Role of Vitamin B in Body Health and Gut Flora

## **Chapter 1**

## Vitamin B Complex and Body Weakness

*Hayder Lateef Al-msaid, Hydar Muhsin Khalfa and Hasan Hadi Ali*

### **Abstract**

B vitamins are crucial for metabolism. They are chemically unique vitamins with a variety of uses that are often present in the same meals. The vitamin B often operates in concert to provide the body with a multitude of health advantages. The metabolism has been demonstrated to be supported and speeded up by vitamin B. Maintain toned muscles and healthy skin. Boost immune and nervous system performance. Improved red blood cell development and division help to avoid anemia. Together, these factors also assist in battling the signs and causes of stress, depression, and cardiovascular disease. Water-soluble and found throughout the body, all vitamin B. Any excess that is expelled in the urine daily replenishes them, and a vitamin B shortage may result in a wide range of health issues.

**Keywords:** vitamin B, increasing vitamin B, decreasing vitamin B, vitamin B and body activities, body weakness

## **1. Introduction**

Eight water-soluble vitamins known as B vitamins are crucial for maintaining healthy cell metabolism. In the past, the B vitamins were considered to be a single vitamin known simply as the B vitamin (most people thought it was somewhat similar to vitamin C or vitamin D) [1]. They are chemically separate vitamins that are often present in the same foods and serve a variety of purposes, according to research. Vitamin B complexes are dietary supplements that include all eight B vitamins [2].

The exact name of each vitamin indicates which B vitamin supplements are being taken individually (e.g., B1, B2, and B3), The B vitamins often operate in concert to provide the body with a multitude of health advantages [3]. The metabolism has been demonstrated to be supported and speeded up by B vitamins. Maintain toned muscles and healthy skin, and boost immune and nervous system performance. Improved red blood cell production helps to avoid anemia. Together, these factors also serve to battle the signs and causes of stress, depression, and cardiovascular disease [4].

Water soluble and found throughout the body, all B vitamins. Any extra excreted in the urine is daily replaced with them. A large number of different health issues

may be brought on by vitamin B deficiency [5]. Important new research in this field is presented in this book.

Contrary to popular belief, oral vitamin B12, 1 mg daily, is used to treat the majority of vitamin B12 deficient patients worldwide.

There are at least six distinct ways that vitamin B3 (niacin) insufficiency may manifest, although they all overlap. The intake may be inadequate even when the food provides an adequate amount of niacin and there are no issues with absorption or storage [6]. This is because certain people may need unusually high levels of vitamin B-3, which a conventional diet cannot provide, due to hereditary factors. Up to onethird of genetic mutations cause the matching enzyme to have a decreased affinity for its own enzyme, which lowers the pace of the reaction [7].

Therefore, extremely large dosages of the matching enzyme may be employed to cure the roughly 50 hereditary illnesses of humans caused by these faulty enzymes. Vitamin B3 serves as a cofactor in many of the enzymes that are implicated in various hereditary diseases. These include increased risks for cancer and alcoholism brought on by poor aldehyde dehydrogenase binding, phenylketonuria II, and hyperphagia brought on by inadequate dihydropteridine reductase binding [8].

The HM74A and HM74B subtypes of niacin-responsive receptors were only recently identified. Niacin stimulates prostaglandin production *via* the high-affinity receptor HM74A. The HM74A protein is dramatically reduced in areas of the brain of schizophrenia patients, indicating a niacin-related deficiency that results in significantly increased vitamin B3 needs [9].

Niacin deficiency is most often brought on by diets with little to no vitamin B3 in them. For instance, pellagra is often detected in people who have consumed a lot of maize, a grain for which niacin is difficult to come by patients who have issues with absorption and storage are also at risk for vitamin B3 insufficiency. The body's supply of this vitamin and certain antibiotics will be depleted by excessive eating of foods like sweets and carbs [10].

Niacin deficiency is often caused by addiction and may be remedied by taking large amounts of this vitamin. Niacin, for example, is needed as a cofactor for aldehyde dehydrogenase, one of the key enzymes involved, making vitamin B3 essential for the breakdown of alcohol. Niacin and nicotine have chemical similarities; hence, nicotine may occupy receptor sites. High dosages of vitamin B3 have undoubtedly assisted some individuals in kicking their nicotine addiction [11].

The excessive oxidative stress that results in unusually high metabolic demand for this vitamin may also lead to a niacin deficit. It seems that diseases like Parkinson's, amyotrophic lateral sclerosis, and multiple sclerosis are caused by an excessive amount of dopamine being broken down, which produces neurotoxins like dopachrome [12].

This process may be speed up by vitamin B3, although the body often has low levels of the vitamin. Similar to this, individuals with schizophrenia create excessive amounts of adrenaline, as well as its hazardous metabolites, adrenochrome, and other chromium indoles. They, therefore, have niacin depletion, which is now recognized as the disease's diagnostic sign [13]. With aging, the body's capacity to absorb nutrients often decreases. As a consequence, niacin deficiency, among other vitamin inadequacies, is most prevalent among the elderly. These deficiency-related conditions react to high-dose niacin, including lipid imbalances, cardiovascular diseases, stroke, and arthritis. The recommended daily therapeutic intervention varies from 10 mg in newly diagnosed instances of pellagra from 6 to 10 grams for cholesterol normalization, cardiovascular disease, and stroke, according to the literature and Dr. Abram Hoover's experience with more than 5000 patients [14].

## **2. Health and folic acid**

There is no evidence that folic acid is also important for the development of the central nervous system. Folic acid has long been recognized to cause a kind of anemia known as megaloblastica, but there is no evidence that it may cause problems early in pregnancy and at the time of conception [15].

The neural tube develops with birth abnormalities as a result. Inadequate amounts of folic acid have recently been linked to increased blood levels of the amino acid homocysteine (Hcy). Hcy is a well-known risk factor for conditions affecting the neurological and cardiovascular systems, as well as for dementia, Alzheimer's disease, osteoporotic fractures, and problems during pregnancy [16].

Folic acid has also been linked to reducing the risk of a variety of cancers. Recent epidemiological studies, for instance, show a negative correlation between folate status and the frequency of colorectal adenomas and carcinomas, indicating that lowering this risk may require maintaining appropriate folate levels [17].

On the other side, a number of studies indicate that excessive intakes, often linked to folic acid supplements, may raise the risk of breast cancer in postmenopausal women, particularly in those who consume moderate amounts of alcohol. Additionally, there is a chance that extensive folic acid fortification may conceal a vitamin B12 shortage, which might result in neurological impairment. Similar to folic acid insufficiency, vitamin B12 deficiency results in anemia and irreparable harm to the central and peripheral neurological systems [18].

However, over many generations, folate fortification may also have an impact on genetic selection for potentially deleterious genotypes and epileptic seizure management. There is a lot of interest in learning if dietary supplements and food products include folic acid, which is increasingly being considered on a global scale as an essential functional food element [19].

Folic acid fortification may be beneficial or damaging to health. Crohn's disease (CD), which may affect any portion of the gastrointestinal system, and ulcerative colitis (UC), which can affect the colon, are the two primary manifestations of inflammatory bowel disease (IBD), which is a chronic relapsing–relapsing inflammatory disorder of uncertain cause. The cornerstone of therapy for the majority of IBD patients is medical care with aminosalicylates (5-ASA), steroids, and immunosuppressive or immunosuppressive drugs. Surgery is only performed on people who have serious illnesses that are resistant to medical treatment or who have problems [20].

In the development, management, and therapy of IBD, nutrition is crucial. Inflammatory bowel disease patients often experience malnutrition, particularly those with Crohn's disease (CD). Patients with inflammatory bowel illness have been reported to have a variety of vitamin and mineral deficiencies. Despite their pathogenic significance in clinical symptoms and the many consequences associated with IBD, nutritional disorders are often disregarded in the care of patients. There are several factors that contribute to malnutrition in IBD, including inadequate oral nutritional intake, malabsorption, and nutrient loss [21], excessive nutritional needs, iatrogenic justification for surgery or treatment. Members of the "B vitamin complex" include thiamine (vitamin B1), riboflavin (vitamin B2), niacin, pyridoxine (vitamin B6), pantothenic acid, biotin, folic acid (vitamin B9), and vitamin B12. These are substances that dissolve in water and are crucial for the metabolic functions of living cells [22].

They function as coenzymes or as prosthetic groups attached to enzymes. When one of these vitamins is improperly ingested, the utilization of the other vitamins may be compromised. Folic acid and vitamin B12 deficiencies are often reported in IBD patients, and they are also linked to the anemia, thrombosis, and carcinogenesis that are associated with the disease [23].

