Vitamin and Microbes
REVIEW article
Introduction
The intestine is repeatedly uncovered each to poisonous (e.g., pathogenic microorganisms) and useful (e.g., dietary parts, commensal micro organism) compounds and microorganisms; subsequently, the intestinal immune system should preserve a wholesome stability between lively and suppressive immune responses. This stability is managed not solely by host immune elements comparable to cytokines but additionally by a wide range of environmental elements comparable to dietary parts and the composition of the commensal micro organism. Moreover, a number of traces of proof have demonstrated that immune homeostasis within the gut is said not solely to intestinal well being but additionally to the well being of the entire physique (1–3). Due to this fact, immune regulation by environmental elements is attracting consideration as a way of sustaining immunological well being and stopping many illnesses.
Vitamins are important for the event, upkeep, and performance of the host immune system (4, 5). Nutritional vitamins are important micronutrients which might be synthesized by micro organism, yeasts, and vegetation, however not by mammals. Due to this fact, mammals should receive nutritional vitamins from the weight loss plan or depend on their synthesis by commensal micro organism within the gastrointestinal tract. Some nutritional vitamins are water-soluble (e.g., vitamin B household and vitamin C), whereas others are fat-soluble (e.g., nutritional vitamins A, D, E, and Ok). Water-soluble nutritional vitamins aren’t saved by the physique and any extra is excreted within the urine; subsequently, it is very important devour a weight loss plan containing the mandatory quantities of those nutritional vitamins. Vitamin deficiency related to inadequate dietary consumption happens not solely in growing international locations but additionally in developed international locations on account of elevated use of unbalanced weight loss plan (6).
Along with the weight loss plan, the commensal micro organism are acknowledged as vital gamers within the management of host well being (7–9). From the standpoint of nutritional vitamins, commensal micro organism are each suppliers and shoppers of B nutritional vitamins and vitamin Ok. Though dietary B nutritional vitamins are usually absorbed by way of the small gut, bacterial B nutritional vitamins are produced and absorbed primarily by way of the colon (10, 11), indicating that dietary and intestine microbiota-derived B nutritional vitamins are presumably dealt with otherwise by the human physique. B nutritional vitamins are vital cofactors and coenzymes in a number of metabolic pathways, and it has been reported just lately that B nutritional vitamins additionally play vital roles within the upkeep of immune homeostasis (12, 13). Thus, each dietary parts and the intestine microbiota modulate host immune operate by way of B nutritional vitamins. Right here, we evaluate the metabolism and performance of dietary and intestine microbiota-derived B nutritional vitamins within the management of host immunity.
Vitamin B1
Vitamin B1 (thiamine) is a cofactor for a number of enzymes, together with pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, that are each concerned within the tricarboxylic acid (TCA) cycle (14, 15). World Well being Group (WHO)/Meals and Agriculture Group (FAO) suggest a day by day vitamin B1 consumption of 1.1–1.2 mg for grownup (16). Vitamin B1 deficiency causes lethargy and, if left untreated, can grow to be beriberi, a illness that impacts the peripheral nervous system and cardiovascular system. Accumulating proof means that power metabolism—significantly the stability between glycolysis and the TCA cycle—is related to the purposeful management of immune cells, in what’s now known as immunometabolism (17).
Immunometabolism is effectively studied in T cells and macrophages; quiescent or regulatory-type cells (e.g., naive T cells, Treg cells, and M2 macrophages) use the TCA cycle for power technology, whereas activated or pro-inflammatory cells (e.g., Th1, Th2, Th17, and M1 macrophages) use glycolysis (18, 19).
Beforehand, we examined B cell immunometabolism within the gut. Within the gut, naïve immunoglobulin (Ig) M+ B cells differentiate into IgA+ B cells in Peyer’s patches (PPs) by class switching, after which IgA+ B cells differentiate into IgA-producing plasma cells within the intestinal lamina propria (20). Naïve B cells in PPs preferentially use a vitamin B1-dependent TCA cycle for the technology of ATP. Nevertheless, as soon as the B cells differentiate into IgA-producing plasma cells, they change to utilizing glycolysis for the technology of ATP and shift to a catabolic pathway for the manufacturing of IgA antibody (Determine 1). According to the significance of vitamin B1 within the upkeep of the TCA cycle, mice fed a vitamin B1-deficient weight loss plan present impaired upkeep of naïve B cells in PPs, with little impact on IgA-producing plasma cells. Since PPs are the first websites of induction of antigen-specific IgA responses, PP regression induced by vitamin B1 deficiency results in decreased IgA antibody responses to oral vaccines (21).
