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The connection between intestinal microbes and human health has been appreciated since the 1880s with Theodor Escherich’s investigation of Escherichia coli and other fecal bacteria. Escherich hypothesized that indigenous micoorganisms play roles in both digestion and intestinal diseases [1]. In the last century, our understanding of the bacteria, viruses, archaea, and eukaryotes that normally inhabit the gut has expanded alongside the rest of the field of microbiology, and numerous fundamental roles have been established for this community, now termed the microbiome. As speculated by Escherich, these roles definitively include nutrient digestion [2, 3] and protection from invading pathogens [4] but also extend to shortand long-term instruction of the immune system [5–7] and production of a wide range of metabolites that are unable to be produced by human physiology. Although the gut microbiome is typically described as being composed of nonharmful or beneficial microorganisms, it is now appreciated that both individual species [8] or multiple community members acting together [9, 10] can exert pathogenic effects, which are often more subtle than those of classical pathogens. Indeed, the presence of common intestinal microorganisms with discrete virulence factors (e.g., enterotoxins, genotoxins) that may only manifest in diseases like colorectal cancer or inflammatory bowel disease (IBD) over long periods of time or in certain host genetic backgrounds obscures the definition of pathogen. Accelerated in the 2000s by the “-omics” revolution, along with a recent resurgence of cultivation [11–13], countless studies in the past 2 decades have implied or established connections between altered gut microbiomes and many diseases. These studies have demonstrated the malleability (or fragility) of the microbiome in the face of environmental and dietary perturbations encompassing antibiotic use [14], geography [15], immigration [16], and dietary changes, including fiber deprivation [17, 18]. Although Escherich’s original ideas were logically predicted with respect to microbiome effects in the gut, less-anticipated connections between gut microbes and health have extended to neurobiology [19–22] and systemic immune responses that impact allergy [23]. Emerging studies, often extending from omics-based observations, are providing causal and mechanistic understanding of the relationships that connect host responses with changes in the microbiome and its metabolism. Here, we look at recent examples that illustrate how the gut microbiome can augment or perturb host physiology through complementary or novel metabolism often initiating or modifying disease trajectories. The studies we highlight provide details that underscore the importance of gut microbes in human health, which Escherich postulated long ago.

In sickness and health: Effects of gut microbial metabolites on human physiology