Naturally Occurring Microbiota-Accessible Borates: A Focused Minireview

Abstract

Recently, we discovered and proved the essentiality of organic boron species (OBS), such as borate–pectic polysaccharides and borate–phenolic esters, for healthy symbiosis (HS) between microbiota and human/animal (H/A) host. The essentiality of OBS will provide new options for B supplementation in H/A nutrition for a healthy and long life. New knowledge on the essentiality of naturally occurring microbiota-accessible borate species for HS between microbiota and H/A host will allow the use of natural B-based dietary supplements to target the H/A microbiome (the gut, skin, oral, scalp, and vaginal microbiome). In the literature, there is evidence that certain bacteria need B (autoinducer-2 borate) for communication and our preliminary data show that HS takes place when the colonic mucus gel layer contains B. Subsequently, OBS become novel prebiotic candidates and target the colon as novel colonic foods.

1. Introduction

The microbiota is essential for host metabolism, digestion, and nutrition. It has been shown that biological age, and not chronological age, is associated with modifications in the diversity of the gut microbiota (GM). Thus, an increased chronological age does not indicate healthy aging. A fundamental feature of aging is the presence of persistent low-grade inflammation caused by GM dysbiosis (DYS), which is a potential mechanism for accelerating aging. Recently, many studies have reported evidence that interventions targeting microbiota may have therapeutic potential not only for age-related diseases, but also for slowing the aging process and promoting longevity [1,2].

Boron (B) is a prebiotic element essential for life, influencing its origin and evolution. It is crucial for certain bacteria, plants, fungi, and algae. In humans and animals, B supports energy metabolism, calcium metabolism, bone formation, growth, reproduction, immunity, and brain function [3,4,5,6,7]. In addition, for humans and animals, B has not yet been classified as an essential micronutrient because its biological role has not been clearly identified. It has recently been proposed that indigestible and microbiota-accessible B is essential for healthy symbiosis (HS) between microbes and the human/animal (H/A) host, with a potential role in modulating the microbiota composition [8,9,10].

Consequently, the concept of “prebiotic” for the B element has two meanings: (i) in the origin and evolution of life, B is the proposed catalyst in the prebiotic chemical synthesis of nucleosides [3,4,11,12] and polypeptides [13,14]; (ii) in nutrition, B is part of the microbiota-accessible indigestible compounds called prebiotics and is a substrate selectively used by the host microorganisms, conferring a health benefit [8,9,10,15]. Thus, naturally occurring B species are essential for the HS between the microbiome and the H/A host [5,10]. Recent research indicates that B compounds can positively influence the composition of the GM, with potential prebiotic effects [10,15], and it has not yet been experimentally proven that digestible B can physiologically participate in cellular metabolism [9,16].

Recent scientific research on B has yielded significant findings: (i) B is crucial for the symbiosis between commensal microorganisms within the microbiome and the H/A host. (ii) B is not required as a nutrient for human cells, as these cells do not have a nutritional need for B. Rather, B is crucial for sustaining a healthy symbiotic relationship between the host organism and the microbiome in the gut, scalp, mouth, skin, and vagina. (iii) Some naturally occurring prebiotic boron complexes (PBCs) have recently been identified as accessible to microbiota [8,9,15]. Additionally, newly discovered chlorogenic acid (CA)–borate complexes, specifically diester chlorogenoborate (DCB), have emerged as promising prebiotic candidates due to their indigestibility and accessibility to microbiota (Figure 1a,b). In contrast, inorganic B compounds such as boric acid (BA) and borate salts are digestible and may present toxicity risks under certain conditions [8].

A new group of microbiota-accessible natural compounds that feed the microbiota, microbiota-accessible borates (MABs), are food compounds that the GM utilizes and are crucial in determining the composition of the GM ecology and in the HS with host microbes [15].

We have defined the concept of “microbiota-accessible borates”, which are defined as organic borates of pectic polysaccharides and polyphenols that can be utilized as growth substrates by GM that have the enzymatic capacity to do so. This definition excludes insoluble borates (as they cannot be utilized by the GM) and digestible borates (which are absorbed in the small intestine), such as BA and inorganic B salts [5,8,9].

Recently, it has been characterized as a B–phenolic compound (DCB) that is considered MAB and is found in plant-based products with high phenolic content: apricots, avocado, blueberries, currants, dates, figs, peaches, prunes, raisins, raspberries, and green coffee beans (GCBs) [8,9].

