Microbes in gastrointestinal health and disease

Abstract

Most, if not all, animals coexist with a complement of prokaryotic symbionts that confer a variety of physiologic benefits. In humans, the interaction between animal and bacterial cells is especially important in the gastrointestinal tract. Technical and conceptual advances have enabled rapid progress in characterizing the taxonomic composition, metabolic capacity, and immunomodulatory activity of the human gut microbiota, allowing us to establish its role in human health and disease. The human host coevolved with a normal microbiota over millennia and developed, deployed, and optimized complex immune mechanisms that monitor and control this microbial ecosystem. These cellular mechanisms have homeostatic roles beyond the traditional concept of defense against potential pathogens, suggesting these pathways contribute directly to the well-being of the gut. During their coevolution, the bacterial microbiota has established multiple mechanisms to influence the eukaryotic host, generally in a beneficial fashion, and maintain their stable niche. The prokaryotic genomes of the human microbiota encode a spectrum of metabolic capabilities beyond that of the host genome, making the microbiota an integral component of human physiology. Gaining a fuller understanding of both partners in the normal gut-microbiota interaction may shed light on how the relationship can go awry and contribute to a spectrum of immune, inflammatory, and metabolic disorders and may reveal mechanisms by which this relationship could be manipulated toward therapeutic ends.

Figure 1

Mechanisms of microbiota and gut crosstalk. Both parties in the symbiotic dyad possess means to alter and shape each other, resulting in a “negotiated settlement” at equilibrium. A breakdown on this crosstalk may result in a “dysbiotic” microbiota and clinical consequences.

Figure 2

Cellular consequences to bacterial stimuli. Bacterial MAMPs may stimulate pattern recognition receptors (including extracellular TLRs and formylated peptide receptors, or intracellular Nods). Intensity, duration, and spatial origin of the subsequent signaling responses are integrated by an intricate and interrelated network of transduction pathways that determine if MAMP perception warrants a “low gain” cytoprotective response, a “medium gain” inflammatory reaction, or “high gain” programmed cell death result.

Figure 3

Preferred sites of commensal/probiotic interaction with the gut. Cecum/ascending colon is a “bioreactor” with the greatest amounts of bacteria, metabolic activity, and SCFA fermentation. Concentration of SCFA diminishes along the colon. The distal ileum is enriched in GALT (Peyer's patches) and is the dominant site of luminal sampling and mucosal adaptive immune activity.