Vitamin B1 is present in excessive concentrations as thiamine pyrophosphate (TPP) in meat (significantly pork and rooster); eggs; cereal sprouts and rice bran; and beans. Dietary TPP is hydrolyzed by alkaline phosphatase and transformed to free thiamine within the small gut (22). Free thiamine is absorbed by the intestinal epithelium by way of thiamine transporters (e.g., THTR-1, THTR-2) and transported to the blood for distribution all through the physique (11). Free thiamine is transformed again to TPP and is used for power metabolism within the TCA cycle.
Numerous forms of intestinal micro organism, principally within the colon, additionally produce vitamin B1 as each free thiamine and TPP (11, 23). Within the colon, free bacterial thiamine is absorbed primarily by thiamine transporters, transported to the blood, and distributed all through the physique; this mechanism is much like how free dietary thiamine is taken up within the small gut. Nevertheless, not like within the small gut, TPP produced by the intestine microbiota isn’t transformed to free thiamine, as a result of alkaline phosphatase isn’t secreted within the colon (24). As a substitute, TPP is absorbed instantly by the colon by way of TPP transporters (e.g., TPPT-1) which might be extremely expressed on the apical membrane of the colon (25). The absorbed TPP enters the mitochondria by way of MTPP-1, a TPP transporter that’s expressed within the mitochondrial interior membrane and is used as a cofactor for ATP technology (26). This implies that bacterial TPP is vital for power technology within the colon. Thus, dietary and bacterial vitamin B1 seems to have completely different roles within the host.
The vitamin B1 construction consists of a thiazole moiety linked to a pyrimidine moiety. Micro organism receive the thiazole moiety from glycine or tyrosine and 1-deoxy-d-xylulose-5-phosphate, and vegetation and yeasts synthesize it from glycine and 2-pentulose (27–30). In each micro organism and vegetation, the pyrimidine moiety is derived from 5-aminoimidazole ribonucleotide, an intermediate within the purine pathway (29). Metagenomic analyses of the human intestine microbiota predict that Bacteroides fragilis and Prevotella copri (phylum Bacteroidetes); Clostridium difficile, some Lactobacillus spp., and Ruminococcus lactaris (Firmicutes); Bifidobacterium spp. (Actinobacteria); and Fusobacterium varium are vitamin B1 producers (Desk 1) (10, 46), implying that many intestinal micro organism possess an entire vitamin B1 synthesis pathway, which incorporates pathways for the synthesis of thiazole and pyrimidine. Certainly, Lactobacillus casei produces thiamine throughout the manufacturing of fermented milk drinks (31), and Bifidobacterium infantis and B. bifidum produce thiamine in tradition supernatant (32). Nevertheless, Faecalibacterium spp. (Firmicutes) lack a vitamin B1 synthesis pathway regardless that they require vitamin B1 for his or her progress (10). Due to this fact, these micro organism should receive their vitamin B1 from different micro organism or from the host weight loss plan by way of a thiamine transporter, suggesting that there’s competitors for vitamin B1 between the host and sure intestinal micro organism.
Vitamin B2 – “b vitamin metabolism”
Vitamin B2 (riboflavin) and its lively kinds (flavin adenine dinucleotide [FAD] and flavin mononucleotide [FMN]) are cofactors for enzymatic reactions within the TCA cycle and in fatty acid oxidization (often known as β-oxidization) (15). WHO/FAO recommends a day by day vitamin B2 consumption of 1.0–1.3 mg for adults (16). Vitamin B2 deficiency suppresses the exercise of acyl-CoA dehydrogenases concerned within the oxidation of fatty acids to generate acetyl-CoA, which is utilized by mitochondria to supply ATP by way of the TCA cycle. Fatty acid oxidization is concerned within the activation, differentiation, and proliferation of immune cells by way of the technology of acetyl-CoA and its entry into TCA cycle (47). This implies that vitamin B2 is related to the management of differentiation and performance of immune cells by way of regulation of fatty acid oxidization (Determine 1); nevertheless, the immunological roles of vitamin B2 within the management of host immunity stay to be investigated. Along with power technology, vitamin B2 is related to reactive oxygen species (ROS) technology in immune cells by way of the priming of NADPH oxidase 2 (48); ROS are vital effector and signaling molecules in irritation and immunity.