New findings, thus, show that prebiotic B as MAB is necessary for a healthy symbiotic relationship between the microbiota and the human host, and through these effects, prebiotic B nutrient intakes have been shown to moderate or attenuate several pathological conditions associated with aging, including cognitive decline, cancer, bone health, and sarcopenia [5,15]. These findings indicate that a MAB-rich diet will promote healthy aging and longevity.

Our paper reviews the evidence supporting the essentiality of naturally occurring B species both for prebiotic chemistry and for HS between microbiota and H/A host, highlighting the role of borate–pectic polysaccharides (BPPs) and borate–phenolic esters (BPEs) as novel prebiotic candidates targeting the colon.

2. Naturally Occurring Boron-Containing Complexes: From Prebiotic Chemistry to Biological Life

2.1. Prebiotic Chemistry

A specific chemistry, referred to by us as “chemical life”, is the field of study that aims to unravel the chemical pathways that led to the emergence of life [3,4]. Unfortunately, neither chemists nor laboratories were present on early Earth to observe this chemistry directly. It is clear that this chemistry is much narrower than conventional chemical synthesis, which is generally defined as prebiotic chemistry [17].

The fundamental problem is that there is not even the slightest experiment to identify chemical life. The only experiment was performed in 1976 on the planet Mars, which had a very contradictory problem: the fundamental features of life were positive, but the presence of organic molecules was negative. Explanations have been numerous from both supporters and skeptics [18,19]. The very small ordinal sizes of 2–3 ribosomes of the putative Mars microbial fossils found in the Allan Hills 84001 (ALH 84001) meteorite [20,21] may in fact be the first ribonucleic acid (RNA) replicons coated with an inorganic matrix. But all these discoveries have given rise only to hypotheses.

The presence of B on Mars [22,23] highlights new habitability possibilities due to the role borate may have played in prebiotic chemistry on early Earth [3]. Ribose, the simple sugar that forms the backbone of RNA with phosphate, is stabilized by borates [11,24]. The discovery of B in Gale crater raises questions about the potential for life on Mars [25]. If borate–organic molecules are observed in Gale crater, it could provide insights into the early hydrologic system on Mars and its relevance to life’s origins on Earth. This makes the search for borates a priority for the Curiosity rover and future Mars missions. The debate over the Viking lander-labeled release experiment’s findings regarding potential life on Mars remains one of the most discussed paths to understanding the emergence of life [19,26].

Also, what are those chemical processes that were the basis of the organized chemical mixture that signified the chemical phase of life, which we call chemical life? What is the fundamental feature of this organized chemical mixture that led to the biological life we know? It is a chemistry specific to the emergence of life, indispensable for the emergence of life on Earth, and contributes to the selection and evolution of chemical structures to a chiral chemical system capable of producing genetic and metabolic information. Chemical life as the “first-RNA” replicons can select chirality to regenerate, not replicate like biological life [27,28,29,30,31].

The fundamental characteristic of chemical life is, in our view, to guide chemical processes to the essential molecules of biological life: nucleotides, proteins, and lipids. In this general principle, B is the essential ingredient that accompanies pentose carbohydrates in the emergence of nucleosides and nucleotides. It also accompanies phosphate to enter in this direction, i.e., it guides phosphate to phosphorylate nucleosides, etc. We need to focus more on chemical life, which, in our opinion, still exists on Earth, and coexists with natural organic material and should be sought here, and not on other planets [3,31].

Why is B, a chemical element that does not abound but ubiquitous on Earth, so important? Many scientific theories about the origin of life suggest that life began by spontaneously forming a “first-RNA” replicator within a specific chemical mixture [4,29,31,32]. B species may, thus, have been an essential bridge from produced organic molecules to RNA-based protolife on Earth [3,25]. We were some of the pioneers of this past scientific projection of B’s role in the origin of life, based solely on its ability to protect certain chemical structures essential for the likely prebiotic evolution of the “first-RNA” replicons [3,4,11,12].

