Beyond Infectious Disease: Welcome to the Era of Population Microbiology

Matthew R. Pincus, MD, PhD Matthew.Pincus2@va.gov,     SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA

Zhiheng Pei, MD, PhD, FASCP zhiheng.pei@va.gov,     New York University Medical Center, 550 First Avenue, New York, NY 10016, USA

The emergence of the germ theory of disease coupled with Robert Koch’s famous postulates has shaped nearly all aspects of clinical microbiology since the late nineteenth century and laid the foundation for a new medical discipline: infectious diseases. Under the guidance of the one pathogen-one disease paradigm, many diseases have been demonstrated to have a microbial cause and are classified as infectious diseases. The paradigm also provides essential principles in research and development of specific diagnosis with pathogen isolation and identification, targeted treatment with antibiotics, and effective prevention with vaccines. The development of the infectious disease concept is one of the greatest achievements in public health that alone contributed to a sharp drop in infant and child mortality and to the 29.2-year increase in life expectancy in the twentieth century.1

However, the limitation to one pathogen in one disease has sharply narrowed our vision by selecting and focusing on single colonies and ignoring the large majority until the last decade, when the technical advances in high throughput sequencing and bioinformatics made it possible to scrutinize the entire microbial community (microbiota/microbiome) in the human body. Commensal bacteria colonize all mucosal and skin surfaces and outnumber human cells by a factor of 10. During millions of years of mutual hosting, commensal bacteria have evolved into a symbiotic relationship with human hosts, performing essential functions in the development of the immune system, digestion of dietary nutrients beyond our own capability, and prevention of pathogenic bacterial colonization. If these functions are vital to humans, one would expect disturbance to the bacterial population could affect susceptibility of an individual to various diseases. In this special issue dedicated to microbiome in human diseases, eight reviews explore the state of microbiome in a variety of clinical conditions.

The human microbiome recently received heightened attention in cancer research after the landmark discovery that Helicobacter pylori induces peptic ulcer and is strongly associated with cancer of the stomach and of the association of bacterial microbiota with cancers of the colon, pancreas, mouth, and perhaps the esophagus. In this issue, three reviews summarize the most recent advances in cancer cause in the context of the human microbiome. Drs Cho, Carter, Harari, and Pei discuss the interrelationships of the gut microbiome and inflammation in colorectal carcinogenesis. An important concept has been drawn from animal models of colitis-associated colorectal cancer that inflammation induced by knockout of genes related to immunity or the presence of bacteria and bacterial metabolites is necessary, but each factor alone is not sufficient to promote tumorigenesis, pointing to the need to study both the host genetics and the microbes in colorectal cancer.

Then, Drs Wang and Ganly summarize the oral microbiome in oral cancer. Here, bacteria play roles in the metabolism of chemical carcinogens. In vitro studies have demonstrated that oral commensal bacteria are capable of converting ethanol to acetaldehyde, a recognized carcinogen and activating procarcinogen in cigarette smoke.

Drs Baghdadi, Chaudhary, Pei, and Yang provide a new insight into the cause of the recent surge in the incidence of esophageal adenocarcinoma with the possible role of dysbiosis contributing to carcinogenesis. In the esophagus, bacteria may enhance and maintain chronic inflammation induced by gastroesophageal reflux via triggering activation of the toll-like receptors on the NFκB pathway.

Three reviews further explore the role of microbiome in microbial and inflammatory diseases. Drs Salas and Chang discuss recent findings on microbiome alteration in HIV infection. The review broadly covers multiple mucosal compartments relevant to systemic and local manifestations of HIV infection. With HIV as the known cause of AIDS, study of the microbiome in HIV infection is often aimed at whether the microbiome plays accessory roles in disease acquisition and progression. Microbiome shifts following HIV infection as observed in several recent studies may activate the immune system that promotes viral replication and drives CD4+ T-cell depletion, hence shortening the course to reach the AIDS stage.

Drs Huang, Fettweis, Brooks, Jefferson, and Buck provide us with a changing landscape of the vaginal microbiome. The well-known old school of thought states that healthy vaginal communities are dominated by only one or two Lactobacillus species, which inhibit pathogen colonization by lowering the pH through lactic acid production and by competing for nutrients and space. However, deep sequence analysis of the vaginal microbiome is revealing an unexpected complexity. There are several distinct types of communities, and the prevalence of these communities varies significantly among different racial and ethnic groups. While Lactobacillus species dominates most healthy women's vaginal microbiome, paradoxically, many women with bacterial vaginosis exhibit homogenous vaginal microbiomes dominated by lactobacilli; Gardnerella vaginalis, a signature for bacterial vaginosis, has been found to be the dominant species in the vagina of healthy women, especially in African women. It appears that bacteria with identical 16S rRNA sequences may have vastly different beneficial/pathogenic potentials encoded by genes located outside of the 16S rRNA genes in the genomes.

Dr Hu reviews gut microbiome in Crohn disease (CD) in the context of host genetics. CD has long been suspected to have both genetic and microbial causes but remained a mystery because it does not fit into the paradigm of one gene-one disease or one pathogen-one disease. Single-nucleotide polymorphism profiling now has identified more than 140 loci predisposing to CD and high-throughput sequencing discovered gut microbiome composition associated with carriers of some of the CD susceptibility genes.

Except for food and antibiotics, few exogenous factors are known to cause changes in the human microbiome. In this issue, two reviews explore treatments that affect the gut microbiome in clinical practice. Drs Freedberg, Lebwohl, and Abrams address the impact of proton pump inhibitors (PPIs) on the human gastrointestinal microbiome. PPIs, widely used for the treatment of gastroesophageal reflux and Helicobacter gastritis, may alter the gastrointestinal microbiome via suppression of gastric acid secretion, induction of hypergastrinemia and hyperparathyroidism, interference with nutrient absorption, and inhibition of proton pumps of bacteria. Studies have found that PPIs deplete esophageal gram-negative bacteria and facilitate H pylori eradication but promote gastric dysbiosis, cause small intestinal bacterial overgrowth, and increase the risk for Clostridium difficile infection.

This issue concludes with the review by Drs Kassam, Lee, and Hunt on the emerging treatment of C difficile infection with fecal microbiota transplantation and insights into future challenges. It is well-known that C difficile infection is caused by alteration of the normal gut microbiota by antibiotics, which remove the resistance to C difficile colonization. Restoration of gut microbiome by fecal microbiota transplantation represents one of the most fruitful therapies developed out of translational medicine. This triumph of translational medical research will enable clinical personnel to implement effective therapy for this serious infectious disease.

These reviews discuss specific examples of inflammatory, infectious, and neoplastic diseases. Although these conditions are different, they all involve the human-microbe relationship in the context of the entire bacterial population. Bacterial flora population-based microbiology is introducing a new category of diseases (ie, microbiome diseases or microecological diseases) into clinical practice. Unlike infectious diseases, it can be expected that new diseases would be promoted and/or caused by specific mixes of bacterial community. These diseases, even though caused by multiple bacteria, are not infectious and are not preventable by vaccination. These features render Koch’s postulates not suitable for proving cause.

Established methods in clinical microbiology laboratories designed to detect and identify single pathogens such as selective media and colony picking or even specific PCR could be replaced by high-throughput but low-cost sequencing technologies to allow the detection of specific pathogens for the diagnosis of infectious diseases as well as profiling the entire microbial population for microbiome diseases or microecological diseases.

This work was supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development and grants U01CA18237, UH3CA140233, R01AI110372, R01CA159036, R21ES023421, and R03CA159414 from...