Footnotes – Does Vitamin C Kill Probiotics
People have misplaced their vitamin C-synthesizing capacities throughout evolution. Subsequently, the uptake of this important compound from exterior sources is obligatory with the intention to stop vitamin C-deficient situations leading to extreme morbidities equivalent to scurvy. The potent antioxidant, immunomodulatory, and antiinfectious results of vitamin C are identified for the reason that Thirties. We right here (i) overview the affect of vitamin C on innate and adaptive immune features, (ii) present an summary of its antimicrobial, antibacterial, antiviral, antiparasitic, and antifungal properties, and at last, (iii) focus on vitamin C as an adjunct therapy possibility for the fight of human infections by micro organism, significantly by rising multidrug-resistant species. Key phrases: vitamin C, ascorbic acid, immunomodulatory properties, anti-microbial synergy, antibacterial results
Introduction
Within the Twenties, vitamin C was first recognized by the possible Nobel laureate Albert Szent-Györgyi from Szeged College in Hungary, who unraveled the position of this important vitamin for the therapy and prevention of scurvy ensuing from vitamin C deficiency [1–5]. Vitamin C is the generic time period for L-threo-hexo-2-enono-1,4-lactone [6], which constitutes a low molecular weight carbohydrate [1, 7]. Chemically, vitamin C is a gluconic acid lactone derived from glucuronic acid and water-soluble ketolactone with 2 ionizable hydroxyl teams with distinguished antioxidant properties [1, 6]. In nature, the two important isomeric molecules of vitamin C are present in equal elements, particularly the lowered type D-ascorbic acid and the chemically lively and oxidized type L-ascorbic acid [8], that are mutually interchangeable [1, 6, 9, 10]. Vitamin C has a robust potential to cut back distinct molecules whereas being reversibly oxidized to dehydroascorbic acid (DHA), which could be lowered again to vitamin C exhibiting full organic exercise [1, 6, 11]. The intracellular transport of vitamin C takes place in each sort of cells as DHA by means of glucose transporters (GLUT) following a focus gradient as a result of construction similarity to glucose [8, 12] or actively as ascorbic acid by way of the sodium-dependent vitamin C transporters (SVCT)-1 and -2 [13, 14] in particular organs such because the small intestines, liver, kidneys, adrenal glands, mind, and retina [15]. Contained in the cell, DHA is subsequently lowered to ascorbic acid [16]. As a result of these traits, vitamin C in concerned in a number of very important processes equivalent to power metabolism and gene transcription, in addition to in regulation of hormonal and epigenetic pathways [17]. The pure sources of vitamin C are citrus fruits, kiwi, mango, strawberries, papaya, tomatoes, inexperienced leafy greens, and broccoli, for example [1, 7, 10, 18–20]. Curiously, the overwhelming majority of vertebrates can synthesize vitamin C from glucose, however a couple of mammals together with guinea pigs and people have misplaced this capacity attributable to an absence of L-glucono-γ-lactone oxidase, which is important for the synthesis of vitamin C in vivo [1, 2, 7, 8, 10, 18, 21, 22]. Subsequently, people want to amass vitamin C from a eating regimen that provides 100 to 200 mg of vitamin C per day to cowl the overall human wants [23, 24] and to lower the danger of vitamin C-deficient situations leading to scurvy, which is likely to be deadly if left untreated [7]. With the intention to stop scurvy, a low day by day dose of 10 mg is required [25]. People with scurvy exhibit down-regulated immune responses [26] and are therefore extremely inclined in the direction of infections [2, 17]. On condition that vitamin C is actually concerned in collagen biosynthesis and restore, the dearth of ascorbic acid impairs integrity of basement membranes, mucosal epithelia, and connective tissues, which is causative for the devastating periodontal illness noticed in scurvy. Moreover, the vitamin is required for correct wound therapeutic and bone improvement, each of which linked to the position of ascorbic acid in collagen synthesis. Different biochemical features of vitamin C embody carnitine synthesis, redox-reactions, manufacturing of adrenal steroids and catecholamines, metabolism of amino acids and ldl cholesterol, and iron absorption [5, 27, 28]. A number of research revealed that vitamin C possesses antimicrobial properties, thus decreasing the danger of infections, and have immunomodulatory features, significantly in excessive concentrations [8]. Nevertheless, one must think about that inappropriate storage, processing and preparation procedures of meals would possibly lead to vitamin C degradation [7], additional supporting the demand of acceptable dietary supplementation of this important vitamin with the intention to scale back the danger of deficiency. Moreover, provided that vitamin C is water-soluble, intoxication upon extra consumption is just about not possible since vitamin C in concentrations exceeding the day by day calls for will likely be excreted by way of the kidneys [29]. Given its anti-infectious and immunomodulatory properties on one facet and the dearth of undesirable negative effects on the opposite, vitamin C constitutes a promising antibiotic-independent technique to fight and/or stop bacterial (together with enteropathogenic) infections. Subsequently, this overview will concentrate on the immunomodulatory and antimicrobial results of vitamin C.