The essential question is, though, which B species did all this? B-containing molecules (not necessarily the currently existing B species) are among the first molecules involved in the appearance of life on Earth. How can we define this aspect of B’s necessity, or essentiality, in the chemical life phase, pre-metabolic chemistry? What are the borate species that guided the pre-metabolic cycles in the life emergence stage? Chemical life without guiding molecules cannot evolve into biological life, essential for this transition. The hypothesis of a borate-constrained pre-metabolic cycle that guides ribose formation starting from formaldehyde and glycolaldehyde has been advanced as a hypothesis, examining how borate might guide and possibly inhibit large-scale formaldehyde fixation cycles in which the prebiotic glycolaldehyde would be a catalyst [33]. Also, Kim and Benner showed that after nucleoside synthesis, the reaction of ribose-1,2-cyclic phosphate [34], borophosphates regioselectively phosphorylate nucleosides by complexing 2- and 3-oxygens, and borate obviously directs the phosphorylation reaction toward the 5-hydroxy group, preventing the formation of the product complex (in other words, borate guides the phosphate to phosphorylate nucleosides) [4,35]. Thus, in addition to pre-metabolic carbohydrate guidance, B species in evaporative geo-organic contexts provide a solution to the phosphate problem in the “first-RNA” model for the origins of life [35,36].

The dream of chemical life was genetic information, the dream of cellular life was consciousness and intelligence, and why would not the dream of artificial/digital/quantum life be the creation of new universes?

RNA is considered an ideal initial molecule for supporting Darwinian evolution during the emergence of life on early Earth. The “first-RNA” hypothesis [27] postulates that RNA was spontaneously synthesized on early Earth through specific chemical pathways. Consequently, numerous research groups using this hypothesis as a foundation have endeavored to integrate laboratory chemistry with models of early Earth’s geology and atmospheric evolution to generate RNA building blocks [28,37,38]. These studies indicate that all four glycosidic linkages in the canonical nucleosides of RNA can be synthesized directly from ribose 1,2-cyclic phosphate 3 and nucleobases under intermittently dry, hot conditions (100 °C) reminiscent of early Earth’s environment [36]. Moreover, while the selective prebiotic synthesis of high-yield ribose has not yet been demonstrated, the mineral borate exhibits a selective affinity for and stabilization of ribose [11,12,30].

These findings suggest that the high-yield selective synthesis of ribose is essential for achieving successful prebiotic RNA synthesis. The discovery of ribose and other bio-essential sugars in two distinct types of carbon-rich meteorites—NWA 801 (CR2 type; carbonaceous meteorites rich in metal) and Murchison (CM2 type; carbonaceous chondrite meteorites)—which are isotopically distinct from terrestrial sugars, offers compelling evidence for the extraterrestrial origin of these sugars in primitive meteorites and supports the idea that prebiotic sugars may have been transported to ancient environments on Earth and potentially Mars [39].

Consequently, “first-RNA” hypothesis proponents must rely on particular B species or geologic events (e.g., meteorite impacts) to control, guide, or initiate a particular reaction or reaction sequence. These suggest that a chemical system capable of producing information was necessary in the emergence of biological systems [31]. Darwin also envisioned the possibility that life evolved from a very well-defined and particular chemical system [40]. The claim that the problem of the origin of life is the problem of the “first-RNA” origin and that everything that followed is in the domain of natural selection seems today more and more scientifically powerful [28].

Our hypothesis is that in addition to inorganic B compounds (BA and borate salts), at the beginning of the existence of chemical life on Earth, the reactions between organic B species (OBS) and monosaccharides and B compounds and nitrogen donors were possible. There are more and more hypotheses showing that borate–ribose esters could have been diester compound protocells guiding molecules in particular chemical mixtures [13]. The ability of these B complexes to guide certain chemical reactions is extremely stringent.

2.2. Biological Life

What are the B compounds found in biological nature, the current biological life? The most important compounds are in bacteria and plants and were recently identified only by one laboratory in the colonic mucus gel as borate–mucin compounds. It remains to be confirmed by other laboratories and to identify the structure of borate–mucin [5,9].

Thus, the following natural B compounds have been discovered in plants: (i) BPP complexes, i.e., borate–rhamnogalacturonan II (RG-II) or borate–laminarin and borate–alginic acid, reported in marine green algae (Chlorophyta) [41,42,43]; (ii) oligosaccharide–borate complexes, compounds with vicinal hydroxy groups, such as fructose–borate complex, glucose–borate complex, fructose–sorbitol–borate complex, and bis-sucrose–borate complex; (iii) sugar alcohol–borate complexes (sorbitol–borate complex and mannitol–borate complex); (iv) polyhydroxy organic acid–borate esters (malic acid–neutral borate complex, mono-malic acid–borate complex, and bis-malic acid–borate complex); (v) amino acid–borate esters (bis-N-acetyl-serine–borate complex); (vi) DCB (recently identified in GCB); (vii) borolithochromes (BA esters with phenolic fragments), a unique class of fossil organic pigments resulted from the fossilization of borate–phenolic acid complexes [8,44,45,46].

