Microbiota, disease, and back to health: a metastable journey

Abstract

Alterations in the composition of the commensal microbiota have been observed in many complex diseases. Understanding the basis for these changes, how they relate to disease risk or activity, and the mechanisms by which the symbiotic state of colonization resistance and host homeostasis is restored is critical for future therapies aimed at manipulating the microbiota.

Fig. 1

Factors at the commensal-host interface associated with health and disease. Environmental and host factors (which are under genetic control) determine the composition and functional consequences of the components within the lumenal milieu. The lumenal milieu consists of commensal microbiota and their products and secreted factors of the host (blue). These lumenal states are metastable at any given point in time and likely age-dependent. Health is associated with symbiosis of the commensal microbiota and host responses (lumenal, epithelial, and subepithelial), which are a reflection of homeostasis. Disease on the other hand is characterized by dysbiosis of the commensal microbiota and the corollary host responses. Whether symbiosis or dysbiosis is a primary or secondary factor in disease development remains an open question. The ultimate development of disease at any given set point in this model is dependent on many factors, which determine tissue tolerance and include genetic susceptibility among others. GPCR43, G protein–coupled receptor 43; PSA, polysaccharide antigen A; Treg, T regulatory cell; ER, endoplasmic reticulum; wt, wild-type allele; mut, mutant allele; TMA, trimethylamine; Th, T helper; IL, interleukin; TGFβ, transforming growth factor–β; IFNγ, interferon-γ; iNKT, invariant natural killer T.

Fig. 2

Cycles of equilibrium and imbalance at the commensal-host interface. Homeostasis is associated with symbiotic commensalism and colonization resistance together with epithelial and immune balance. Perturbations, such as enteropathogenic invasions, disrupt this balance by inducing inflammation, resulting not only in tissue destruction but also breakdown in the state of commensalism and, consequently, dysbiosis. Dysbiosis can be associated with the evolution of pathobionts that function as inflammatory allies (for example, Proteobacteria), which are able to flourish in the inflammatory milieu and further promote inflammation induced by the invading pathogen. Some types of perturbations, such as antibiotics, can lead directly to breakdown in commensalism and subsequent colonization by pathobionts and pathogens that are able to take advantage of the niche (for example, C. difficile). Under normal circumstances, the host can restore a metastable state of commensalism associated with control of pathobionts and pathogens, reestablishment of colonization resistance, and tissue repair. Individuals who are unable to accomplish this develop chronic disease. Factors that affect each of these hypothetical parts of this health-disease cycle include genetics, age, and environmental experiences among others. NADPH, reduced form of nicotinamide adenine dinucleotide phosphate; AIEC, adherent-invasive E. coli.