Vitamin B2 is discovered at excessive ranges in leafy inexperienced greens, liver, and eggs. Dietary vitamin B2 exists as FAD or FMN and is transformed to free riboflavin by FAD pyrophosphatase and FMN phosphatase within the small gut (49, 50). Free riboflavin is absorbed by way of riboflavin transporter expressed on the epithelium of the small gut and is then launched into the blood. Within the blood, free riboflavin is transformed again to FAD or FMN and distributed all through the physique (51–53).
Bacterial vitamin B2 is synthesized from guanosine triphosphate (GTP) and d-ribulose 5-phosphate (54). Bacterial vitamin B2 exists as free riboflavin, which is instantly absorbed within the massive gut, transformed to FAD or FMN, and distributed all through the physique as described above (23). A metagenome evaluation of the human intestine microbiota by Magnúsdóttir et al. (10) has predicted that Bacteroides fragilis and Prevotella copri (Bacteroidetes); Clostridium difficile, Lactobacillus plantarum, L. fermentum, and Ruminococcus lactaris (Firmicutes) categorical elements important for vitamin B2 synthesis, suggesting that these micro organism are an vital supply of vitamin B2 within the massive gut (Desk 1). In distinction, Bifidobacterium spp., and Collinsella spp. (Actinobacteria) lack a vitamin B2 pathway. Supplementation of fermented soymilk containing Lactobacillus plantarum with riboflavin poor weight loss plan has been proven to advertise vitamin B2 manufacturing and forestall vitamin B2 deficiency in mice (35). L. fermentum remoted from sourdough can synthesize riboflavin in vitro (36). Moreover, current proof signifies that some species in Bacteroidetes phylum produce extra riboflavin than do Actinobacteria and Firmicutes phyla (55). Nevertheless, Actinobacteria and Firmicutes phyla nonetheless categorical riboflavin transporter and the enzymes needed for FAD and FMN technology from free riboflavin (i.e., FAD synthases and flavin kinases) (10, 56), suggesting that each one micro organism, together with these which might be unable to synthesize vitamin B2 themselves, require FAD and FMN for his or her progress and survival. Thus, as with vitamin B1, there may be probably competitors for riboflavin between the host and the commensal micro organism.
Along with having the ability to produce vitamin B2, some micro organism (e.g., commensals comparable to Lactobacillus acidophilus and pathogens comparable to Mycobacterium tuberculosis and Salmonella typhimurium) produce the vitamin B2 intermediate (57–59), 6-hydroxymethyl-8-d-ribityllumazine (60, 61). 6-Hydroxymethyl-8-d-ribityllumazine binds to main histocompatibility complicated class I-related gene protein (MR1) on antigen-presenting cells; this causes mucosal-associated invariant T (MAIT) cells, an ample inhabitants of innate-like T cells, to supply cytokines comparable to interferon gamma and interleukin (IL) 17, which contribute to host protection towards pathogens (Determine 2) (62). It’s thought that stimulation by commensal micro organism contributes to the event and activation of MAIT cells for immunological surveillance towards pathogens. MAIT cells additionally produce inflammatory cytokines and have tissue-homing properties, suggesting that these cells are additionally concerned within the growth of autoimmune and inflammatory illnesses (63).
Vitamin B3
Vitamin B3 (niacin) is generally called nicotinic acid and nicotinamide. These compounds are precursors of nicotinamide adenine dinucleotide (NAD), a coenzyme within the mobile redox response with a central position in cardio respiration. WHO/FAO recommends a day by day vitamin B3 consumption of 11–12 mg for adults (16).
Vitamin B3 can be a ligand of GPR109a, a G-protein coupled receptor expressed on a number of forms of cells, together with immune cells (64). Vitamin B3–GPR109a signaling induces differentiation of regulatory T cells and suppresses colitis in a GPR109a-dependent method (65). Vitamin B3 additionally inhibits the manufacturing of the pro-inflammatory cytokines IL-1, IL-6, and tumor necrosis issue alpha (TNF-α) by macrophages and monocytes (Determine 3) (66). Thus, vitamin B3 has anti-inflammatory properties by modulating host immune cells and taking part in an vital position within the upkeep of immunological homeostasis. Certainly, in people, vitamin B3 deficiency causes pellagra, which is a illness characterised by intestinal irritation, diarrhea, dermatitis, and dementia (67).
