Role of the Microbiota in the Modulation of Vaccine Immune Responses

Abstract

The human immune system and the microbiota co-evolve, and their balanced relationship is based on crosstalk between the two systems through the course of life. This tight association and the overall composition and richness of the microbiota play an important role in the modulation of host immunity and may impact the immune response to vaccination. The availability of innovative technologies, such as next-generation sequencing (NGS) and correlated bioinformatics tools, allows a deeper investigation of the crosstalk between the microbiota and human immune responses. This review discusses the current knowledge on the influence of the microbiota on the immune response to vaccination and novel tools to deeply analyze the impact of the microbiome on vaccine responses.

Keywords: gut microbiota; immune system; microbiome; next-generation sequencing; vaccines.

FIGURE 1

Interactions between the microbial community and the immune system at mucosal surfaces. Interactions between microbiota and host cells occur mainly at the intestinal epithelium surface, which constitutes the principal physical and chemical barriers for maintaining intestinal immune homeostasis. The gut microbiota is separated from the intestinal epithelium by a layer of mucus secreted by goblet cells (GCs). Microbe-associated molecular patterns (MAMPs), expressed on the bacterial surface, are recognized by pattern recognition receptors (PRRs), expressed by intestinal epithelial cells (IECs), and induce a variety of effects to block bacteria such as the production of the antimicrobial peptides (AMPs). IEC-released factors, such as retinoic acid (RA) and TGF-β, promote the development in the lamina propria of tolerogenic DCs that stimulate the differentiation of T cells into Treg. B cells differentiate into plasma cells (PCs) secreting IgA that translocate through the epithelium and are released into the mucus layer where control bacteria adhesion to host tissues. Macrophages, stimulated by signals such as flagellin, release IL-23, which in turn promotes the production of IL-22 by ILC3. IL-22 stimulates the release of RegIIIγ, an antimicrobial peptide produced by IECs. ILC2 contributes to the control of mucus by secreting IL-13, a cytokine that drives the differentiation of intestinal epithelial stem cells toward GC, which in turn produce mucin glycoproteins.

FIGURE 2

Factors affecting the immune response to vaccination. Immune responses to vaccination are affected by factors related to the vaccine, the host immune system, and the microbiota. The vaccine formulation (including the delivery system or adjuvant), the antigen dose, the route of vaccine administration (parenteral or mucosal), and the prime-boost strategies selected for the vaccination schedules deeply influence the host immune response to vaccination. At the same time, the host immune system is affected by age, genetic background, and possible disorders (allergy, autoimmunity, immunodeficiency, etc.). The host gut microbiota, susceptible to age, nutritional and environmental factors, gender, hygiene conditions, antibiotic treatment, use of probiotic, or chronic infections, also impact the capacity to respond to vaccination. Vaccination outcome is the result of the complex interplay of these different factors.

FIGURE 3

Integrated approach for analyzing the relationship between microbiota and immune response following vaccination. A deep characterization of the gut microbiome can be obtained by NGS approaches, including metataxonomics, metagenomics, metatranscriptomics, and metabolomics. Advanced technologies, including multiparametric flow cytometry and transcriptomic analysis, allow to profile both the humoral and cellular immune responses. A systems biology integration of microbiome characterization with host response analysis upon vaccine administration could allow to better correlate the influence of the intestinal microbiome on vaccine responses.