Introduction

The gut is a stable ecosystem governed by interactions between the host immune system and trillions of gut-resident microbes. Dietary vitamin A has long been identified as the anti-infective agent that plays a key role in regulating multiple aspects of the gut immune system. Recent studies show that both commensal and pathogenic bacteria drastically alter vitamin A metabolism in the host. How microbial regulation of vitamin A metabolism influences enteric infections is not fully understood. Elucidating the molecular mechanisms underlying vitamin A metabolism during healthy and diseased states is critical for designing optimal nutritional therapies to treat infectious disease. Here, we discuss how the complex interplay between dietary vitamin A, mucosal immunity, and commensal bacteria influences the outcome of enteric infections.

Vitamin A shapes host–microbe interactions in the gut

Vitamin A is an essential micronutrient derived from the diet in the form of carotenoids and retinyl esters. Upon absorption by epithelial cells in the intestine, these carotenoids are sequentially converted into retinol and then the active form, retinoic acid (RA), or the liver storage form, retinyl esters. RA drives transcription programs within cells, which are vital for cell fate determination in the embryo and for the development of the immune system [1].

Vitamin A is central to immune homeostasis in the gut, coordinating both innate and adaptive immunity. RA stimulates the migration of immune cells including dendritic cells, T cells, and B cells to the intestine and helps inform their function [2–4]. Vitamin A directly regulates proliferation and differentiation in the intestinal epithelium, which is crucial to the maintenance of the gut barrier [5].

The effect of vitamin A is not limited to the host. Acute vitamin A deficiency triggers a significant change in the community structure in human gut microbiota–associated mice [6]. RA regulates the levels of antimicrobials as well as secretory immunoglobulin A (IgA), which also influences the microbial composition in the gut [7, 8]. A recent study has discovered synthetic retinoids that have direct antibacterial properties, adding a new dimension to vitamin A–microbiome interactions [9].

Microbial regulation of vitamin A metabolism

The potency of RA necessitates that its synthesis be tightly controlled. A suite of metabolic enzymes determine how much vitamin A becomes RA and how much is sent to the liver for storage. Intestinal epithelial cells (IECs) as well as dendritic cells express the vitamin A metabolic machinery; however, not much is known about its regulation. Recently, the gut microbiome has been identified as a new player in host vitamin A metabolism. Germ-free mice express higher levels of RA-synthesizing enzymes in their intestinal epithelium than mice with a regular microbiome express. Colonization of the gut by microbes reduces RA levels in the intestine, which is balanced by an increase in the liver storage form. This regulation appears to be dynamic and microbe specific. Spore-forming bacteria such as Clostridia promote the reduction in RA levels, whereas dysbiotic microbial communities have the opposite effect [10]. This is a novel feedback loop in the gut wherein vitamin A modulates the microbiome, which in turn tunes host immunity via vitamin A metabolism in the gut.

Altered vitamin A status during infection

The first response to infection involves rapid and dramatic changes in protein synthesis of acute-phase proteins [11]. Both retinol-binding protein (RBP) and transthyretin, which transport retinol, decline during acute-phase response to the infection, resulting in undetectable levels of serum retinol. Low serum retinol, i.e., hyporetinolemia, has been reported in children and adults in association with acute infections (e.g., measles, malaria, diarrhea, HIV), multiple morbidities, and trauma. It has been established that retinol and RBP concentrations are inversely correlated with serum concentrations of interleukin-6. This cytokine is the major regulator of the acute-phase response and induces the gene expression of many acute-phase proteins [12]. In animal models in which acute-phase response was induced by injecting lipopolysaccharide (LPS), it was noted that serum hyporetinolemia is caused by a reduction in liver RBP synthesis initiated by the reduced transcription of Rbp4 [13]. In contrast to reduction in RBP4 during infection, alternate acute-phase proteins called serum amyloid A (SAA1 and 2) that bind retinol with high affinity are strongly up-regulated in the intestinal as well as liver tissues [14]. SAAs are required to generate T helper 17 (Th17) cells that modulate antimicrobial production and thus microbial composition in the gut [15]. Up-regulation of SAAs during microbial infection suggests that the host engages an alternate vitamin A mobilization machinery to mount a specific antimicrobial response (Fig 1).

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Fig 1. Vitamin A (retinol) handling during health and disease.

(A) During homeostasis, gut bacteria suppress the conversion of dietary retinol into RA and promote its storage. Retinol transporter RBP4 is the main transporter of retinol to and from the liver. (B) During infection, RBP4 amounts drop, reducing retinol transport and storage in the liver. Acute-phase RBPs, such as SAAs, increase in the intestinal tissue and up-regulate local immune response to infection. RA, retinoic acid; RBP, retinol-binding protein; SAA, serum amyloid A.

https://doi.org/10.1371/journal.ppat.1007750.g001

Future perspectives

Vitamin A is critical to many aspects of health, from embryonic development to immune homeostasis. In developing countries, vitamin A deficiency is a chronic problem that leads to high susceptibility to enteric infections in children. Maternal malnutrition is an underappreciated factor in infection susceptibility. Maternal vitamin A status influences immune development in the fetus [23]. Furthermore, the maternal microbiota is a prominent factor governing immune competency in the fetus, another aspect that could be affected by maternal vitamin A deficiency [24]. Surprisingly, irrespective of maternal vitamin A status, newborns have negligible stores of vitamin A in the liver. They rely on breast milk and other dietary factors to build liver stores. How stores of vitamin A in liver, serum, or tissues affect immune competency and infection susceptibility is an exciting area for future research. What we do know is that the relationship between vitamin A and infection is not black and white. Both too little and too much vitamin A can have negative consequences based on the infection context. Also, vitamin A metabolism in different tissue compartments can have differing effects on immunity and infection. In populations at risk for vitamin A deficiency, vitamin A supplementation in young children (<5 years old) significantly reduces the mortality associated with diarrhea. Interestingly, supplementation has no significant effect on diseases such as measles and respiratory illnesses [25]. This underscores the clinical benefits of interventions correcting vitamin A deficiency, especially for enteric diseases. A more comprehensive understanding of vitamin A metabolism and distribution in the body is required to better inform how we define vitamin A deficiency and help us design effective dosing and delivery strategies to reduce the morbidity associated with enteric diseases. Furthermore, probiotics can be mined for their ability to modulate vitamin A metabolism. A combination of probiotics and vitamin A supplements can be a holistic way to restore vitamin A sufficiency while maintaining host–commensal homeostasis.