD88-negative mice developed robust diabetes, yet in mice with a complement of gut microbes similar to the normal human gut, diabetes was reduced. This raises the prospect that live 'friendly' microbes, or microbial products might be therapeutic options for type 1 diabetes.

Letter | | Nature

Finely tuned control of strain engraftment and abundance in the mouse gut microbiota was achieved using the marine polysaccharide porphyran, which could exclusively be used by an introduced subset of wild-type or genetically modified Bacteroides strains.

Letter | | Nature

Our gut microbes do us a service by performing metabolic chores that we have not evolved to do for ourselves. In a sense their genes are part of the 'metagenome' that is Homo sapiens. That is illustrated by two related papers in this issue that present evidence for a microbial component to obesity. A study of the abundance of the two dominant groups of bacteria in the gut of obese individuals shows that increased numbers of Bacteroidetes bacteria correlate with weight loss. And a study of genetically obese mice reveals that their gut microbial community has a greater capacity for harvesting energy than that of lean littermates: the trait is transmissible by transplanting the community into germ-free mice. This work suggests that the gut microbiome associated with obesity might be a biomarker and possibly a therapeutic target.

Article | | Nature

Our gut microbes do us a service by performing metabolic chores that we have not evolved to do for ourselves. In a sense their genes are part of the 'metagenome' that is Homo sapiens. That is illustrated by two related papers in this issue that present evidence for a microbial component to obesity. A study of the abundance of the two dominant groups of bacteria in the gut of obese individuals shows that increased numbers of Bacteroidetes bacteria correlate with weight loss. And a study of genetically obese mice reveals that their gut microbial community has a greater capacity for harvesting energy than that of lean littermates: the trait is transmissible by transplanting the community into germ-free mice. This work suggests that the gut microbiome associated with obesity might be a biomarker and possibly a therapeutic target.

Brief Communication | | Nature

Bifidobacteria, sometimes used in yoghurts and other food products as 'probiotics', are natural inhabitants of the human gut and are known to protect us from infection. A possible mechanism for at least part of that protective action has now been found in the form of acetate. Oral application of a subtype of Bifidobacterium longum in mice seems to protect them from potentially fatal Escherichia coli O157:H7 by promoting host-defence mechanisms in epithelial cells.

Letter | | Nature

Antibiotic treatment can kill many members of the normal commensal gut microbiota, leaving patients susceptible to intestinal infection. Among infections that can result from antibiotic-mediated commensal flora destruction, Clostridium difficile colitis is one of the most common and difficult to treat. Eric Pamer and colleagues screened the mouse microbiota with a panel of antibiotics and looked for distinct microbiota changes associated with susceptibility to C. difficile. They identified resistance-associated microbiota constituents common to mice and humans, including Clostridium scindens, which they show confers resistance to infection by synthesizing C. difficile-inhibiting metabolites from host-derived bile salts. These findings could point the way towards novel approaches to the treatment and prevention of C. difficile colitis such as replenishment of secondary bile acids or biosynthesis-competent bacteria as adjuncts to faecal microbiota transplants.

Letter | | Nature

The Human Microbiome Project (HMP), supported by the National Institutes of Health Common Fund, has the goal of characterizing the microbial communities that inhabit and interact with the human body in sickness and in health. In two Articles in this issue of Nature, the HMP Consortium presents the first population-scale details of the organismal and functional composition of the microbiota across five areas of the body. An associated News & Views discusses the initial results — which, along with those of a series of co-publications, already constitute the most extensive catalogue of organisms and genes related to the human microbiome yet published — and highlights some of the major questions that the project will tackle in the next few years.

Article | Open Access | | Nature

The Human Microbiome Project (HMP), supported by the National Institutes of Health Common Fund, has the goal of characterizing the microbial communities that inhabit and interact with the human body in sickness and in health. In two Articles in this issue of Nature, the HMP Consortium presents the first population-scale details of the organismal and functional composition of the microbiota across five areas of the body. An associated News & Views discusses the initial results — which, along with those of a series of co-publications, already constitute the most extensive catalogue of organisms and genes related to the human microbiome yet published — and highlights some of the major questions that the project will tackle in the next few years.

Article | Open Access | | Nature

The composition of the human gut microbiome is determined by many factors. Eran Segal and colleagues performed an extensive statistical analysis of the largest metagenomics-sequenced human cohort so far to determine the contribution of host genotype to microbiome composition. Host genetics has only a minor influence on microbiome variability, which is more strongly associated with environmental factors such as diet. The authors propose a 'microbiome-association index' that describes the association of the microbiome with host phenotype. Combining this measurement with host genetic and environmental data improves the accuracy of predictions about several human metabolic traits, such as glucose and obesity traits.