In contrast to the opposite B nutritional vitamins, vitamin B3 may be generated by mammals by way of an endogenous enzymatic pathway from tryptophan and is saved within the liver, though additionally it is obtained from the weight loss plan (68). Animal-based meals comparable to fish and meat include vitamin B3 as nicotinamide, and plant-based meals comparable to beans include vitamin B3 as nicotinic acid. Each nicotinamide and nicotinic acid are instantly absorbed by way of the small gut, the place nicotinic acid is transformed to nicotinamide.
Vitamin B3 can be synthesized from tryptophan by intestinal micro organism (69, 70). Bacteroides fragilis and Prevotella copri (Bacteroidetes); Ruminococcus lactaris, Clostridium difficile (Firmicutes); Bifidobacterium infantis (Actinobacteria); Helicobacter pylori (Proteobacteria); and Fusobacterium varium (Fusobacteria) possess a vitamin B3 biosynthesis pathway (Desk 1) (10, 71). Thus, many intestinal micro organism from varied genera can produce vitamin B3, suggesting that each dietary and commensal bacteria-derived vitamin B3 are vital for host immunity.
Vitamin B5
Vitamin B5 (pantothenic acid) is a precursor of coenzyme A (CoA), which is a necessary cofactor for the TCA cycle and fatty acid oxidation (72). WHO/FAO recommends a day by day vitamin B5 consumption of 5.0 mg for adults (16). Like nutritional vitamins B1 and B2, vitamin B5 is concerned within the management of host immunity by way of power technology by immune cells. Vitamin B5 deficiency causes immune illnesses comparable to dermatitis, in addition to non-immune-related situations comparable to fatigue and insomnia (73). In a randomized, double-blind, placebo-controlled examine in adults, dietary supplementation with vitamin B5 was proven to enhance facial pimples (74), suggesting that epithelial barrier operate improves by way of the promotion of keratinocyte proliferation and differentiation into fibroblasts (75). To take care of vitamin B5 ranges throughout instances of deficiency, CoA is transformed again to vitamin B5 or cysteamine by way of pantetheine (76). Nevertheless, cysteamine inhibits peroxisome proliferator-activated receptor gamma (PPARγ) signaling, inflicting irritation (77). Certainly, colitis has been improved in pantetheine-producing-enzyme knockout mice (78). Thus, vitamin B5 deficiency causes irritation by way of each dysfunction of the epithelial barrier and the manufacturing of pro-inflammatory molecules.
By way of immune responses, vitamin B5 enhances protecting exercise towards Mycobacterium tuberculosis an infection by selling innate immunity and adaptive immunity. In mice, vitamin B5 supplementation prompts phagocytosis and cytokine manufacturing (together with IL-6 and TNF-α) by macrophages and subsequently promotes Th1 and Th17 responses for the clearance of M. tuberculosis from the lungs (79). Thus, vitamin B5 contributes to host protection by activating immune responses, suggesting that this vitamin has an vital position as a pure adjuvant.
Vitamin B5 is present in excessive concentrations as CoA or phosphopantetheine in liver, eggs, rooster, and fermented soybeans. CoA and phosphopantetheine are transformed to free pantothenic acid by endogenous enzymes comparable to phosphatase and pantetheinase within the small gut. Free pantothenic acid is absorbed by way of sodium-dependent multivitamin transporter (SMVT) expressed on the epithelium of the small gut and is then launched into the blood (80). Lastly, free pantothenic acid is transformed again to CoA and distributed all through the physique, significantly to the liver and kidney.
Bacterial vitamin B5 is synthesized from 2-dihydropantoate and β-alanine by way of de novo synthesis pathways (10). Bacterial vitamin B5 exists as free pantothenic acid, which is instantly absorbed within the massive gut, transformed to CoA, and distributed in the identical method as dietary vitamin B5. In line with a genomic evaluation, Bacteroides fragilis and Prevotella copri (Bacteroidetes); some Ruminococcus spp. (R. lactaris and R. torques) (Firmicutes); Salmonella enterica and Helicobacter pylori (Proteobacteria) possess a vitamin B5 biosynthesis pathway, indicating that intestinal commensal micro organism can produce vitamin B5. In distinction, most Fusobacterium (Fusobacteria) and Bifidobacterium spp. (Actinobacteria) and a few strains of Clostridium difficile, Faecalibacterium spp., and Lactobacillus spp. (Firmicutes) lack such a pathway (Desk 1), though a few of them do categorical pantothenic acid transporter to make the most of vitamin B5 for power technology (10), suggesting that these micro organism compete with the host for vitamin B5.