The Jeremiah Metzger Lecture: Global Warming Redux: The Disappearing Microbiota and Epidemic Obesity

In 2004, I presented my lecture “Global Warming of the Stomach: Microecology Follows Macroecology” at the 117th American Clinical and Climatological Association meeting (1). In that lecture, I highlighted how the disappearance of Helicobacter pylori, the ancient, dominant, highly interactive bacteria that colonize the human stomach is affecting human health. Now, 7 years later, I return to that theme, and describe the relationship of our changing microbiota and obesity. Animals have had residential microbes, probably since the days of our earliest ancestors (2). Of the residential microbial populations colonizing humans, we can consider them ancient, niche-specific, and often persisting for years or decades. Collectively, these organisms represent the human microbiome (3). Certain microbial taxa are conserved among most or all of us, whereas others may be relatively host-specific. Each particular niche in the human body has its own major bacterial populations; there is considerable intra-individual variation by site and inter-individual conservation at higher taxonomic levels (e.g., phylum) (4–6). A number of biological questions (7) are important to consider: What is the identity of these microbes? What are they doing? How is the host responding to them? What are the forces that maintain equilibrium among the populations? What are the unique characteristics of each individual? We have developed a model of the interactions between co-evolved colonizing microbes and their host (7–11) (Figure 1). In this view, individual organisms (Figure 2A) and networks of organisms (Figure 2B) form equilibriums that may oscillate but generally remain stable for long periods within a defined range. The question we pose is what happens when these organisms are perturbed, and in the extreme, when they become extirpated (or extinct) in an individual host (Figure 2C)? Fig. 1 Who are we? An estimated 90% of the cells in the human body are microbial, with the human cells represented in red. An estimated 99% of the unique genes in the human body are microbial, with the human genes represented by the ant (at right). Together, ... Fig. 2 Schematic of interaction between co-evolved colonizing microbes and their host. In the model, the microbes and the host cross-signal and maintain an equilibrium state (A). Multiple organisms are doing this simultaneously in an integrated process; the ... H. PYLORI AS A PARADIGM H. pylori, curved, gram negative bacteria, are ancient in humans, and colonize the gastric mucus layer (12, 13). These organisms have adapted to human biology with an intimate attachment to host cells and the injection of its own constituents (e.g., the cagA-encoded protein) into host cells, where they affect signal transduction in a variety of ways (12–15). Through interactions regulating cell cyclins, they affect cell cycle, and can alternatively signal through the SHP2/ERK and JAK/STAT pathways, which are cross-inhibitory (14, 15). In total, the interaction of H. pylori and humans is most consistent with an integrated circuit, affecting the metabolism of the bacteria and host cells and tissues (Figure 1). We can generalize from our relationship with this ancient, conserved, highly host-interactive microbe to suggest that the microbiome as a whole, in conjunction with host genes, represents a metabolome. However, as discussed previously (1), the prevalence of H. pylori in the United States and other developed countries decreased dramatically during the 20th century; from near ubiquity to less than 10% carriage among children in the early 21st century (16, 17).