Although gut microbiota is by far the most investigated, the blood microbiome has grown in parallel since the early stages

Using his newly developed microscopes, Antonie van Leeuwenhoek described 5 different types of bacteria in feces and observed differences between health and disease.

Pasteur, Metchnikoff, Koch, Escherich, Kendall and others laid the foundations of future human microbiota research. Koch developed the agar plate method to cultivate fecal bacteria and to analyze stools. Early on, Pasteur, Metchnikoff and Escherich foresaw the essential role of the endogenous flora for human health and the importance of understanding the interaction between non-pathogenic microorganisms and their host to comprehend the intestinal physiology and pathologies.

Alfred Nissle isolated the first probiotic bacterial strain, Escherichia coli Nissle 1917, from a soldier who remained unafflicted during a dysentery outbreak and used it as a treatment. He later showed that this bacterial strain prevents the establishment of other pathogens through a colonization resistance mechanism.

Robert E. Hungate revolutionized the culture of anaerobic bacteria with his roll-tube method and successfully cultivated Clostridium cellobioparus, a cellulose-degrading bacterium from bovine rumen. He published a complete description of his approach in 1950 and its adaptations to culture strictly anaerobic methanogens in 1969. (Hungate, J Bacteriol)

After other treatments failed, four patients with pseudomembranous enterocolitis made a successful and rapid recovery after receiving fecal enema from healthy donors (Eiseman et al., Surgery). Fecal microbiota transplantation (FMT) is now widely recognized for helping with recurrent Clostridium difficile infections.

Schadler and colleagues fed germ-free (GF) mice with cultures of several anaerobic bacteria isolated from conventional mice and showed the stability of such microbial transfers for several months as well as the reduction of the typical caecum enlargement in GF mice and their offspring (Schadler et al., J Exp Med)

Early studies described some components of the microbial succession in early life, but in 1981 three landmark studies quantitatively characterized the gut microbiota acquisition in infants and how it is shaped by feeding (Rotimi and Duerden, J Med Microbiol / Tompkins et al., J Hyg / Daoulas et al., Arch Fr Pediatr).

Thanks to the pioneering work of Woese, Pace and others to identify environmental bacteria, Wilson and Blitchington used the 16S rRNA gene sequencing approach to compare cultivated and non-cultivated bacteria in human feces. The bacterial diversity inhabiting the human gut was so far largely underestimated due to the inability to cultivate a large fraction of the microorganisms. (Wilson and Blitchington, Appl Environ Microbiol)

Several studies showed strong relationships between microbiota dysbiosis and diseases leading to the question “what is a healthy microbiota and, what are the normal variations?” A study by the De Vos group first revealed, using a molecular fingerprint approach, the individuality of the microbiota and its stability over time in adults (Zoetendal et al., Appl Environ Microbiol). Much is still unknown regarding the description of a healthy core microbiota and its “normal” dynamics.

Historically, the relationship between the immune system and bacteria was only seen as antagonistic and through the host defense against pathogens. Early studies in germ-free animal models suggested the education of the immune system by infections. Rakoff-Nahoum and colleagues showed that under physiological conditions, the immune system recognizes microbiota commensals through PRRs (Pattern Recognition Receptors) and that this mechanism is essential for tissue repair (Rakoff-Nahum et al., Cell). This study opened a new perspective on the beneficial and symbiotic role of microbiota-immune system interactions.

From blood samples of 60 healthy donors, 35% of the red blood cell fractions and 53% of the plasma-fractions gave positive bacterial cultures, bringing more evidence that at least some members of the healthy blood microbiota are alive and viable (Damgaard et al., PLoSOne).

Turnbaugh and colleagues showed that the obese microbiome harvests more energy from the diet and that the obese phenotype is transferable from obese to lean mice through fecal microbiota transplantation (Turnbaugh et al., Nature). This study confirmed the underlying contribution of the gut microbiome to the pathophysiology of obesity.

The National Institutes of Health launched the HMP, a US community resource program aiming to provide widely available and reliable clinical, analytical and computational tools and protocols. The phase 1 (2008-2012) surveyed the microbiome of 5 major habitats among 242 donors to evaluate whether host health status can be associated with a specific microbial signature.

Funded by the European Union, the MetaHIT consortium gathered 13 partners from 8 countries (Denmark, France, Germany, Italy, Netherlands, Spain, United Kingdom and China) to establish an extensive catalog of genes and genomes of the human intestinal microbiota in health and diseases (inflammatory bowel diseases and obesity).

Thanks to the advances in high-throughput sequencing, the MetaHIT consortium published an extensive gene catalog of the fecal microbiome in a large human cohort of 124 European adults. Qin and colleagues evaluated that the entire cohort harbored around 1,150 bacterial species with the microbiota of each individual comprising at least 160 species (Qin et al., Nature).

Several studies in mouse models showed the gut microbiota effects on behavior, gene expression in the brain and the development of the nervous system and suggested the influence of the gut microbiome on the critical period of brain development (Diaz Heijtz et al., PNAS / Neufeld et al., Neurogastroenterol Motil / Berick et al., Gastroenterol / Bravo et al., PNAS).

The phase 2 of the HMP project (2013-2016) called the integrative HMP aimed to integrate longitudinal and multi-omics data from both the microbiome and the host in pregnancy, preterm birth and the onset of inflammatory bowel diseases and type 2 diabetes. 

Three compelling studies also showed that the short-chain fatty acids derived from the gut microbiota promote the production of regulatory T cells, crucial for the immune homeostasis (Smith et al., Science / Atarashi et al., Nature / Arpaia et al., Nature).

Several studies observed an impact of commonly used medication like metformin and proton-pump inhibitors on the gut microbial communities and bacterial gene expression, which may have beneficial or harmful effects on human health (Tsuda et al., Clin Transl Gastroenterol / Freedberg et al., Gastroenterology / Forslund et al., Nature). Indeed, the Zitvogel’s group showed that the efficiency of cancer immunotherapy depends on distinct Bacteroides species. No antitumor effects of CTLA-4 blockade were observed in antibiotic-treated or germ-free mice (Vétizou et al., Science).

Following earlier preclinical studies in murine models, several human studies showed an association between gut microbiome and response to immunotherapy in cancer patients. Metagenomic studies revealed differences in bacterial diversity and functions in responding patients, suggesting an enhanced systemic and antitumor immunity with a favorable gut microbiome (Routy et al., Science / Gopalakrishnan et al., Science / Matson et al., Science)