Patients with IBD have also been shown to have low blood concentrations of other "vitamin B complex" members because of their deficiencies. By changing branchedchain carbonic acids into straight-chain branched carbonic acids, adenosylcobalamindependent CoA-carbonyl mutations accelerate the 1,2-rearrangement of carbonyl groups. Only two mutants of this enzyme family are now known, isobutyryl-CoA and methylmalonyl-CoA (MCM, EC 5.4.99.2). Both of these mutants have undergone substantial research [24].

All of the substances are significant water and soil contaminants; therefore, the novel cobalamin and CoA-carbonyl mutations play a hitherto unrecognized function in both natural and induced bioremediation processes. Consequently, the pathways that have not yet been connected to CoA-carbonyl mutation action. Additionally, it is probable that the enzyme structure and the fold that were used to predict the development of substrate specificity are related. Finally, the potential biological and kinetic effects of using a cobalamin-dependent enzyme to bend the routes are explored [25].

The water-soluble, catalytically active form of vitamin B6 is called pyridoxal 5′-phosphate (PLP), and it functions as a cofactor for several crucial human enzymes. Unique to a range of reactions to amino acids are PLP-dependent enzymes. They have the capacity to catalyze (transport, decarboxylation, or substitution/deletion). Various reactions happen without an enzyme. However, the protein portion simultaneously directs the enzyme's catalytic power toward a particular process. This specificity is not absolute, however. Physiologically significant side reactions that most PLP enzymes catalyze may also provide fascinating stereochemical and mechanical details about the structure of the enzyme's active site [1].

Dental spirochetes include cytolysin, a PLP-dependent C-S lyase whose most significant interaction is the removal of, from L-cysteine to create pyruvate, ammonia, and H2S. The latter is most likely in charge of the catalytic enzyme's hemolytic and hemeoxide-related action. One of the best examples of PLP-dependent enzymes' very versatile catalysts is cystalysin. In reality, it has only recently been shown that cetalicin is present [26].

Additionally, it may catalyze the transition between L- and D-alanine with turn numbers estimated in minutes, as well as the cracking of both isoforms of alanine, desulfurization of sulfuric acid L-cysteine, and decarboxylation of L-aspartate and oxalacetate. The cofactor binding mode, substrate specificity, formation of intermediate reactions typical of most PLP enzymes, and involvement of some active site residues in primary and secondary catalytic reactions are just a few of the intriguing characteristics of cystalysin that have been revealed through extensive biochemical investigations [27].

### **3. High homocysteine levels**

Plasma from patients with renal failure, hypothyroidism, and methyltetrahydrofolate reductase polymorphism as well as those with homocystinuria, a hereditary disorder with a recessive pattern, was examined. The most crucial cerebral impairment, osteoporosis, lens shift, and arterial and venous thrombosis are among clinical symptoms of elevated plasma homocysteine levels. About 50% of deaths in patients with chronic renal failure are caused by cardiovascular illnesses, which are the main

*Vitamin B Complex and Body Weakness DOI: http://dx.doi.org/10.5772/intechopen.109486*

source of morbidity and mortality in the general population. Hyperhomocysteinemia is decreased by vitamin B6, vitamin B12, and folic acid. Transformation of sulfur and the remethylation process [28].

Although vitamin B medications often fail to correct plasma homocysteine levels, their long-term benefits are helpful in lowering the life-threatening vascular dangers that patients with homocystinuria face.

Patients with chronic renal failure, particularly those with stage V chronic kidney disease, are found to have hyperhomocysteinemia. The outcomes of observational clinical investigations on the consequences of increased plasma homocysteine levels on cardiovascular disease in hemodialysis patients have varied. In fact, several studies have shown a relationship between hypohomocysteinemia and cardiovascular disease fatalities in addition to hyperhomocysteinemia. The strong correlation between homocysteine and inflammatory indicators of malnutrition may be the cause of these contradicting observations [29].

Malnutrition-atherosclerotic syndrome is a serious clinical disease that often affects dialysis patients, interfering with homocysteine levels. My colleagues and I recently noticed in a clinical study that dialysis patients who were receiving vitamin B treatment and had high protein catabolism and low homocysteine levels outlived the other three groupings by a substantial margin. Recent prospective clinical trials that looked at the effects of moderate hyperhomocysteinemia patients receiving vitamin B treatment to decrease homocysteine on cardiovascular events revealed no therapeutic benefits. Because some of the patients had normal homocysteine levels, the follow-up period may have been too little, and confounding variables were not taken into consideration, these findings may be deceptive [30].

The study discusses the interesting mystique surrounding homocysteine and highlights the most relevant information about the impact of vitamin B therapy on cardiovascular events.

### **4. Vitamin B12**

Two important enzyme pathways the conversion of homocysteine to methionine and the conversion of methylmalonyl coenzyme A to succinyl coenzyme are affected physiologically by it. Elevated blood homocysteine and methylmalonic acid result from disruption of any of these processes brought on by vitamin B12 deficiency. When folic acid levels are low, homocysteine levels also increase. It has been proposed that serum homocysteine rather than serum vitamin B12 analysis is more sensitive to intracellular functional vitamin B12 insufficiency. As a result, in the so-called one-carbon cycle, homocysteine, vitamin B12, and folic acid are strongly tied to one another [31]. The suggested mechanism is connected to methylation processes involving the nervous system's metabolism of homocysteine. The coenzyme that is required for its effective functioning is vitamin B12 methionine can only be produced when 5-methyletrahydrofolate donates its methyl group to tetrahydrofolate. On the other side, folate stimulates the remethylation of homocysteine, a cytotoxic molecule that contains sulfur, making it a cofactor in one-carbon metabolism [32].

Amino acids have the ability to cause DNA strand breaks, oxidative damage, and cell death. What or what appears to be consistent with the widespread belief that vitamin B12 and folic acid, either directly through the maintenance of two functions, DNA synthesis and methylation reactions, or indirectly, as a result of their deficiency, which results in methylation reactions mediated by SAM that are inhibited by its

product SAH, and from through the related toxic effects of homocysteine causing direct damage to the vascular endothelium and inhibition of N-methyl-D [33].

This vitamin functions in a rising number of organs and bodily systems, the list of which is constantly expanding. The peripheral and central neurological systems, bone marrow, skin, mucous membranes, bones, and blood vessels are all impacted, in addition to children's typical growth. In addition to a sophisticated chemical structure, vitamin B12 (cobalamin) also includes the trace element cobalt, which is vital for human health. Vitamin B12 has significant immunological and neurotrophic effects in addition to playing a significant role in DNA synthesis. The human body's many systems must remain in balance. Even under the worst illness stressors, the individual is the ideal illustration of a system that always strives to attain optimum control. Consider that everything is standard and replaceable (as needed) if vitamin B12 is one of these things, why is it important, it is conceivable that therapy with vitamin B12 may rectify abnormalities brought on by other physiologically active chemicals even when the blood cobalamin level is normal [34]. This has been shown to be effective in treating recurrent aphthous stomatitis with vitamin B12 (regardless of blood level!**)** in the authors' research. This phenomenon is referred to as the "master switch" effect. Deficiency in vitamin B12 is a widespread issue that affects the entire population. Clinically significant is the early identification of vitamin B12 insufficiency, and there is evidence that deficiency occurs more often than anticipated. Patients who are unable to absorb vitamin B12 from food and people with dietary habits that exclude animal foods are both at risk for vitamin B12 insufficiency [35]. In addition, owing to the association between meat, cholesterol, and cardiovascular disease, there is a widespread inclination to steer clear of foods rich in vitamin B12, such as beef. Additionally, there is a propensity toward vegetarianism due to ideological reasons, particularly among the younger population. Two key causes of the low consumption of animal products, particularly red meat, are changes in lifestyle among population groups with high socioeconomic status and the prevalence of poverty. As a result, the amount of vitamin B12 in the general population is declining, which has an impact on the pathology caused by vitamin B12 deficiencies (e.g., neurological and hematological disorders). If more studies corroborate the link between homocysteine and vitamin B12, the authors may also report an increase in cardiovascular disease. Instead of these changes, major health issues should be avoided [36].