Immunomodulatory Properties of Vitamin C
A vital basal focus of vitamin C is important for a standard and well-functional host protection mechanism, and pharmacological software of vitamin C is believed to boost immune operate [30]. A number of research revealed that experimentally induced vitamin C deficiency reduces mobile [31–33] and humoral immune responses [33, 34]. Moreover, the impact of vitamin C on totally different immune cell populations has been proven in each experimental in vivo fashions and in people [35–38]. In medical research, vitamin C therapy of wholesome topics promoted and enhanced pure killer cell actions, lymphocyte proliferation, and chemotaxis [30, 39]. Moreover, excessive doses of vitamin C not solely stimulated murine immune cells, primarily dendritic cells, to extra distinct interleukin (IL)-12 secretion [40], but additionally activated T and B cell features [34, 41]. As well as, the observations that vitamin C concentrations in immune cells equivalent to leukocytes are 10- to 100-fold larger than these measured within the plasma [6] and the truth that these cells accumulate vitamin C in opposition to a focus gradient additional underline the immunological significance of vitamin C [42, 43] and assist its position as essential participant in numerous facets of immune cell features, equivalent to immune cell proliferation and differentiation [17, 44–46], moreover its anti-inflammatory properties [47, 48]. Furthermore, the newly characterised hydroxylase enzymes, which regulate the exercise of the hypoxia-inducible components (HIF), gene transcription, and cell signaling of immune cells, require vitamin C as a cofactor for optimum exercise [49–52]. Within the gastrointestinal tract, vitamin C performs an essential position as important micronutrient and antioxidant defending intestinal cells from inflammatory stimuli [1, 53]. Nevertheless, within the infected mucosa of sufferers affected by continual inflammatory bowel illness (IBD) equivalent to Crohn’s illness and ulcerative colitis [54, 55], the mucosal vitamin C concentrations are extremely lowered [56]. Moreover, when making use of vitamin C to duodenal explants derived from sufferers affected by coeliac illness attributable to a hypersensitivity response to wheat gliadin and related proteins from rye and barley [57], a decreased secretion of pro-inflammatory mediators in response to gluten might be assessed [58]. As well as, in a small examine cohort, intravenous excessive dose vitamin C software was discovered to be useful as an adjunct therapy possibility of colorectal most cancers [59]. Therefore, vitamin C has been proven to exhibit potent immunomodulatory exercise in the midst of distinct gastrointestinal inflammatory morbidities. Within the following paragraph, we’ll concentrate on the impact of vitamin C on distinct immune cell populations.