Moreover, B-containing natural compounds have been identified also in Bacteria kingdom, as follows: (i) borophycin, an acetate-derived polyketide, a B-containing metabolite isolated from Nostoc linckia and N. spongiaeforme var. tenue, exhibiting potent cytotoxicity against some pathogenic bacteria and human cervical adenocarcinoma (KB) and human colorectal adenocarcinoma (HT-29) cell lines; (ii) boromycin, first isolated from an African soil sample containing Streptomyces antibioticus; (iii) aplasmomycins A, B, and C, originally isolated from S. griseus; (iv) tartrolones A, B, C, and E, isolated from a Gram-negative eubacteria living in soil and related habitats (Sorangium cellulosum); (v) furanosyl borate diester (autoinducer-2 borate; AI-2B), which is produced by bacteria to regulate quorum sensing (QS)-associated activities, such as symbiosis, motility, biofilm formation, virulence, and antibiotic biosynthesis—actually, AI-2B has been proposed to serve as a “universal” bacterial QS signal containing B for communication between the bacterial community; (vi) siderophores such as vibrioferrin (isolated from Vibrio parahaemolyticus and Gymnodinium catenatum), rhizoferrin (isolated from Rhizopus microsporus and Zygomycota fungi), and petrobactin (a bis-catecholate isolated from Marinobacter hydrocarbonoclasticus marine bacterium)—B exhibited a high affinity for complexing siderophores that usually bind and solubilize Fe(III) for transport, thus having key roles in cell signaling pathways [45,47,48,49].

Scientific data suggest that only plants have the ability to metabolize BA/borate and convert it into B–carbohydrates and B–polyphenols; humans and animals do not have this ability [5,8,46]. The indigestibility of B–carbohydrates in the plant diet of humans and animals is on average 10% [50], while B–polyphenols have an average indigestibility of 90% [8,9]. B–polyphenol species being, thus, accessible to the microbiota cause an increase in the level of volatile fatty acids (FAs) due to the increase in the activity of commensal bacteria, especially the level of butyrate (BUT) producers [5,8,15].

3. MABs and Healthy Host–Microbiome Symbiosis

Recently, many studies have reported evidence that interventions targeting GM may have therapeutic potential not only for age-related diseases, but also for slowing the aging process and promoting longevity [51]. GM DYS is associated with many pathological conditions, such as type 2 diabetes (T2D), malnutrition, obesity, chronic hepatitis, hepatic steatosis, irritable bowel syndrome, metabolic syndrome, cardiovascular diseases (CVDs; hypertension, atherosclerosis, and hypercholesterolemia), neurodegenerative diseases, neuropsychiatric conditions, neurological disorders, autoimmune diseases, kidney diseases, respiratory diseases, cancer, sarcopenia, autism spectrum disorders, sleep disorders, insomnia, allergies, and infections [52]. DYS inflammation can result in elevated levels of reactive oxygen species (ROS), leading to the inactivation of the Firmicutes phylum in the gut, which worsens inflammation and contributes to aging-related diseases [53]. With aging, the abundance of beneficial gut microbes progressively declines, while pro-inflammatory microbes become more prevalent, potentially causing age-related diseases and premature death. A shift in the microbiota towards a predominantly Bacteroidetes phylum population has been observed in older compared to younger individuals [54]. Furthermore, a significant positive association was also identified between the relative abundance of Bacteroides spp. and the increased risk of all-cause mortality independent of age [55]. Studies have shown that aging is correlated with many changes, such as the decreased diversity of the GM, decreased Firmicutes/Bacteroidetes ratio, increased abundance of pathogens, and decreased abundance of short-chain fatty acid (SCFA)-producing bacteria, such as BUT, acetate, and propionate, necessary to maintain the integrity of colonic mucus and stop inflammation in the gut. It is well known that the Firmicutes/Bacteroidetes ratio is low in children and the elderly, whereas in adults, this ratio increases [56].

B is recognized as a prebiotic nutritional element that plays a steering role in healthy H/A host–microbiota symbiosis [5,9] and is also an essential micronutrient for certain bacteria, plants, fungi, and algae. For both humans and animals, B contributes to various biological functions including energy metabolism, calcium metabolism, bone formation, immunity, brain function, growth, and reproduction [49].