## **5. Vitamin B6**

This vitamin is made up of a number of pyridoxal-containing substances, including pyridoxol, pyridoxamine, pyridoxaldehyde, and its derivatives. Structure the pyridoxine transporter at the sinusoidal pole has a determining hepatocyte absorption of pyridoxal, the catalytically active form of vitamin B6. Because pyridoxal may be transported to cells by an organ transport system when pyridoxine transporters in hepatocytes can specifically detect and bind to the structure. Thus, pyridoxine may be used as a liver-targeting group and added to big molecules and low molecular weight drugs to be used as contrast in MRI agents and anticancer comparisons [37]. The study of medication transport to the liver advances. The insertion of pyridoxine into these compounds has been shown to boost their liver absorption, and the molecules that include pyridoxine groups have liver-targeting characteristics.

## **6. Conclusions**

B vitamins are crucial for metabolism. They are chemically unique vitamins with a variety of uses that are often present in the same meals.

The B vitamins often operate in concert to provide the body with a multitude of health advantages. The metabolism has been demonstrated to be supported and speeded up by vitamin B. Maintain toned muscles and healthy skin. Boost immune and nervous system performance. Improved red blood cell development and division help to avoid anemia. Together, these factors also assist to battle the signs and causes of stress, depression, and cardiovascular disease.

Water soluble and found throughout the body, all B vitamins. Any excess that is expelled in the urine daily replenishes them, and a vitamin B shortage may result in a wide range of health issues.

## **Author details**

Hayder Lateef Al-msaid\*, Hydar Muhsin Khalfa and Hasan Hadi Ali Department of Biology, Kufa University, Najaf, Iraq

\*Address all correspondence to: haiderl.ligan@uokufa.edu.iq

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## Vitamin B, Role of Gut Microbiota and Gut Health

*Satrio Wibowo and Almira Pramadhani*

## **Abstract**

The human gastrointestinal system is constantly exposed to pathogenic microorganisms and beneficial compounds, such as food components and commensal bacteria. Vitamin B are a class of water-soluble organic compounds obtained through diet, supplementation, and gut microbiota synthesis. B vitamins are absorbed for host metabolism in the small intestine, whereas microbes produce and absorb B vitamins in the large intestine. The authors have accumulated evidence from various studies that each B vitamin plays an essential role in gastrointestinal health and has a reciprocal relationship with the gut microbiota. Previous studies have also proven that microbial imbalance in the gut lead to competition for the utilization of B vitamins between the host and microbes, affecting the gut microbial composition, gut health, and host metabolism. This review aims to explain further the types of B vitamins in human digestion, the mechanism of B vitamin synthesis, and the role of B vitamins in the composition of the gut microbiota and the health of the gastrointestinal tract. Thus, it can help practitioners to consider administering B vitamins to maintain the patient's gut health.

**Keywords:** B vitamins, microbiota, intestine, biosynthesis, gut health

## **1. Introduction**

The human gastrointestinal system is continuously exposed to toxic compounds, such as pathogenic microorganisms, and beneficial compounds, such as food components and commensal bacteria. Therefore, the immunity of the gastrointestinal system must be balanced between an active and suppressive immune response. Vitamins are micronutrients essential for normal human metabolism because they have various physiological effects, one of which is immunity. So, vitamin deficiency causes an increased risk of infectious diseases, allergies, and inflammation that can damage the gastrointestinal system. Over the past decade, a large number of studies have investigated the role of vitamins in various gastrointestinal diseases, including their potential in the prevention or treatment of various malignancies, inflammatory diseases, and hepatobiliary disorders [1, 2].

One of the vitamins that have a role in the gastrointestinal system is vitamin B, a group of water-soluble organic compounds with various functional roles, including cofactors in many enzymatic reactions, cellular energy-producing reactions, neurotransmitter synthesis, cell signaling, nucleic acid biosynthesis, and immune

function. The intestine is an important organ, especially for storing and absorbing food. The gut also has the densest microbiota in the body, consisting primarily of four major phyla, that is, Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria. The microbiota will maintain a symbiotic relationship with the host and protect against harmful pathogens. Some gut microbiota also produces limited amounts of B vitamins, and some require B vitamins for growth. Much evidence has shown that a healthy gut is associated with a healthy microbiota ecology, and B vitamins play an essential role in modifying the gut microbiota [3].

Although B vitamins from food are mainly absorbed in the small intestine, excess B vitamins cannot be absorbed in the small intestine and are transferred to the more distal intestine. Thus, the biosynthesis of B vitamins is mostly supplied by the distal gut microbiota. B vitamins in the distal intestine are dominant in performing important physiological functions in the body, including acting as nutrients for the host and microbiota, regulating immune cell activity, mediating drug efficacy, suppressing colonization of pathogenic bacteria, and modulating colitis. Therefore, the deficiency of B vitamins will certainly damage normal cell metabolism and trigger the development of several pathogenic microorganisms in the intestines [3, 4].

## **2. Types of B Vitamins in human digestion**

Vitamins are essential micronutrients that all living cells need to carry out biochemical reactions. Vitamins are classified into fat-soluble and water-soluble. The fat-soluble vitamins are vitamins A, D, E, and K, while the water-soluble vitamins include vitamin C, biotin (vitamin H or B7), and a series of B vitamins—thiamin (B1); riboflavin (B2); niacin (B3); pantothenic acid (B5); pyridoxine, pyridoxal, pyridoxamine (B6); folic acid (B9), and cobalamin (B12) [5]. Fat-soluble vitamins act as essential elements of cell membranes, and the excess is stored by cells. Water-soluble vitamins function as coenzymes for specific chemical biochemical reactions, and the excess is excreted in the urine [6].

#### **2.1 Vitamin B1**

Vitamin B1 (thiamin) is a cofactor for several enzymes, including pyruvate dehydrogenase and a-ketoglutarate dehydrogenase, which are involved in the tricarboxylic acid (TCA) cycle. The thiamin molecule consists of a pyrimidine ring (4-amino-2-methylpyrimidine) and a thiazolium (4-methyl-5-(2-hydroxyethyl)-thiazolium), linked by a methylene bridge between the C3 carbon atom of the pyrimidine ring and the N3 nitrogen atom of the thiazolium ring. Vitamin B1 is found in high concentrations as thiamin pyrophosphate (TPP) [2, 7]. Thiamine strengthens the immune system, degrades glucose, helps nerve communication, and maintains processes in cells and tissues [8].

The intestinal epithelium absorbs free thiamine through thiamine transporters, that is, THTR-1 and THTR-2, which are transported to the blood for distribution throughout the body. Free thiamine is converted back to TPP and used for energy metabolism in the TCA cycle. The mechanism of thiamine absorption from food and microbiota is relatively similar. However, TPP produced by the gut microbiota is not converted to free thiamin because alkaline phosphatase is not secreted in the large intestine. Thus, TPP from the microbiota is absorbed directly by the large intestine.

The TPP transporter is widely expressed in the apical membrane of the colon. Absorbed TPP enters the mitochondria via MTPP-1 and is used as a cofactor for ATP formation. This suggests that TPP microbiota is vital for energy generation in the large intestine, by a mechanism that differs between vitamin B1 from the diet and from the microbiota [2].

### **2.2 Vitamin B2**

Vitamin B2 (riboflavin) and its active forms (flavin adenine dinucleotide FAD] and flavin mononucleotide FMN]) are cofactors for enzymatic reactions in the TCA cycle and electron transport mediators of fatty acid oxidation (β-oxidation). Riboflavin is also involved in the metabolism of folate, vitamin B12, and vitamin B6, so it helps maintain the integrity of the mucosa, skin, eyes, and nervous system. Riboflavin is essential in the early development of the brain and postnatal gastrointestinal tract, as it can modulate some metabolic activities such as DNA repair, iron absorption and distribution, inflammation, and immune responses [2, 9].

The process of riboflavin absorption in the small intestine and colon is specific and mediated by the transporters RFVT-1, RFVT-2, and RFVT-3. All three are products of the SLC52A1, SLC52A2, and SLC52A3 genes expressed in the human gut, respectively, with RFVT-3 expression being the dominant one [9]. Exogenous vitamin B2 in the form of FAD or FMN is converted into free riboflavin by FAD pyrophosphatase and FMN phosphatase in the small intestine [2].

#### **2.3 Vitamin B3**

Niacin and niacinamide, known as nicotinic acid (NA) and nicotinamide (Nam), are different forms of vitamin B3. Vitamin B3 is a biosynthetic precursor for nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+), which are coenzymes in respiratory oxidation processes, the Krebs cycle, the formation and inhibition of reactive oxygen species (ROS), posttranslational protein and regulatory protein modification, and the formation of a second messenger. Vitamin B3 also functions for DNA proliferation. Thus, vitamin B3 is the center of homeostasis and cellular growth [2, 8, 10].