Monocytes and Macrophages
As pivotal elements of the innate immune system, monocytes and macrophages are the primary line of protection in opposition to invading pathogens [60]. The excessive vitamin C concentrations measured in monocytes [17, 26, 61] underline the regulatory position of this vitamin in monocyte and macrophage features. In assist, an in vitro examine revealed that intracellular accumulation of pharmacologic vitamin C concentrations might successfully inhibit apoptotic pathways in human monocytes [16]. Vitamin C may additionally regulate distinct genes expressed in human macrophages, that are induced by lipopolysaccharide (LPS) by way of nuclear issue kappa-light-chain-enhancer of activated B cells (NF-κB) activation [62]. Furthermore, vitamin C software to monocytes derived from human entire blood diminished secretion of pro-inflammatory cytokines equivalent to IL-6 and tumor necrosis issue (TNF)-α [63]. As well as, vitamin C therapy was proven to stimulate and improve phagocytosis and clearance of macrophages in vitro [17, 33]. Taken collectively, these findings underline the essential position of vitamin C in host protection in opposition to pathogens.
Neutrophils
The publicity of neutrophils to oxidants inhibits their motility, which is said to oxidation of membrane lipids and affecting cell membrane fluidity [17]. As a potent water-soluble antioxidant, vitamin C can neutralize reactive oxidants and likewise regenerate mobile and membrane antioxidants equivalent to glutathione and vitamin E (tocopherol) [64]. With the intention to shield themselves from oxidative injury, neutrophils accumulate millimolar (mM) concentrations of vitamin C [65], leading to improved mobile motility and migration in response of chemotactic stimuli [66] and, subsequently, in enhanced phagocytosis of microbes and era of reactive oxygen species (ROS) [17]. In assist, oral administration of vitamin C has been proven to boost neutrophilic features and to lead to elevated serum immunoglobulin ranges in ageing sufferers [67]. Curiously, neutrophils remoted from sepsis sufferers exhibited compromised practical capabilities relating to chemotaxis and the era of ROS [68, 69]. These phenomena is likely to be related to decreased vitamin C concentrations within the plasma and leukocytes throughout infectious ailments and stress situations [6, 33], which is said to the oxidation of ascorbic acid to DHA, the lively type of vitamin C [6, 70].
T Lymphocytes
T lymphocytes as key gamers in acquired (adaptive) immunity are impacted by vitamin C, as proven by each in vitro [40, 41] and in vivo research [8]. The event and maturation of murine [37, 71] and human [72] T cells are enhanced within the presence of vitamin C in physiological concentrations, whereas proliferation and viability of T lymphocytes are additionally affected [37]. In a medical examine with aged sufferers who obtained vitamin C (500 mg/day) versus placebo for one month, an elevated T cell proliferation might be assessed within the serum as in comparison with the placebo group [73]. These outcomes are supported by a number of in vitro research with human and murine T cells. In human peripheral lymphocytes, vitamin C software promoted T cell proliferation [72, 74]. In one other report, nevertheless, a decreased variety of human IL-2 producing T cells might be assessed within the presence of vitamin C, whereas TNF-α and interferon (IFN)-γ expressing T lymphocytes weren’t affected [63]. In murine splenic T cell cultures, solely excessive vitamin C ranges (0.25–0.5 mM) have been proven to lower T cell viability and secretion of pro- and anti inflammatory cytokines equivalent to TNF-α, IFN-γ, and IL-4 by activated T cells, which was not the case following incubation with decrease vitamin C concentrations [41]. In assist, a latest in vivo examine revealed that vitamin C administration throughout sepsis modified regulatory T cell exercise by instantly enhancing cell proliferation and by inhibiting the expression of distinct transcription components, cytokines, and antigens directed in opposition to regulatory T cells [75]. Moreover, T cell activation has been proven to extend expression of SCVT2 [8, 17], which is instantly associated to a extra pronounced mobile uptake of ascorbic acid, additional underlining the pivotal position of vitamin C throughout T cell activation. On condition that ROS are fashioned throughout T cell activation and act as a second messenger [76–78], it’s extremely doubtless that vitamin C impacts T cell activation as an antioxidant [8].
