The gut microbiome: Relationships with disease and opportunities for therapy

Abstract

Over the past decade, our view of human-associated microbes has expanded beyond that of a few species toward an appreciation of the diverse and niche-specialized microbial communities that develop in the human host with chronological age. The largest reservoir of microbes exists in the distal gastrointestinal tract, both in the lumen, where microbes facilitate primary and secondary metabolism, and on mucosal surfaces, where they interact with host immune cell populations. While local microbial-driven immunomodulation in the gut is well described, more recent studies have demonstrated a role for the gut microbiome in influencing remote organs and mucosal and hematopoietic immune function. Unsurprisingly, therefore, perturbation to the composition and function of the gut microbiota has been associated with chronic diseases ranging from gastrointestinal inflammatory and metabolic conditions to neurological, cardiovascular, and respiratory illnesses. Considerable effort is currently focused on understanding the natural history of microbiome development in humans in the context of health outcomes, in parallel with improving our knowledge of microbiome-host molecular interactions. These efforts ultimately aim to develop effective approaches to rehabilitate perturbed human microbial ecosystems as a means to restore health or prevent disease. This review details the role of the gut microbiome in modulating host health with a focus on immunomodulation and discusses strategies for manipulating the gut microbiome for the management or prevention of chronic inflammatory conditions.

Figure 1.

Tools for analyses of the human gut microbiome. Microbiome studies are facilitated by next-generation sequencing (NGS) and liquid/gas chromatography (LC/GC) mass spectrometry (MS) platforms that permit analysis of composition, function, and productivity of the microbiome. Ideally, these approaches are applied in parallelto provide the most comprehensive view of host microbiomes.

Figure 2.

The infant gut bacterial microbiome rapidly diversifies over the first year of life in healthy infants but is delayed in those who develop allergy or asthma or who are malnourished. A number of pre-, peri-, and postnatal environmental exposures are known to modulate risk for childhood disease, e.g., formula feeding, antimicrobial use, and exposure to environmental tobacco smoke (ETS) or animals. These same exposures also relate to gut microbiome composition at discrete developmental time points and to successional trajectories in early life.

Figure 3.

In healthy adults, the gut microbiome exists in a state of mutual symbiosis with its host. The environment of the gut dictates both the composition and functional productivity of the adult gut microbiota, which may interact with the host through presentation of various ligands such as pathogen-associated molecular patterns (PAMPs) and production of metabolites, e.g., SCFAs. These molecules modulate immune homeostasis in the GI tract and at remote mucosal surfaces and organs via their entry into the circulation.

Figure 4.

A strategic framework for a personalized integrated approach to microbiome manipulation. Due to microbial heterogeneity across populations, personalized nutrition in combination with the administration of live, functionally defined microbial strains to reengineer microbiome composition, functional gene capacity, and metabolic output may prove most effective in rehabilitating perturbed gut microbiomes for effective disease prevention or management.