In contrast to other B vitamins, vitamin B3 can be produced by mammals via the endogenous enzymatic pathway from tryptophan and stored in the liver. However, vitamin B3 must also be obtained from food [2]. Vitamin B3 deficiency is endemic in some areas of the world where malnutrition is common. In more developed countries, vitamin B3 deficiency is caused by poor food choices, adverse drug reactions, alcoholism, and infectious or autoimmune diseases [6, 10].

### **2.4 Vitamin B5**

Vitamin B5 (pantothenic acid) is a coenzyme A (CoA) precursor, an important cofactor for the TCA cycle and fatty acid oxidation. CoA has a role in various human biochemical reactions, such as cell growth, intermediate metabolism, and neurotransmitter synthesis. The structure of CoA functions as an activating carbonyl group and as an acyl group carrier to help facilitate these reactions. Like vitamins B1 and B2, vitamin B5 is also involved in controlling host immunity through energy production by immune cells [2, 11].

From dietary sources, vitamin B5 is found in high concentrations as CoA or phosphopantethein. CoA and phosphopantetheine are then converted to free pantothenic acid by endogenous enzymes such as phosphatase and pantetheinase in the small intestine. Whereas, from the microbiota, Vitamin B5 is produced in the form of free pantothenic acid, which is directly absorbed in the large intestine, converted to CoA, and distributed in the same way as vitamin B5 from food [2].

#### **2.5 Vitamin B6**

Vitamin B6 has the basic structure of 2-methylpyridine, 3-hydroxypyridine, and 5-hydroxymethyl pyridine. Vitamin B6 consists of various forms, that is, pyridoxal (aldehyde, eCHO), pyridoxine (alcohol, eCH2OH), and pyridoxamine (amine, eCH2NH2). These forms of vitamin B6 are precursors of the coenzymes pyridoxal phosphate (PLP) and pyridoxamine phosphate (PMP), which are involved in various cellular metabolic processes, including amino acid, lipid, and carbohydrate metabolism. Vitamin B6 also plays a role in nucleotide synthesis, neurotransmitter metabolism, and heme synthesis. So, this vitamin affects almost all aspects of metabolic function and cellular homeostasis. Vitamin B6 deficiency causes inflammation such as allergies and rheumatoid arthritis, as well as nerve dysfunction [2, 12].

Dietary vitamin B6 is available in the form of PLP or PMP, which is then converted into free vitamin B6 by the endogenous enzyme pyridoxal phosphatase and subsequently absorbed by the small intestine. Absorption of B6 from food sources occurs primarily in the small intestine jejunum, with the absorption rate varying according to the B6 species present. Meanwhile, microbial-synthesized vitamin B6 in the form of PLP is converted into free vitamin B6 in the large intestine, then absorbed through passive transport, transported to the blood, and distributed throughout the body [2, 12, 13].

#### **2.6 Vitamin B7**

Biotin (vitamin B7 or vitamin H) is a B-complex vitamin that acts as an essential coenzyme for five carboxylases: pyruvate carboxylase, 3-methylcrotonyl-CoA carboxylase (MCC), propionyl-CoA carboxylase (PCC), and acetyl-CoA carboxylase 1 and 2. This carboxylase helps several chemical processes in cells, including gluconeogenesis, amino acid metabolism, and fatty acid synthesis. Acetyl-CoA carboxylase 1 is found in the cytoplasm and catalyzes the binding of bicarbonate to acetyl-CoA during the synthesis of fatty acids, while another carboxylase is found in mitochondria. PCC catalyzes a critical step in the metabolism of propionyl-CoA, which is derived from the catabolism of odd-chain fatty acids and several other nutrients. Meanwhile, MCC catalyzes the metabolism of the amino acid leucine. Pyruvate carboxylase catalyzes the conversion of pyruvate into oxaloacetate, which is a key step in gluconeogenesis [14, 15].

The enzyme holocarboxylase synthetase (HLCS) catalyzes the binding of biotin to all five carboxylases, thus playing an essential role in biotin-dependent metabolic pathways. In addition, HLCS also functions in gene regulation at the chromatin level. Meanwhile, the biotinidase enzyme in the small intestine catalyzes the release of biotin from the breakdown product of carboxylase, thus playing an important role in biotin recycling. Free biotin is then absorbed via the biotin transporter SMVT [2, 15].

#### **2.7 Vitamin B9**

Vitamin B9 (folate), in its active form as tetrahydrofolate, is a cofactor in several metabolic reactions, including the synthesis of DNA and amino acids. A folic acid is a synthetic form of folate found in supplements. Bacteria use folate to synthesize the nucleic acids that make up their DNA. In an animal model of endometrial carcinoma study, folate was found to be the most important B-complex vitamin for nucleic acid synthesis, amino acid conversion, and antioxidant properties for eliminating free radicals [16]. In addition to DNA synthesis, folate also functions as a cofactor in homocysteine methylation and reduces the risk of *neural tube defects* [8]. Folate supplementation studies have also demonstrated a role in preventing other diseases, such as neurological disorders and cognitive and psychiatric disorders, and protection against degeneration in ulcerative colitis [17].

Vitamin B9 in food is available in monoglutamate and polyglutamate folate. In the intestinal epithelium, the folate transporter PCFT deconjugates polyglutamate folate to monoglutamate folate, which is then absorbed in the small intestine. Before being transported to the blood, monoglutamate is converted to tetrahydrofolate (THF), an active form and cofactor. Intestinal bacteria produce vitamin B9 as THF from GTP, erythrose 4-phosphate, and phosphoenolpyruvate. Bacterial THF is absorbed directly in the large intestine via PCFT and circulated throughout the body by the blood [2]. Folic acid is converted by the body into DHFR (DiHydro-Folate Reductase), which commensal and pathogenic bacteria can use to form nucleic acids, thus being the basis of their survival and reproduction cycles [2, 17].

#### **2.8 Vitamin B12**

Vitamin B12 (cobalamin) is composed of a corrin ring, with a cobalt center, and has upper and lower ligands as coordinates. The active forms of this vitamin are methylcobalamin and adenosylcobalamin, which catalyze the synthesis of methionine. Food vitamin B12 is decomposed from protein into free vitamin B12 by pepsin in the stomach. Free vitamin B12 is then absorbed by small intestinal epithelial cells via intrinsic factor (IF), a gastric glycoprotein. In epithelial cells, the IF-vitamin B12 complex is decomposed into free vitamin B12 by lysosomes and then released into the blood, becoming an active form and distributed throughout the body. Cobalamin and cobamide contain cobalt, but cobamide has a lesser ligand consisting of 5, 6-dimethylbgensiidazole (DMB). Mechanically, the lower DMB ligand is essential for binding Vitamin B12 to intrinsic factor (IF); then, it can be recognized by cubilin and megalin, which facilitate endocytosis in intestinal epithelial cells. Bacterial Vitamin B12 is synthesized from precorrin-2 to produce adenosylcobalamin, which is absorbed directly by the large intestine and distributed throughout the body [2, 18].

Vitamin B12 functions for nucleotide synthesis, branched-chain amino acid regulation, long-chain fatty acid metabolism, and cellular development. Vitamin B12 is also a vital cofactor in cytoplasmic methionine synthase and in mitochondrial methylmalonyl-CoA mutase, leading to homocysteine methylation to methionine and the conversion of methylmalonyl-CoA to succinyl-CoA. Furthermore, Vitamin B12 is a cofactor that other gut microbiota use to regulate the breakdown of short-chain fatty acids such as butyrate, propionate, and acetic acid. Vitamin B12 has also been shown to maintain healthy nerve cells and help red blood cell synthesis. This vitamin plays a role to immune homeostasis, utilization of microbial metabolites, and cellular metabolism, making it an essential factor in immunity against pathogens [2].

## **3. Synthesis of Vitamin B and role of microbiota**

Humans cannot synthesize vitamins except for vitamin D. So, other vitamins must be obtained exogenously from food or the gut microbiota. Commensal bacteria found in the gut, such as Lactobacillus and Bifidobacterium, can synthesize de novo vitamins in the human body. Members of the gut microbiota can synthesize vitamin K and most of the water-soluble B vitamins, such as vitamins B12, B9, B6, B2, and B1 [6]. Each of the B vitamins has a different synthesis mechanism, and the microbiota synthesize most.