B Lymphocytes
B lymphocytes are the principle elements of adaptive humoral immunity and management the antigen-specific immunoglobulin (Ig) manufacturing [37]. Like T cells, B lymphocytes are able to accumulating vitamin C, whereas within the absence of vitamin C, the viability of B cells derived from murine spleens was proven to be decreased [79], additional underlining the important position of vitamin C in proliferation, viability, and performance additionally of B cells. Curiously, an in vitro examine revealed a slight dose-dependent apoptosis induction in vitamin C-pretreated murine IgM/CD40-activated B cells, whereas decrease vitamin C concentrations promoted antioxidant properties in activated B cells and didn’t have an effect on cell proliferation and expression of distinct floor molecules, equivalent to CD80 and CD86 [34]. Additional research addressed the impact of vitamin C on antibody manufacturing by B cells. To analyze if vitamin C is likely to be useful for vaccination methods directed in opposition to infectious bursal illness, particular pathogen-free (SPF) chickens obtained 1 g/mL vitamin C supplementation and confirmed larger immunoglobulin ranges as in comparison with placebo controls [80, 81]. In assist, a medical trial with wholesome male college college students revealed that vitamin C supplementation was related to a major enhance within the serum IgA and IgM concentrations [82]. Thus, these outcomes underline the regulatory results of vitamin C in B cell proliferation and performance.
Pure Killer Cells
Pure killer (NK) cells are arising from the identical lymphoid progenitors as T and B lymphocytes [37] and play essential roles within the elimination of pathogens together with viruses [83]. Proliferation of human NK cells derived from peripheral blood mononuclear cells might be accelerated by co-incubation with vitamin C leading to larger cell numbers with correct practical capability [84]. Moreover, the cytotoxic capabilities of NK cells might be blocked by way of platelet aggregation round migrating tumor cells, whereas in vitro vitamin C software elevated the cytotoxic exercise of NK cells directed in opposition to tumor cells [85]. Sufferers affected by β-thal-assemia main are identified to show compromised cytotoxic exercise of NK cells [86], which might be rescued by vitamin C software [87]. In wholesome topics, nevertheless, the cytotoxic capacities of NK cells couldn’t be additional enhanced by vitamin C stimulation [87]. Future in vivo trials must additional unravel the vitamin C associated results on NK cell features.
Antimicrobial Properties of Vitamin C
As early because the Thirties, vitamin C has been identified for its antimicrobial results directed in opposition to Mycobacterium tuberculosis, the infectious brokers of human tuberculosis [88–91]. An in vivo examine from 1933 revealed that administration of tuberculosis sputum to vitamin C-deficient guinea pigs led to intestinal tuberculosis, whereas the guinea pigs that had obtained vitamin C-containing tomato juice didn’t undergo from the illness [92]. Initially it was hypothesized that the antimicrobial properties of vitamin C have been attributable to its pH reducing impact [93]. One other examine, nevertheless, might show potent antimicrobial results of vitamin C directed in opposition to group A hemolytic streptococci, even in an almost pH-neutral surroundings [94]. Additional research assessed the antibacterial results of vitamin C in opposition to distinct bacterial (opportunistic) pathogens, in additional element, making use of microdilution assays. Vitamin C concentrations of 0.31 mg/mL might successfully inhibit Pseudomonas aeruginosa development in vitro [95]. As well as, vitamin C software at low focus (0.15 mg/mL) was proven to inhibit the expansion of Staphylococcus aureus [95]. Moreover, vitamin C might even successfully counteract biofilm formation by methicillin-resistant S. aureus (MRSA), displaying low-level resistance to vitamin C (8 to 16 μg/mL) [96]. Curiously, pH-neutralized vitamin C had solely a minor inhibitory impact on S. aureus development [97]. Moreover, low focus of vitamin C (0.15 mg/mL) was proven to have