MABs are defined as non-digestible organic borates (such as BPPs and BPEs) metabolized by microbes. MABs play a crucial role in facilitating symbiosis between organisms from different kingdoms and significantly influence the relationship between the H/A host and its microbiota. This interaction may impact the development of natural B-based nutraceuticals designed to target the colon. The mechanism of action (MoA) of MAB species involves the AI-2B signaling molecule, reinforcement of the colonic mucus gel layer with B species derived from MAB-rich diets, inhibition of pathogenic bacteria, enhancement of gut barrier integrity, improvement of immunity, and overall supporting for host health. In addition, prebiotic MAB deficiency in the diet correlates with reduced levels of AI-2B in the microbiota, with direct consequences on the inhibition of the growth of Firmicutes bacteria, which are the main BUT producers, with direct effects on healthy H/A host–microbiota symbiosis [5,8,9].

The DYS of the microbiome is an amplifier of aging and thus, DYS accelerates aging. GM DYS is a “millstone” for human genetic potential. Recent evidence shows that GM DYS is linked to decreased BUT production [57]. The effects of prebiotic MAB deficiency translate into decreased Firmicutes phylum, decreased AI-2, and, consequently, decreased AI-2B. More than 200 bacterial species of the Firmicutes phylum are major contributors to the commensal microbiota. MABs increase the levels of SCFAs, especially BUT, with effects on the brain, bone, and gut–immune system. The absence of MABs results in DYS, mucus degradation, reduced BUT levels in the microbiota, and the stimulation of pathogenic bacteria. This leads to a negative pleiotropic effect on the musculoskeletal system (the gut–bone and gut–cartilage axes) and the immune system, causing inflammation in the cardiovascular (CV) system and brain, and autoimmune pathologies. It has recently been shown that the Firmicutes phylum increases gut levels of AI-2 and BUT [58]. BUT is an essential potential inhibitor of unhealthy aging by virtue of its manifold properties of delaying physiological decline and host aging. These properties include preventing inflammation by several pathways, such as downregulating adipogenesis, improving barrier function, and acting as an energy source for colonocytes. Acetate and propionate are the main products of Bacteroidetes phylum enrichments. Thus, increased AI-2 levels favored the expansion of Firmicutes and inhibited Bacteroidetes in antibiotic-treated GM, thereby counteracting antibiotic treatment-induced DYS [59,60]. Most BUT producers in humans belong to the Firmicutes phylum, including species such as Butyrivibrio fibrisolvens, Clostridium butyricum, C. kluyveri, Eubacterium limosum, and Faecalibacterium prausnitzii. In addition, other bacteria also produce BUT, such as Anaerostipes spp., Bifidobacterium spp., and E. hallii, which generate BUT from lactate (a product of glucose metabolism) and acetate. All primary but BUT-producing bacteria (BPB) are anaerobes, which means that they can only grow in low-oxygen environments, e.g., the colon [58].

A number of bacterial species (referred to as Group 1) were determined to decrease with increasing age (Faecalibacterium spp., Roseburia spp., Coprococcus spp., E. rectale, Bifidobacterium spp., and Prevotella spp.), while other bacterial species (referred to as Group 2) were associated with unhealthy aging, mostly pathobionts (Eggerthella spp., Bacteroides fragilis, Clostridium hathewayi, C. bolteae, C. clostridioforme, C. scindens, C. difficile, Ruminococcus torques, R. gnavus, Coprobacillus spp., Streptococcus spp., Bilophila spp., Actinomyces spp., Desulfovibrio spp., Campylobacter spp., Atopobiaceae spp., Veillonella spp., Enterococcus spp., and Enterobacteriaceae). In addition, another category of bacteria (named Group 3) was associated with healthy aging (Akkermansia spp., Christensenellaceae, Odoribacter spp., Butyricimonas spp., Butyrivibrio spp., Barnesiella spp., and Oscillospira spp.). Taxa in Group 1 decreased with age and were associated with healthy aging, Group 2 consisted of pathobionts that increased with age and were associated with unhealthy aging, while Group 3 increased with age but was observed to deplete in unhealthy aging. From this perspective, it has recently been proposed that the increased abundance of Group 2 bacteria and the depletion in Group 1 and Group 3 are analogous to the “buttons” that lead to unhealthy aging. In general, a higher abundance of Firmicutes and a lower population of Bacteroidetes was found in people from rural areas compared to those from cities. In summary, long-lived individuals in both populations had a high proportion of the Clostridium XIVa cluster, Christensenellae and Ruminococcaceae (Firmicutes), and Akkermansia spp. (Verrucomicrobiota), which are considered as beneficial bacteria [61].