Article | | Nature

As part of the second phase of Human Microbiome Project, the Multi-Omic Microbiome Study: Pregnancy Initiative presents a community resource to help better understand how microbiome and host profiles change throughout pregnancy as well as to identify new opportunities for assessment of the risk of preterm birth.

Article | Open Access | | Nature Medicine

Deep profiling of transcriptomes, metabolomes, cytokines, and proteomes, alongside changes in the microbiome, in samples from individuals with and without prediabetes reveal insights into inter-individual variability and associations between changes in the microbiome and other factors.

Article | Open Access | | Nature

The Inflammatory Bowel Disease Multi’omics Database includes longitudinal data encompassing a multitude of analyses of stool, blood and biopsies of more than 100 individuals, and provides a comprehensive description of host and microbial activities in inflammatory bowel diseases.

Article | Open Access | | Nature

Gut microbes influence our health and may contribute to human adaptation to different lifestyles. Here, the authors describe the gut microbiome of a community of hunter-gatherers and identify unique features that could be linked to a foraging lifestyle.

Article | Open Access | | Nature Communications

Imbalances of the gut microbiota significantly contribute to inflammatory and allergic states, and therefore the manipulation of gut microbes holds promise for treating these immune disorders. This paper reports the isolation of 17 strains of human-derived Clostridia capable of stimulating the immune response by inducing the accumulation and functional maturation of regulatory T cells. Oral administration of a cocktail of these Clostridia attenuates disease in mouse models of colitis and allergic diarrhoea, suggesting that these strains may be candidates for the development of oral bacterial therapeutics to treat inflammatory disorders.

Letter | | Nature

Several lines of evidence indicate that subsets of commensal microbes shape the gut immune system. For instance, colonization with Clostridia promotes extrathymic generation of regulatory T (Treg) cells that have a central role in the suppression of inflammatory and allergic responses. However, the molecular basis of such microbe-mediated Treg induction remains unknown. Two papers in this issue of Nature show that the colonic microbial fermentation product butyrate significantly accelerates the differentiation of colonic Treg cells and ameliorates colitis in conjunction with an increase in histone H3 acetylation at the Foxp3 promoter. This finding links butyrate to the induction of functional Treg cells in the colonic mucosa, and also provides molecular insight into the therapeutic application of butyrate.

Letter | | Nature

The majority of systemic bacterial infections are caused by endogenous pathogens from human microbiota, and the opportunistic pathogen Staphylococcus aureus, commonly found in the external opening of the nostrils, is one of the most clinically important because of the prevalence of multi-drug resistant strains. The mechanisms that permit or interfere with pathogen colonization have remained unclear. This study shows that S. lugdunensis, a commensal bacterium that shares the nasal niche with S. aureus and is associated with a reduced S. aureus carriage rate in humans, produces a novel cyclic peptide antibiotic (lugdunin) that inhibits colonization by S. aureus in animal models. Lugdunin is bactericidal against major pathogens and not prone to causing development of resistance in S. aureus, suggesting that lugdunin or lugdunin-producing commensals could be valuable for preventing staphylococcal infections.

Article | | Nature

There is growing evidence from metagenome-wide association studies that several common human disorders, such as type 2 diabetes mellitus (T2D), are associated with intestinal dysbiosis, an unhealthy imbalance of the gut microbiota. However, the contribution of antidiabetic drug treatment to dysbiosis is often not accounted for. Oluf Pedersen and colleagues analysed two previous metagenomic studies of T2D patients that yielded divergent conclusions regarding the association of the disease with dysbiosis, together with a novel cohort, to determine the effects of the widely prescribed antidiabetic drug metformin. They find that metformin is indeed a confounding factor, but that a unified signature of gut microbiome shifts in T2D is still apparent.

Letter | | Nature

A consortium of 11 bacterial strains from the healthy human gut microbiota can strongly induce interferon-γ-producing CD8 T cells in the intestine, and enhance both resistance to bacterial infection and the therapeutic efficacy of immune checkpoint inhibitors.

Article | | Nature

The known species repertoire of the collective human gut microbiota is substantially expanded with the discovery of 1,952 uncultured bacterial species that greatly improve classification of understudied African and South American samples.

Article | Open Access | | Nature