antibacterial results directed in opposition to Enterococcus faecalis [95]. These outcomes are contrasted by one other examine revealing that the E. faecalis development was not affected upon co-incubation with 0.22 mg/mL of vitamin C [98]. Thus, the antibacterial results of vitamin C is likely to be each, bacterial pressure and focus dependent. In assist, vitamin C had solely a marginal impact on the expansion of Escherichia coli ATTC 11775 pressure [97]. Together with lactic acid, nevertheless, vitamin C inhibited replication of E. coli O157:H7 pressure when incubated in mind coronary heart infusion broth or in carrot juice [99], whereas one other examine reported that vitamin C even lowered the sensitivity of E. coli MG1655 to streptomycin [100]. Notably, the co-administration of vitamin C might sufficiently improve the antibacterial results of different brokers equivalent to epigallocatechin gallate directed even in opposition to multidrug-resistant bacterial species equivalent to MRSA [101], which additionally held true for vitamin C together with deferoxamine in opposition to Gram-positive cocci, equivalent to S. aureus and S. epidermidis, in addition to in opposition to Gram-negative bacilli, together with E. coli, Klebsiella pneumoniae and Proteus mirabilis [102]. Synergistic antibacterial results is also noticed upon co-administration of vitamin C and quercetin [97], whereas the mix of vitamin C with pure extracts equivalent to pomegranate rind extracts [103] and white tea [104] resulted in enhanced anti-S. aureus properties of the latter. Within the following paragraph, we’ll concentrate on the antimicrobial impact of vitamin C on distinct food-borne Gram-negative bacterial pathogens inflicting frequent human ailments – some resulting in distinguished morbidity.
Anti-Helicobacter Results of Vitamin C
In an in vitro examine, 10 to twenty mg vitamin C per ml might successfully inhibit Helicobacter pylori development below microaerobic situations, whereas in an cardio milieu, vitamin C even promoted H. pylori survival in concentrations starting from 2 to twenty mg/mL [105]. These observations is likely to be defined by the antioxidant properties of vitamin C, defending microaerophilic micro organism in opposition to poisonous results of ROS. Following one-week therapy of H. pylori-infected Mongolian gerbils with 10 mg vitamin C day by day, gastric pathogen hundreds might be considerably lowered [106]. In assist, a number of medical research reported more practical H. pylori eradication upon vitamin C software to contaminated people [107–109]. As well as, oxidative stress, apoptotic responses, and decreased mobile viability that had been induced in an H. pylori-infected human gastric adenocarcinoma cell line might be counteracted by vitamin C software in its L-ascorbic acid-2-glucoside type [110].
Anti-Salmonella Results of Vitamin C
It was reported that vitamin C didn’t exhibit important antibacterial exercise in opposition to Salmonella enterica in cantaloupe puree [111]. In distinction, vitamin C exhibited antibacterial results in opposition to Salmonella Enteritidis in an in vitro examine utilizing a broiler-digestive mannequin together with the crop compartment, the proventriculus, and the gut [112]. Curiously, within the crop compartment, vitamin C alone might much more successfully inhibit Salmonella development inhibition, as in comparison with a mixture with curcumin and boric acid, whereas conversely, within the proventriculus and gut, solely the mix of vitamin C, curcumin and boric acid exhibited important antibacterial exercise in opposition to S. Enteritidis [112]. Moreover, a latest examine revealed that the antibacterial impact of vitamin C in opposition to S. enterica subsp. enterica serovar Typhi and Vibrio fluvialis might be enhanced when utilized in a mixture with linalool and copper [113]. The impact of this triple mixture on bacterial morphology was demonstrated by scanning electron microscopy utilizing V. fluvialis, which confirmed extreme membrane injury, whereas no toxicity might be assessed in human embryonic kidney (HEK293) cells at synergistic concentrations (16.3 μM, 8 mM, and 1.298 mM vitamin C) [113].
