Chapter 459: The Human Microbiome

INTRODUCTION

Nearly two and a half millennia after Hippocrates made this statement, we are just coming to truly appreciate its profundity. Since the beginning of humankind, scholars have been investigating the underpinnings of disease with an almost singular focus on the human side of the equation. Microbes were not recognized as an important cause of disease until the inception of the “germ theory” in the late nineteenth century. During the first century of medical microbiology, research largely centered on the role of microbes as pathogens. Only recently has there been a resurgence of interest in understanding how commensal organisms—the bacteria, viruses, fungi, and Archaea that make up the microbiota—impact human physiology. The idea that these microorganisms are vital to the well-being of humans has challenged our traditional notions of “self.” Indeed, a human being can most accurately be described as a holobiont: a complex assemblage of human cells and microorganisms interacting in an elaborate pas de deux that drives normal physiologic processes.

Aimed at a better understanding of this relationship, myriad studies during the past decade have begun to catalogue the microbiota at various body sites and in a multitude of disease conditions. Diseases in virtually every organ system have been associated with changes in the microbiota. Indeed, the microbiota has been linked to intestinal disorders, disturbances in metabolic function, autoimmune diseases, and psychiatric conditions and has been shown to influence susceptibility to infection and the efficacy of pharmaceutical therapies. Knowledge of the specific mechanism(s) underlying most of these microbe–disease associations is lacking; it remains unclear whether the disease-associated alterations in the microbiota represent mere biomarkers of disease, a causal relationship, or a combination of the two. Although cause-and-effect relationships are still being elucidated for many diseases, it is clear that humans coexist in an intricate relationship with commensal organisms. This chapter explores in detail the nature of these host–commensal interactions, focusing on how this information might be translated into clinically meaningful interventions.

HISTORICAL PERSPECTIVE

Massive undertakings, such as the Human Microbiome Project (HMP) sponsored by the National Institutes of Health and MetaHIT sponsored by the European Commission, have catalogued all the bacteria present at multiple body sites in people with and without disease. Coupled with the confluence of advances in sequencing technologies (Chap. 474), gnotobiotic animal availability, and microbial culture, significant progress has been made toward an understanding of the interplay between the microbiota and human health. However, recent findings were foreshadowed by work done centuries ago.

The human microbiota was first explored in 1683 when Antony van Leeuwenhoek described in a letter to the Royal Society of London the “very little living animalcules, very prettily a-moving” that he had observed in the plaque between his teeth. Leeuwenhoek went on to perform the first comparative “microbiota” studies by assessing how fecal and oral bacteria differ, ...