#### **3.1 Vitamin B1**

Various gut microbiota, mainly in the large intestine, produce vitamin B1 as free thiamin and TPP. *Bacteroides fragilis* and *Prevotella copri* (phylum Bacteroidetes); *Clostridium difficile*, some *Lactobacillus spp*., *Ruminococcus lactaris* (Firmicutes); *Bifidobacterium sp.* (Actinobacteria); and *Fusobacterium varium* are microbiota that can produce vitamin B1 through thiazole and pyrimidine synthesis pathways [2]. It is estimated that synthesizing thiamin by gut microbes supplies about 2.3% of the daily requirement of human vitamin B1. The enzymes involved in the thiamin biosynthetic pathway are dominantly found in enterotype 2, which is one of the gut microbiota clusters rich in *Prevotella sp.* [4]*.* In the intestine, there is *Faecalibacterium spp.* (Firmicutes), which lacks the vitamin B1 synthesis pathway and requires vitamin B1 for growth. Therefore, these bacteria must obtain vitamin B1 from other bacteria or from the host's diet via thiamin transporters in the mucosa. This indicates that there is competition for vitamin B1 requirements between the host and specific microbiota [5].

#### **3.2 Vitamin B2**

Not much different from vitamin B1, the synthesis of vitamin B2 is also widely played by the microbiota. Riboflavin from food, plus riboflavin produced by commensal bacteria, causes excess riboflavin in the distal intestine. In addition to the common lactic acid bacteria producing riboflavin in the gut, genomic analysis of 256 species of human gut microbiota has found 56% of the microbiota possess a cluster of genes for de novo riboflavin biosynthesis [4]. *B. fragilis, P. copri, C. difficile, Lactobacillus plantarum, Lactobacillus fermentum,* and *R. lactaris* have important factors for the synthesis of vitamin B2, so these bacteria are important sources of vitamin B2. *Bacillus subtilis* and *Escherichia coli* can also carry out riboflavin biosynthesis. Riboflavin biosynthesis requires guanosine 5′-triphosphate (GTP) and ribulose 5-phosphate as precursors. The first step of the branch of the GTP-dependent biosynthetic pathway is encoded by ribA, which catalyzes the 3,4-dihydroxy-2-butanone 4-phosphate configuration of ribulose 5-phosphate [5]. In clinical trials, it was found that daily consumption of 200 g of yogurt for 2 weeks can contribute to total vitamin B2 in the body, which is reflected in an increase in plasma-free riboflavin levels. This clinical trial also showed that most of the Lactobacilli strains consume riboflavin, thereby reducing its bioavailability in fermented products. Tempe, a traditional Indonesian fermented soybean meal, has been shown to increase the concentration of B vitamins such as riboflavin due to its microbial biosynthesis. The last article also reported that bacterial isolation from tempeh, which was shown to belong to Streptococcus and Enterococcus, significantly increased the concentration of riboflavin in this fermented product [19].

## **3.3 Vitamin B3**

Unlike other B vitamins, vitamin B3 can be synthesized by the body from the amino acid tryptophan through endogenous enzymatic pathways and then stored in the liver. Niacin is a group of nicotinamide and nicotinic acid. These two metabolites are precursors for nicotinamide adenine dinucleotide (NAD), so nicotinamide and nicotinic acid can also be produced by recycling NAD in cells. An organism is considered a niacin producer when it contains the de novo synthesis pathway of NAD. These organisms include *B. fragilis, P. copri, R. lactaris, C. difficile, Bifidobacterium infantis, Helicobacter pylori,* and *F. varium* [2, 20]. Colonocytes have mechanisms that mediate niacin uptake transporters. Supplementation of microcapsules containing niacin will release its contents in the ileocolonic area, which increases the serum niacin concentration according to the dose consumed. Intake of 900 to 3000 mg niacin microcapsules will significantly increase the Bacteroidetes population [4].

## **3.4 Vitamin B5**

For the synthesis of vitamin B5, bacteria synthesize from 2-dihydropantoate and beta alanine via the de novo synthesis pathway. Bacteria that have a biosynthetic pathway for vitamin B5 include *B. fragilis*, *P. copri*, some *Ruminococcus spp.*, *Salmonella enterica*, and *H. pylori*. Some bacteria synthesize free pantothenic acid, which is directly absorbed in the large intestine to be converted into Co, and distributed in the same way as vitamin B5 from food. Various bacteria, including *E. coli*, *Salmonella typhimurium*, and *Corynebacterium glutamicum*, can synthesize vitamin B5. Some of these bacteria use aspartate and intermediate metabolites of valine biosynthesis to produce vitamin B5. In contrast, most of the *Fusobacterium spp.*, *Bifidobacterium spp*., some strains of *C. difficile*, *Faecalibacterium spp*., and *Lactobacillus spp.* do not have this pathway, and some express pantothenic acid transporters to utilize vitamin B5 as an energy source. This indicates that these bacteria compete with the host for vitamin B5 [2, 3, 6, 21].

## **3.5 Vitamin B6**

There are various forms of vitamin B6 in the body, that is, pyridoxine, pyridoxal, and pyridoxamine. Vitamin B6 in food is converted into free vitamin B6 by endogenous enzymes, such as pyridoxal phosphatase, before being absorbed by the small intestine. Microbiota with a biosynthetic pathway for vitamin B6 includes *B. fragilis*, *P. copri*, *Bifidobacterium longum*, *Collinsella aerofaciens*, and *H. pylori*. In contrast, most of the Firmicutes genera (*Veillonella, Ruminococcus, Faecalibacterium,* and *Lactobacillus spp.*) lack the vitamin B6 biosynthetic pathway [2].

## **3.6 Vitamin B7**

As much as 40% of the human gut microbiota can synthesize de novo vitamin B7. The microbiota produce this vitamin as free biotin, which is synthesized from malonyl CoA or pimellate via pimeloyl CoA. Microbiota with a biosynthetic pathway for vitamin B7 include *B. fragilis, P. copri*, *F. varium,* and *Campylobacter coli.* The production of vitamin B7 affects others microbiota; for example, *B. longum*, which produces pimelate, a precursor of vitamin B7 that certainly increases the production of vitamin B7 by other gut microbiota. Biotin absorption in the small and large intestines occurs via a transporter-mediated process encoded by the SLC5A6 gene. Lipopolysaccharides inhibit colonic biotin uptake by impairing the expression of these membrane transporters. Biotin utilization also occurs between the host and bacteria, like *Lactobacillus murinus*, which consumes and reduces the biotin available in the intestine [2, 4].

#### **3.7 Vitamin B9**

The gut microbiota synthesizes vitamin B9 as tetrahydrofolate (THF) from GTP, erythrose 4-phosphate, and phosphoenolpyruvate. Dihydropteroate synthase catalyzes Folate biosynthesis, which reduces dihydrofolate to tetrahydrofolate [5]. THF is then directly absorbed in the large intestine and distributed throughout the body. Microbiota such as *B. fragilis*, *P. copri*, *C. difficile*, *L. plantarum*, *Lactobacillus reuteri, Lactobacillus delbrueckii ssp. bulgaricus,* and *Streptococcus thermophilus* and several species of *Bifidobacterium spp*., *F. varium*, and *S. enterica* have folate biosynthetic pathways. It shows that almost all species in all phyla of microbiota produce folate. However, the ability of some of these bacteria to produce and utilize folate varies widely due to straindependent properties. Some Bifidobacteria do not produce folate when this vitamin is present, whereas others produce it regardless of vitamin concentration. Microorganisms are also able to increase folate content in a wide variety of foods [2, 19].

#### **3.8 Vitamin B12**

Vitamin B12 is a vitamin that contains cobalt, with the active forms being methylcobalamin and adenosylcobalamin. Dietary vitamin B12 forms a complex with dietary protein, further decomposed into free vitamin B12 by pepsin in the stomach. Free vitamin B12 is then absorbed by small intestinal epithelial cells via a gastric glycoprotein, intrinsic factor (IF). In epithelial cells, the IF-vitamin B12 complex is decomposed into free vitamin B12 by lysosomes and then released into the blood, which is further converted into the active form and distributed throughout the body [2].

Vitamin B12 is produced by aerobic and anaerobic pathways, with 30 different enzymes required for its biosynthesis. Several genes express enzymes essential for de novo vitamin B12 biosynthesis [18]. Bacterial vitamin B12 is synthesized from precorrin2 to produce adenosylcobalamin, which is then absorbed directly by the large intestine and distributed throughout the body. Microbiota with a biosynthetic pathway for vitamin B12 include *B. fragilis*, *P. copri*, *C. difficile, Faecalibacterium prausnitzii*, *R. lactaris*, *Bifidobacterium animalis, B. infantis*, *B. longum*, and *F. varium*. In addition to the microbiota, *L. plantarum* and *Lactobacillus coryniformis* also produce vitamin B12 from fermented foods, and *B. animalis* synthesizes vitamin B12 during milk fermentation [2, 21].