Anti-Campylobacter Results of Vitamin C
Supported by a number of in vitro research within the Nineteen Eighties, vitamin C in a mixture with linalool and copper was proven to exhibit synergistic actions in opposition to Campylobacter jejuni [113]. Fletcher et al. demonstrated the inhibitory impact of vitamin C (0.5 mg/mL) on C. jejuni development in vitro, primarily brought on by vitamin C oxidation merchandise equivalent to L-dehydroascorbic acid or L-diketogulonic acid [114]. Curiously, vitamin C in concentrations beneath 1 mM even stimulated C. jejuni development, whereas 5 mM of vitamin C killed the bacterial cells [115]. This bactericidal results of vitamin C was additional confirmed on C. jejuni-contaminated turkey meat, provided that C. jejuni loss of life charges elevated in vitamin C handled samples (5 mmol/kg) [116]. Thus far research addressing potential anti-C. jejuni results of vitamin C in vivo are lacking, nevertheless.
Anti-Viral, Anti-Parasitic and Anti-Fungal Results of Vitamin C
The antimicrobial properties of vitamin C should not restricted to bacterial cells. A number of research reported that vitamin C, particularly in type of DHA, inhibited the replication of herpes simplex virus kind 1, poliovirus kind 1 [117], and influenza virus kind A [117, 118]. Furthermore, vitamin C successfully inactivated the rabies virus in vitro [119]. Additionally, anti-parasitic results of vitamin C might be demonstrated. A earlier in vivo examine revealed lowered parasite counts in Trypanosoma cruzi [120] and Plasmodium yoelii 17XL [22]-infected mice, when handled with vitamin C as in comparison with placebo management animals, which could even be as a result of immunomodulatory properties of vitamin C. In assist, one other examine demonstrated that top doses of vitamin C software (i.e., 8.56 mg/kg physique weight) can dampen malarial parasitaemia in contaminated mice, however surprisingly, the co-administration of vitamin C and the anti-malaria drug artemether [121] lowered parasitic clearance in Plasmodium berghei malaria contaminated mice as in comparison with artemether software alone [122]. As well as, anti-fungal results of vitamin C have additionally been reported. One examine confirmed vitamin C-associated inhibition of Hsp90-mediated morphogenesis in Candida albicans, whereas in one other examine, vitamin C exhibited low-level fungistatic actions in opposition to C. albicans [95]. Thus, vitamin C possesses potent antimicrobial properties decreasing pathogenicity of micro organism, viruses, parasites, and fungi.
Abstract and Conclusions
For a couple of vertebrate species together with people having misplaced their capacities to synthesize vitamin C themselves throughout evolution, the uptake of this important compound from exterior sources is obligatory with the intention to stop from vitamin poor situations leading to extreme morbidities equivalent to scurvy. Nevertheless, vitamin C supplementation is nicely tolerated and protected, given a digital absent danger of intoxication upon uncompromised renal operate. The organic position of vitamin C is said to its reversibly oxidized type and is concerned in a large number of each enzymatic and non-enzymatic processes. Moreover, vitamin C is a strong antioxidant compound directed in opposition to free radicals and ROS. Leukocytes together with lymphocytes can actively accumulate vitamin C in opposition to a focus gradient, which underlines not solely vitamin C dependent practical but additionally developmental immune cell options. Actually, vitamin C has a pivotal affect on each innate and adaptive immune responses. Vitamin C can also be concerned in bacterial metabolism. It’s identified that a number of micro organism can ferment vitamin C, whereas the presence of this vitamin exposes others to oxidative stress, which can lead to bacterial development inhibition. The potent antibacterial results of vitamin C are, at the least partly, attributable to its low pH and thus milieu-modifying properties. Notably, vitamin C is ready to inhibit the expansion of S. aureus and streptococci even below impartial pH situations. Potent growth-inhibitory results in opposition to multi-drug resistant (MDR) micro organism equivalent to MRSA and confirmed synergistic results with synthetic or natural antibiotic compounds open novel avenues for the fight of infections with rising MDR bacterial species. Nevertheless, each in vitro and in vivo (experimental and medical) research are wanted to higher perceive the molecular mechanism of antimicrobial synergies. This is applicable not solely to bacterial, but additionally to viral, parasitic, and fungal infections.