Disruption of the gut microbiome as a risk factor for microbial infections

Abstract

The discovery that microorganisms can be etiologic agents of disease has driven clinical, research and public health efforts to reduce exposure to bacteria. However, despite extensive campaigns to eradicate pathogens (via antibiotics, vaccinations, hygiene, sanitation, etc.), the incidence and/or severity of multiple immune-mediated diseases including, paradoxically, infectious disease have increased in recent decades. We now appreciate that most microbes in our environment are not pathogenic, and that many human-associated bacteria are symbiotic or beneficial. Notably, recent examples have emerged revealing that the microbiome augments immune system function. This review will focus on how commensal-derived signals enhance various aspects of the host response against pathogens. We suggest that modern lifestyle advances may be depleting specific microbes that enhance immunity against pathogens. Validation of the notion that absence of beneficial microbes is a risk factor for infectious disease may have broad implications for future medical practices.

Figure 1. The intestinal microbiota promotes three levels of protection against enteric infection

I, Saturation of colonization sites and competition for nutrients by the microbiota limit pathogen association with host tissue. II, Commensal microbes prime barrier immunity by driving expression of mucin, immunoglobulin A (IgA) and antimicrobial peptides (AMPs) that further prevents pathogen contact with host mucosa. III, Finally, the microbiota enhances immune responses to invading pathogens. This is achieve by promoting IL-22 expression by T cells and NKp46+ cells, which increases epithelial resistance against infection, as well as priming secretion of IL-1B by intestinal monocytes (MΦ) and dendritic cells (DCs), which promotes recruitment of inflammatory cells into the site of infection. In conditions in which the microbiota is absent, such as following antibiotic treatment, there is reduced competition, barrier resistance and immune defense against pathogen invasion.

Figure 2. The commensal microbiota primes barrier immunity

Direct stimulation of epithelial Toll-like receptors (TLRs) by commensal MAMPs primes expression of RegIIIγ (a). Production of RegIIIγ is essential to limit microbial contact with host mucosa. As such, defects in TLR function results in deficient RegIIIγ expression resulting in an increased association of commensal microbes with host tissue as well as a heighten risk of infection with enteric pathogens (b). Additionally, reduced TLR stimulation as a consequence of the depletion of the microbiota is sufficient to reduce RegIIIγ expression and render the host susceptible to infection.

Figure 3. Disruption of host-microbial symbiosis as a risk factor for infectious disease

Exposure to pathogenic microorganisms is often insufficient to cause disease. Rather, susceptibility to infectious disease reflects deficient immune resistance to pathogen challenge. As such, exogenous and endogenous factors that directly compromise individual immune function (including genetic immune defects and chemotherapy) are significant risk factors for infection. We extend this model by proposing that the factors that disrupt the protective benefits of the commensal microbiota similarly compromise individual immune integrity and predispose to infectious disease.