### **4. Sources of B Vitamins from the diet**

Sources of B vitamins can be obtained apart from the biosynthetic mechanism, that is, exogenously from food. Vitamin B1 is found in high concentrations as thiamin pyrophosphate (TPP) in meat, especially pork and chicken; egg; cereals and rice; as well as nuts. The *World Health Organization* (WHO) / *Food and Agriculture Organization* (FAO) recommends a daily intake of 1.1–1.2 mg of vitamin B1 for adults [2].

Vitamin B2 is found in many animal sources, such as poultry, fish, liver, and eggs. Dairy products and cheese can also be sources of riboflavin, which makes a significant *Vitamin B, Role of Gut Microbiota and Gut Health DOI: http://dx.doi.org/10.5772/intechopen.109485*

contribution to children and adults. Vegetable sources such as cereals, grain products, and bread can be a source of riboflavin-rich foods in some developing countries. Leafy greens, such as broccoli, mustard, and turnips, are also good sources of riboflavin. Natural grain products tend to be relatively low in riboflavin, but when intake is increased, these foods increase the bioavailability of riboflavin. WHO/FAO recommends a daily intake of 1.0–1.3 mg of vitamin B2 for adults [2, 15].

Animal foods such as fish and meat contain vitamin B3 as nicotinamide, and plant foods such as nuts and mushrooms contain vitamin B3 as nicotinic acid. WHO/FAO recommends a daily intake of 11–12 mg of vitamin B3 for adults. Vitamin B5 is high in concentrations of CoA or phosphopantetheine in the liver, eggs, milk, chicken, beef, salmon, cereals, grains, and fermented soybeans. WHO/FAO recommends a daily intake of 5 mg of vitamin B5 for adults [1, 2, 11].

Vitamin B6 is abundant in salmon, chicken, tofu, sweet potatoes, potatoes, bananas, and avocados. Vitamin B6 found in food is in the form of PLP or PMP. WHO/FAO recommends a daily intake of 1.3–1.7 mg of vitamin B6 for adults. Vitamin B7 is abundant in foods such as egg yolks, heart, cereals such as oats, nuts, vegetables such as spinach and mushrooms, rice, and vegetable oil. Dairy and breast milk products also contain biotin. Raw egg whites contain large amounts of avidin, which binds tightly to vitamin B7 and prevents its absorption in the intestines. WHO/FAO recommends a daily intake of vitamin B7 of 30 g for adults [1, 2, 14].

Foods such as beef liver, spinach, and asparagus are high in vitamin B9. Legumes, red meat, and liver also contain high levels of folate. However, up to 70% of folate is lost during cooking due to thermal degradation or dissolution in the cooking water. WHO/FAO recommends a daily intake of 400 g of vitamin B9 for adults. Most humans get vitamin B12 from food, especially from animal protein and fermented foods. Vitamin B12 is found in beef liver, bivalves, salmon, chicken, eggs, beans, and spinach. WHO/FAO recommends a daily intake of 2.4 g of vitamin B12 for adults [2, 18, 22].

From the explanation of the acquisition of vitamins from these foods, malnutrition will significantly inhibit normal metabolism in infants and the elderly. In the case of dietary supplements, vitamin-containing probiotic products are generally produced as freeze-dried powders and formulated as capsules, powders, and tablets [23]. Parameters influencing the manufacture of this dietary supplement include viable cell count and water activity. For the application of probiotics as food and drink, the product is prepared in the form of vegetative cells and added to food products [24]. Probiotic products require special care for the profile of a product, mitigation of health risks due to pathogens, and maintenance of aseptic conditions [25].

### **5. Role of B Vitamins in gut microbiota**

B vitamins are biosynthetic precursors of essential cofactors in various metabolic pathways and play an important role in immunity. In addition to being needed by the host, B vitamins are also needed by some intestinal microbiota for metabolism. Thus, in addition to producing B vitamins, the gut microbiota also consumes B vitamins for primary enzymatic reactions. The gut microbiota is one of the densest microbial communities in the human body. This microbial community consists primarily of four main phyla, that is, Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria. In the large intestine, the microbiota are grouped into 2, namely, B-vitamin-producing bacteria and auxotrophic bacteria. The survival of bacteria of auxotrophic species is highly dependent on B vitamins. Although most B vitamins are absorbed in the small

intestine, B vitamins are produced and absorbed by bacteria mainly through the large intestine. Many B-vitamin transporters are expressed in the large intestine. As a result, there is competition between the host and bacteria. So that the host experiencing dysbiosis—the gut microbiota is unbalanced, and significantly affects the metabolism of B vitamins in the gut [13].

#### **5.1 Vitamin B1**

Thiamine produced in the gut microbiota has a specific role in the composition or function of the gut microbiome. Thiamin is required by certain gut bacteria, *Bacteroides thetaiotaomicron* and *Faecalibacterium spp.*, which have potential consequences on the host thiamine. Thiamine biosynthesis and its transport system are essential for the growth of B. thetaiotaomicron. Although *Faecalibacterium spp.* has a vitamin B1 synthesis pathway, this species requires more vitamin B1 for growth than production. Therefore, these bacteria must obtain vitamin B1 from other bacteria or host food via transporters, such as *B. thetaoimicron* [2, 4]. Intestinal dysbiosis may lead to a predominance of thiamin-only-consuming bacteria, which may contribute to decreased thiamin availability to the host. *E. coli* in the human fecal microbiota was found to be negatively correlated with fecal thiamin [26].

#### **5.2 Vitamin B2**

Riboflavin is vital in the growth of bacteria that are very sensitive to oxygen as an electron transfer agent. Examples of bacteria that are sensitive to oxygen are *F. prausnitzii* and Roseburia. *F. prausnitzii* is a major butyrate producer in the human microbiota and has anti-inflammatory properties and gut-protective functions. Vitamin B2 is also an essential precursor to flavin mononucleotide and flavin adenine dinucleotide (FAD), coenzymes of glutathione reductase that protect cells from reactive oxygen species (ROS). Thus, vitamin B2 can act as an indirect antioxidant and modifies the gut microbiota condition through ROS reduction. This condition is also proven to reduce the population of *E. coli*. Previous studies showed that supplementation of dietary riboflavin for 14 days increased *F. prausnitzii* and Roseburia and concomitantly reduced *E. coli*. Phylum Actinobacteria and Firmicutes express riboflavin transporters and enzymes required to form FAD and FMN from free riboflavin [2, 4, 27]. Vitamin B2 also directly affects the fecal microbiome, namely, the genera Alistipes and Clostridium. However, this increase occurred only with high doses of riboflavin supplied directly to the large intestine and may not apply to intakes from foods or dietary supplements that are absorbed mostly in the small intestine [27].

#### **5.3 Vitamin B3**

Vitamin B3 is the only B vitamin that humans can synthesize. It is a precursor to nicotinamide adenine dinucleotide (NAD), a coenzyme in cellular oxidation–reduction reactions with a central role in aerobic respiration. Niacin acts as an agonist for the cell surface receptor niacin receptor 1, which pairs with G-proteins. Niacin also has strong antioxidant and anti-inflammatory properties and can function as a modulator of gut protection and prevent bacterial endotoxin production. Thus, niacin deficiency causes intestinal inflammation and diarrhea, which has a direct impact on the gut microbiota population. Vitamin B3 deficiency impacts the diversity and low number of Bacteroidetes, especially in obese individuals. Supplementation with tryptophan

*Vitamin B, Role of Gut Microbiota and Gut Health DOI: http://dx.doi.org/10.5772/intechopen.109485*

and niacin has been shown to restore the composition of the gut microbiota through the angiotensin I (peptidyl-dipeptidase A)-converting enzyme. Furthermore, intake of niacin microcapsules (900 to 3000 mg) significantly increased the Bacteroidetes population. These results suggest that niacin has a beneficial effect on gut microbial composition in humans [2–4].

#### **5.4 Vitamin B5**

*Lactobacillus spp.*, *Streptococcus spp.*, and *Enterococcus spp*. are members of the phylum Firmicutes that do not produce pantothenate but require pantothenic acid for their growth. This indicates that there is a symbiosis in the distal intestine between pantothenic acid-eating bacteria and pantothenic acid-producing bacteria. A study has demonstrated the uptake of pantothenic acid and biotin by the sodiumdependent multivitamin transporter (SMVT, SLC5A6) across the intestinal loop. Mostly Fusobacterium and *Bifidobacterium spp*., some strains of *C. difficile*, and *Faecalibacterium spp*., lack the vitamin B5 synthesis pathway but express the pantothenic acid transporter to utilize vitamin B5 as an energy producer [2, 4].

