Strong interactions between Vitamin D and the gut microbiota via Butyrate and VDR – Dec 2019

Vitamin D and microbiota: Two sides of the same coin in the immunomodulatory aspects

International Immunopharmacology 79 (2020) 106112, https://doi.org/10.1016Zj.intimp.2019.106112
Lucia Malaguarnera
Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia, 97, Catania, Italy

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Table of Contents

The gut microbiota is crucial for host immune response, vitamin synthesis, short chain fatty acids (SCFAs) production, intestinal permeability, nutrient digestion energy metabolism and protection from pathogens. Therefore, gut microbiota guarantees the host’s predisposition to gastrointestinal diseases. Intestinal microbiota may be damaged by environmental components with negative health conditions.
Dysbiosis consisting in alteration in the gut microbiota has been involved in several disorders including

• inflammation,
• allergic reactions,
• autoimmune diseases,
• heart diseases,
• obesity, and
• metabolic syndrome

and even in the state of malignant carcinogenesis existing in humans.
Several epidemiological studies have shown that inadequate solar exposure results in vitamin D insufficiency/deficiency which has a strong impact on different immune responses and the occurrence of a wide range of pathological conditions. Additionally, new evidence indicates that the vitamin D pathway plays a key role in gut homeostasis. Due to the strong connection between vitamin D and microbiota, herein we focus on the new findings about intestinal bacteria-immune crosstalk and the impact of vitamin D in gut microbiota regulation, in order to offer new clarifications on their interaction. Understanding the mechanism by which vitamin D can affect the gut microbiota composition and its dynamic activities, as well as the innate and adaptive state of the immune system, is not only a fundamental research but also an opportunity to improve health status.

Conclusion: Clipped from PDF

The gut is one of the most important target organs of vitamin D, as demonstrated by the local synthesis of 1a,25(OH)2D3 and of VDR expression in most cell types of GI tract. An optimal 1a,25(OH)2D3 status plays an important role in maintaining the gut homeostasis via many regulatory activities such as calcium and phosphate absorption, protection against infection, preservation of the epithelial barrier function, anti-inflammatory action and modulation of the gut microbiota. On the other hand, a number of data have demonstrated a complex connection of the gut microbiota with host metabolism, neuroendocrine andimmune homeostasis, and the potential impairments or disorders of the gut microbiota. Therefore, vitamin D3 and gut microbiota display many similarities in the modulation of the immune system in counteracting the inflammatory responses including

• inhibition of excessive ROS synthesis,
• downregulation of the proinflammatory NF-kB pathway, and
• downregulation of inflammatory markers and
• induction of anti-inflammatory cytokines synthesis.

These similarities could be due, at least in part, to the interaction and the synergistic effect between vitamin D and microbiota metabolites including SCFAs (e.g. butyrate). In fact, we have seen that both exert anti-inflammatory activity by promoting regulatory Tregs function, increasing the levels of the anti-inflammatory cytokine IL-10, affecting the maturation of DC [196]. Both are able to modulate NFkB signalling and to inhibit expression of pro- inflammatory cytokines [46]. Interestingly, it has been reported that the expression and activity of VDR is under the control of butyrate [47].
Butyrate is potent health-promoting effects. It

• maintains an intestinal barrier function,
• decreases inflammation,
• prevents metabolic disorders,
• protects from autoimmune disease and
• carcinogenesis [197].

Therefore the association of both vitamin D3 status and commensal microbiota composition with the host in health and disease states reflects a much more complex interactive network, rather than a simple unidirectional “cause and effect.” Still, the human studies are very limited [198]. Therefore, new experimental investigations should be reviewed and designer suitably to carefully examine at which step of the disease (for example disease onset, early disease stage, disease progression, active or latent disease) in order to understand how vitamin D3 status, intestinal VDR expression and human microbiota composition may influence pathogenetic manifestations. Moreover, different valuations on vitamin D status, vitamin D genomics, dysbiotic features in specific diseases to be correlated with host immune responses. For example, confounding/modifying variables, such as subject-specific factors such as age, gender, ethnicity, lifestyle, diet, infection, genetic, disease and postnatal exposure to maternal and environmental microflora could aid to clarify the interactions between Vitamin D and microbiota and their impact in the immune responses. Finally, it is necessary highlight that excessive vitamin D supplementation lead to hypercalcemia as novel risk factors which promotes worsening of CNS demyelinating disease [199]. In addition, high dose vitamin D worsens the severity of murine colitis induced by DSS, and is associated with diverse modifications in microbial composition that may be a direct dietary effect or as a result of dysregulation of the gut mucosal immune response [200].
Nevertheless, up to date there are few investigations detecting the effect of high vitamin D levels on immune regulation. Therefore, is indispensable further detect the effects of high levels of vitamin D on gut mucosal immunity to better understand if high as well as low vitamin D levels lead to a dysregulation. Collectively, these considerations indicate that it would be stimulating to investigate the benefits of new combination supplements with vitamin D or vitamin D analogues and probiotic and/or prebiotics as alternative disease management options that may affect the outcome of conventional therapies.