Immune Impairment Associated with Vitamin A Deficiency: Insights from Clinical Studies and Animal Model Research

Abstract

Vitamin A (VA) is critical for many biological processes, including embryonic development, hormone production and function, the maintenance and modulation of immunity, and the homeostasis of epithelium and mucosa. Specifically, VA affects cell integrity, cytokine production, innate immune cell activation, antigen presentation, and lymphocyte trafficking to mucosal surfaces. VA also has been reported to influence the gut microbiota composition and diversity. Consequently, VA deficiency (VAD) results in the imbalanced production of inflammatory and immunomodulatory cytokines, intestinal inflammation, weakened mucosal barrier functions, reduced reactive oxygen species (ROS) and disruption of the gut microbiome. Although VAD is primarily known to cause xerophthalmia, its role in the impairment of anti-infectious defense mechanisms is less defined. Infectious diseases lead to temporary anorexia and lower dietary intake; furthermore, they adversely affect VA status by interfering with VA absorption, utilization and excretion. Thus, there is a tri-directional relationship between VAD, immune response and infections, as VAD affects immune response and predisposes the host to infection, and infection decreases the intestinal absorption of the VA, thereby contributing to secondary VAD development. This has been demonstrated using nutritional and clinical studies, radiotracer studies and knockout animal models. An in-depth understanding of the relationship between VAD, immune response, gut microbiota and infections is critical for optimizing vaccine efficacy and the development of effective immunization programs for countries with high prevalence of VAD. Therefore, in this review, we have comprehensively summarized the existing knowledge regarding VAD impacts on immune responses to infections and post vaccination. We have detailed pathological conditions associated with clinical and subclinical VAD, gut microbiome adaptation to VAD and VAD effects on the immune responses to infection and vaccines.

Keywords: gut microbiome; immune responses; infectious diseases; vaccines; vitamin A deficiency.

Figure 1

Multidirectional relationship between VA, gut microbiome, immune response and infections. (A) In normal state, the beneficial gut microbiome promotes RA storage via suppressing conversion of dietary retinol into retinoic acid (RA), hence increasing retinol transporter retinol binding protein 4 (RBP4) and reducing acute-phase RBPs (serum amyloid A (SAA)). However, during infection, RBP4 amounts decrease, resulting in low circulating retinol and low hepatic storage, while SAA levels increase, leading to upregulation of local immune response to infection. (B) Beneficial microbes upregulate the host epithelial barrier function by production of mucus and short-chain fatty acids (SCFAs), and the microbiota stimulates secretion of IL-1β, leading to elevated neutrophil recruitment to infection site, promoting secretion of IL-22 and resulting in release of antimicrobial peptides. Commensals also act through MyD88-dependent mechanism to trigger production of antimicrobials (AMPs) such as α-defensins, C-type lectins and REGIII-γ by Paneth cells. Beneficial microbes promote adaptive immunity by stimulating Th1 and Th17 cells, leading to increased production of IL-22. Finally, the microbiome prevents pathogen colonization by regulating the secretion of IgA by plasma cells and differentiation of T regulatory cells. VA through its metabolite RA is essential in strengthening host–barrier integrity, enhancing innate immune response and modulating adaptive immunity (effect indicated by arrows). Following antigen stimulation, CD103⁺DCs in gut-associated lymphoid tissues (GALT) produce RA that imprints gut-homing specificity on T and B cells expressing both α4β7 and CCR9, which migrate to small intestine tissues and bind to MAdCAM-1 and CCL25, respectively. The X (red) in the arrows indicates immune response pathways affected when the host is deficient in VA (VAD).

Figure 2

(A) Vitamin A (VA) metabolism and factors contributing to VA deficiency (VAD). (B) VA supplementation to VAD hosts reversed the negative impact of VAD on immune system and gut microbiota. Thin solid line with arrow—vitamin A supplementation (VAS) rescued effects of VAD; thin dotted line—VAS did not rescue the effects of VAD in clinical studies; thin solid line without arrow/?—VAS effects not known. RALDH, retinaldehyde dehydrogenase; REH, retinyl ester hydrolase; CRBP, cellular retinol-binding protein; ASCs, antibody secreting cells.