#### **5.5 Vitamin B6**

Vitamin B6 can play an essential role in shaping microbiota composition and metabolic capacity. In bacteria such as *E. coli*, vitamin B6 is synthesized in the PLP form from various precursors, including, deoxyxylulose 5-phosphate, 4-phosphohydroxy-L-threonine, glyceraldehyde-3-phosphate, and D-ribulose 5-phosphate. PLP produced by commensal bacteria works with ribonucleotide metabolism to facilitate the effects of 5-fluorouracil, a drug used to treat colorectal cancer. Vitamin B6 deficiency results in a marked decrease in intestinal arginine biosynthesis, and disruption of this metabolic pathway leads to the selective growth of certain gut bacteria, namely, the Bacteroidaceae family, and an increase in Lachnospiraceae. An increase in vitamin B6-producing bacteria such as *Bacteroides acidifaciens* has been shown to weaken the colonization of S. typhimurium and promote recovery from intestinal inflammation [4, 28].

#### **5.6 Vitamin B7**

Free biotin can affect the composition of the gut microbiota because it is required for the growth and survival of some microbiota. *Prevotella spp.*, *Bifidobacterium spp.*, Clostridium, Ruminococcus, Faecalibacterium, and *Lactobacillus sp.* do not have the vitamin B7 synthesis pathway because it lacks the essential biotin biosynthetic gene. However, they express a free biotin transporter, indicating a need for biotin. These results indicate that these bacteria also utilize biotin from food and bacteria to compete with the host. Therefore, it is necessary to control diseases related to some of these microbes. Another study showed that enzymes in the biotin biosynthetic pathway were overexpressed in the Bacteroides enterotype. Biotin uptake in the small and large intestines occurs via a carriermediated process involving the SMVT system encoded by the SLC5A6 gene [2, 4]. SMVT dysfunction reduces biotin in the intestine, causing dysbiosis, and induces Nox and ROS, which cause damage to enterocyte apoptosis. This mechanism causes the intestinal villi to shrink and increases intestinal permeability, inflammation, and dysplasia, all of which induce dysbiosis [29].

#### **5.7 Vitamin B9**

Folate is essential for several metabolic processes, including carbon transfer, thymidylate synthesis, purine synthesis, and the synthesis of several amino acids. Once absorbed, folate also participates in nucleotide synthesis, DNA repair, and methylation [30]. This function applies to both the host and the microbiota that require folate. The biosynthesis and expression of folate transporters in the gut microbiota are influenced by gut microbes, such as Bifidobacteria. In commensal bacteria, a vitamin B9 metabolite, 6-formylpterin (6-FP), is produced by the photodegradation of folic acid. This metabolite cannot activate MAIT cells (mucosal-associated invariant T), suppressing excessive MAIT cell responses and preventing excessive allergic and inflammatory responses [4].

#### **5.8 Vitamin B12**

Microorganisms use various forms of cyanocobalamin in many reactions, including methionine synthesis, carbon skeleton mutation, elimination reactions, amino mutations, and acetate and methane synthesis [31]. As many as 83% of the microbiota (260/313 species) encode cobalamin-dependent enzymes. Most of these species also lack the genes needed to synthesize cobalamin. In another report, 75.9% of bacteria utilized cobalamin, and only half possessed the cobalamin biosynthetic pathway. An example is *B. thetaiotaomicron*, which does not encode the cobalamin biosynthetic pathway gene but has three homologous cobalamin transporters. This statement indicates that this microbiota depend on the cobalamin absorption mechanism to maintain survival. Supplementation of 3.94 g/ml cyanocobalamin was shown to increase fecal cobalamin, with a lower Bacteroides population condition. Cobalamin and its derivatives also determine pathogenicity in the host gut. The bacterial transcription factor EutR requires ethanol amine, cobalamin precursors, and cobalamin-derived adenosylcobalamin for transcription of virulence factors required for host infection and spread of *enterohemorrhagic E. coli* (EHEC) serotypes O157:H7 and Salmonella [4].

## **6. The role of B Vitamins on human digestive health**

The B vitamins in our body have several crucial physiological functions. The functional roles of these micronutrients are diverse, ranging from cellular energyproducing reactions such as the mitochondrial citric acid cycle to respiratory oxidation, immunity, neurotransmitter synthesis, cell signaling, and nucleic acid biosynthesis. Thus, a deficiency of B vitamins will impair normal cell metabolism and trigger the development of several chronic diseases in humans [4, 32]. Apart from being essential for the human body, B vitamins are also crucial in shaping the diversity and richness of the gut microbiota. A wealth of evidence has shown that a healthy gut lies in a healthy microbial ecology [3, 4].

#### **6.1 Vitamin B1**

Thiamin is a precursor of thiamin pyrophosphate, which is essential for carbohydrate metabolism and nerve function. Energy metabolism, particularly the balance between glycolysis and the citric acid cycle, is related to the functional control of immune cells, which is referred to as immunometabolism. Immunometabolism *Vitamin B, Role of Gut Microbiota and Gut Health DOI: http://dx.doi.org/10.5772/intechopen.109485*

by vitamin B1 is vital for glycolysis-dependent digestive cells, especially Peyer's patch. In the gut, nave immunoglobulin (Ig)M+ B cells differentiate into IgA+ B cells in the Peyer patch, and then, IgA+ B cells differentiate into IgA-producing plasma cells in the lamina propria. The naive B cells in Peyer's patch prefer to use the vitamin B1-dependent citric acid cycle to generate ATP. However, once B cells differentiate into IgA-producing plasma cells, they switch to using glycolysis to generate ATP [2, 3].

Consistent with the importance of vitamin B1 in generating energy in the gut, mice fed a vitamin B1-deficient diet showed impaired maintenance of naive B cells in Peyer's patches. In addition to reducing the number of naive B cells in Peyer's patch, thiamin deficiency also reduces the size of B cell follicles, evidenced by the reduction of naive B cells in female Balb/c experimental animals. The researchers also showed that feeding the mice a vitamin B1-deficient diet caused the vitamin B1 deficiency to last for only a week. Vitamin B1 deficiency that affects the host immune response through the regulation of differentiation and proliferation of these immune cells ultimately affects the gut microbiota [2, 3].

#### **6.2 Vitamin B2**

Riboflavin is required for the development of the gastrointestinal tract after birth and is linked to crypt hypertrophy, crypt bifurcation dysfunction, and a loss of proliferative potential in intestinal cells. These changes are visible during the postnatal and post-weaning stages. These changes were irreversible, even after the experimental administration of riboflavin in vivo and in vitro. Riboflavin deficiency has been shown to reduce the number of villi but, on the other hand, can increase the length of the villi. Reduction of riboflavin in humans has also been associated with shortened duodenal crypts and reduced cell division. In vitro studies using Caco-2, HCT116, and HT29 cells demonstrated a potential mechanism for the riboflavin deficiency phenotype, which led to the result that riboflavin inhibited cell growth by reducing cellular ATP generation and increasing oxidative stress. This impairs mitosis and accumulates aneuploidy cells. These changes in gut morphology may also be associated with an adaptive response to stress-induced deficiency [4].

Riboflavin is also essential for methylation reactions, nucleotide synthesis, and DNA stability and repair. A cohort study in the Netherlands on a diet in cancer suggested that riboflavin was likely to be associated with a reduced risk of proximal colon cancer among women (RR = 0.61; P-trend = 0.07). This finding is reinforced by results from the Women's Health Initiative cohort observational study, which showed that higher total riboflavin intake was associated with a reduced risk of colorectal cancer (HR = 0.81; 95% CI: 0.66–0.99) [1].

#### **6.3 Vitamin B3**

Human and mouse colonic epithelial cells possess efficient and specific mechanisms for vitamin B3 absorption. This vitamin plays an essential role in reducing inflammation, so a deficiency will lead to inflammatory bowel diseases such as ulcerative colitis. Vitamin B3 controls inflammation by inhibiting vascular permeability in intestinal tissue by activating PGD2/DP1 signaling in endothelial cells. This vitamin also modulates the inflammatory response by increasing the rate of ATP generation in Caco-2 cells. In addition, vitamin B3 is involved in various cellular oxidation–reduction metabolic reactions and rapamycin signaling pathways, thereby suppressing colon inflammation [3, 32].

Vitamin B3 synthesized by the gut microbiota contributes to local colonocyte nutrition and maintains intestinal stem cell morphology. Vitamin B3 is also known to protect colonic epithelial cells against dextran-sulfate-sodium (DSS)-induced apoptosis and promote cell proliferation in experimental animals. The mechanism of protection of the intestinal epithelium by vitamin B3 is by activating the prostanoid D 1 (DP1) receptor on macrophages and endothelial and colonic epithelial cells. One study found that retention of vitamin B3-containing enemas effectively promoted mucosal healing in patients with ulcerative colitis, with possible mechanisms of downregulation of colonic inflammatory cytokines and suppression of pro-inflammatory gene expression [3, 4].

#### **6.4 Vitamin B5/pantothenic acid**

Vitamin B5, or pantothenic acid, is an essential coenzyme A (CoA) precursor and acts as a carrier protein. This vitamin is involved in various metabolic pathways, such as the citric acid cycle, cell growth, neurotransmitter synthesis, and fatty acid oxidation [4]. Dietary pantothenic acid supplementation also affects the gut microbial profile. Increased intake of pantothenic acid increased the relative numbers of Prevotella and Actinobacteria [3].

#### **6.5 Vitamin B6/pyridoxine**

Vitamin B6 functions primarily as a cofactor for the biosynthesis and catabolism of amino acids. In addition, this vitamin is also involved in fatty acid biosynthesis and neurotransmitter biosynthesis and as an antioxidant [3]. Relative pyridoxine deficiency is found in 10–25% of Inflammatory Bowel Disease (IBD) cases. Plasma levels of B6 are considered a risk factor for thrombosis in patients with IBD because they have an inverse relationship with homocysteine [1].

A cross-sectional study has shown an association between the severity of intestinal irritation and low dietary vitamin B6 intake. The mechanism of this phenomenon is that the lack of vitamin B6 affects the balance of anti-inflammatory and proinflammatory cytokines. Vitamin B6 deficiency also reduces microbial diversity and significantly alters gut metabolites such as short-chain fatty acids, which also play an essential role in triggering this irritation. In addition, studies of vitamin B6 deficiency in animals have shown a significant reduction in the number of mucus-secreting cells, an important factor in maintaining gut health. Vitamin B6 also decreases cell calcium transport but does not affect the basic morphology of enterocytes, such as cell viability, cell volume, membrane permeability, and protein content [4].

Vitamin B6 can influence colorectal carcinogenesis through its role in DNA synthesis and methylation. Animal studies have shown that this vitamin can inhibit angiogenesis, suppress nitric oxide, and reduce oxidative stress [1].

#### **6.6 Vitamin B7/Biotin**

Vitamin B7 acts as a coenzyme for several biochemical reactions, such as glycolysis, cell signaling, and epigenetic regulation. This vitamin also controls the expression of genes, including nuclear factor kappa B (NF-kB), through a histone-binding mechanism known as biotinylation. Therefore, this vitamin may also have an antiinflammatory effect on the gastrointestinal mucosa [32].

#### **6.7 Vitamin B9/Folate**

Vitamin B9 is essential for the replication and regeneration of nucleic acids, affecting cells' survival rate. Folate is involved in synthesizing S-adenosylmethionine (SAM), which is required for cellular biosynthesis and DNA methylation. This vitamin is essential for replicating and recovering nucleic acids, influencing survival rates through cell proliferation and regeneration. In addition, folate regulates gene activity, regenerates the intestinal lining, reduces lymphocyte growth, and reduces NK cell cytotoxicity [3]. Thus, every living cell, including gastrointestinal cells, requires folate to carry out these various biochemical and biosynthetic processes [4].

Because of its essential role in producing methyl donors, folate deficiency significantly impairs DNA replication. Folate deficiency causes an increase in the crypt depth of the intestinal mucosa in the duodenum and jejunum, resulting in a decreased villi-to-crypt ratio. In experimental animals, induced methyl donor deficiency by feeding a folate-deficient diet accompanied by the antibiotic succinylsulfathiazole 1% has also increased crypt depth and altered gut cell differentiation. In this study, folate deficiency also caused megaloblastic changes in the epithelial cell nuclei and reduced crypt mitosis. These changes are seen more prominently in the ileum with elongation of the crypts, an increase in goblet cells, and a decrease in Paneth cells. Deficiencies of folate, riboflavin, vitamin B6, and vitamin B12 concomitantly alter Wnt signaling in the experimental colon and decrease apoptosis in epithelial cells. Unexpectedly, these changes are irreversible, even with an excess of folate [4].

Folate deficiency significantly alters intestinal cell morphology and is associated with increased intestinal carcinogenesis [3]. Two case–control studies demonstrated that folate supplementation and high red blood cell folate levels significantly reduced the risk of dysplasia and neoplasia in patients with ulcerative colitis. Folate supplementation, in combination with sulfasalazine administration, has a protective effect on the development of colorectal cancer in patients with chronic ulcerative colitis. The mechanism of folate protection against colorectal cancer is to prevent aberrations in DNA synthesis and aberrations in DNA methylation. However, it should be noted that folate deficiency can also occur due to IBD therapy, such as methotrexate and sulfasalazine. A recent meta-analysis of folate supplementation has found that folate plays a role in preventing pancreatic cancer. Individuals with a high dietary folate intake were 34% less likely to develop pancreatic cancer than individuals with a low folate intake [1].

### **6.8 Vitamin B12**

Like folate, cobalamin is involved in the synthesis of methyl donors. These donors are essential for the nucleic acid synthesis and protein and lipid metabolism. Vitamin B12 also acts as a cofactor for methionine synthase in sulfur amino acid metabolism to recycle homocysteine into methionine. The effect of vitamin B12 deficiency on colonic morphology is similar to that of folate deficiency because of its association with several cellular metabolic reactions. Vitamin B12 deficiency protects against DSS-induced inflammation in C57BL/6 mice. Other studies have shown reduced cell differentiation and gut protective factors in vitamin B12-deficient mice. In addition, in patients with vitamin B12 deficiency, the villi become shorter with a reduced villi/ crypt ratio. Deficiency or excess of vitamin B12 affects the growth of gut microbiota.

However, vitamin B12 deficiency did not relatively change the gut microbiota composition in healthy mice but did change it in DSS-induced colitis mice [4, 6, 32].

Vitamin B12, together with vitamins B9 and B6, influence the occurrence of colorectal carcinoma through its role in DNA synthesis and methylation. In addition, these three vitamins have been shown to inhibit angiogenesis, suppress nitric oxide, and reduce oxidative stress in animal models. However, an experimental study that administered a combination of folic acid (2.5 mg), vitamin B6 (50 mg), and vitamin B12 (1 mg) in 1470 subjects did not reduce the risk of colorectal carcinoma after a follow-up period of 9.3 years. Patients with celiac disease also have higher total plasma homocysteine levels than the general population, indicating lower serum levels of vitamins B6, B9, and B12 [1].

The liver is the physiological reservoir of cyanocobalamin in humans. Vitamin B12 deficiency is observed in several liver diseases such as hepatitis, cirrhosis, and hepatocellular carcinoma. Vitamin B12 inhibits HCV through the inhibition of ribosome entry sites. Vitamin B12 is also associated with aphthous stomatitis (**Figure 1**) [1].

## **7. Conclusion**

B vitamins act as cofactors for several cellular metabolic reactions. In addition to vitamin B3, other B vitamins must be obtained through dietary intake, supplementation, and synthesis of the gut microbiota. The biosynthesis of B vitamins in the gut

#### **Figure 1.**

*Summary of the main gut bacteria synthesizing B vitamins and the effects of their deficiency on gut health [3].*

*Vitamin B, Role of Gut Microbiota and Gut Health DOI: http://dx.doi.org/10.5772/intechopen.109485*

is influenced by several factors, including exposure to antibiotics and free radicals, genetic makeup, dietary habits, and lifestyle. Competition between gut microbiota, pathogenic microbes, and the host leads to deficiency conditions, especially if exogenous intake is not optimal. A deficiency of B vitamins ultimately affects the gut microbial composition, gut health, and overall host metabolism.

## **Author details**

Satrio Wibowo1 \* and Almira Pramadhani<sup>2</sup>

1 Department of Pediatrics, Faculty of Medicine, University of Brawijaya, Malang, Indonesia

2 University of Brawijaya, Malang, Indonesia

\*Address all correspondence to: satrio\_wibowo@ub.ac.id

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## Section 2