Numerous preclinical studies have shown that reversing GM DYS has the potential for healthy aging for the aging H/A host, supporting immunity and the musculoskeletal system, and becoming the number one target for a long and healthy life in the future [62,63].

Consequently, the following actions are highlighted for prebiotic MABs [9,15]: (i) the steering of molecules in the HS between the microbiome and the H/A host; (ii) the fortification of colonic mucus gel with B species from B-rich prebiotic diets; (iii) the inhibition of pathogenic bacteria; and (iv) the reversal of GM DYS. It can now be argued that there is a potential link between MAB-rich nutrition, microbiome HS, and H/A host metabolic health. In addition, borate interaction with mucin was also tested and mucin possibly binds borate via the diol moiety on sialic acid and/or fucose residues. AI-2 (bacterial QS signaling molecule)-dependent signaling enhances colonization by commensal BPB: recent in vivo studies support the protective role of AI-2 against pathogens and the restoration of normal microbiota composition after antibiotic treatment. In addition, an increase in AI-2 levels resulted in an increase in BPB that were depleted by treatment with two antibiotics. Therefore, AI-2 signaling may function in a feedback loop that restores the colonization of AI-2-producing bacteria after DYS (Figure 2) [59,64].

4. Feeding Microbiome with Boron: Key Factor for Healthy Symbiosis Between Microbiota and Human/Animal Host

The characteristics of the microbiome and its metabolites have been increasingly associated with human health and disease, with diet being identified as a pivotal factor in this relationship. Microorganisms metabolize the end products of human digestion and indigestible food substrates to generate a wide array of secondary and diet-derived metabolites. These microorganisms and their metabolites communicate with the immune and nervous systems through both known and unknown mechanisms, ultimately influencing human physiology and the onset or progression of diseases. From a practical perspective, the importance of OBS presents new options for B supplementation in H/A nutrition to promote health and longevity. The microbiome has been termed the “next frontier of personalized medicine”. Consequently, personalized nutrition is appealing as an influencer of GM composition, given that the GM itself can be modified. By adjusting the diet to implicitly alter the GM or the metabolites it produces, we may prevent or modulate subsequent diseases [65,66].

Recently, the dietary restriction of some nutrients (sulfur and iron) that favor pathogenic bacteria relate to the following nutrient categories: (i) nutrients that require dietary restriction for a healthy and long life, such as S, Fe, and gluten; (ii) nutrients that need to be high in the food consumed for a long and healthy life, such as prebiotic B, omega-3 FAs, polyphenols, SCFAs (mainly BUT), medium-chain fatty acids (MCFAs; mainly caproic acid), and probiotic foods obtained by fermentation (yogurts, cheese, and pickles).

4.1. Nutrients Requiring Dietary Restriction

4.1.1. Low Sulfur-Containing Foods

There is evidence that restricting protein—particularly reducing meat intake—could be important for healthy aging. Studies have shown that reducing the intake of certain sulfur-containing amino acids (SCAAs) can increase longevity in rats by about 30% [67]. More recently, a research team led by scientists at Harvard University conducted a series of animal studies in which they restricted the intake of two SCAAs (cysteine and methionine) to study what effects this had. The result of this research is that the restricted intake of foods containing high levels of SCAAs may reduce the risk of chronic diseases such as T2D and heart disease and promote healthy aging [68]. As these SCAAs are abundant in meat, dairy products, and eggs, we eat on average 2.5 times our daily S requirement. Red meat is particularly rich in SCAAs. Switching to plant-based proteins would help reduce this intake. Legumes, lentils, and beans, in general, are good sources of protein that are also low in SCAAs. However, soy protein, which underpins foods such as tofu, is surprisingly high in SCAAs. Some vegetables like broccoli contain a lot of S but not in the form of amino acids. Sulfur-restricted diet (SRD) increases the plasma levels of SCFAs and reduces the plasma and urinary levels of nitrogenous compounds in mice, which implies improvements in GM functions. In addition, Desulfovibrio spp. are lipopolysaccharide (LPS)-producing bacteria and sulfate-reducing bacteria, opportunistic pathobionts whose presence shows a significantly positive correlation with the plasma levels of LPS, potent inflammatory molecules for the human organism [69]. SRD significantly increased the proportion of Firmicutes and the Firmicutes/Bacteroidetes ratio in the colonic contents of the mouse compared to the control and increased intestinal glucose and lipid absorption. Animals fed SCAA-restricted diets also had health improvements including reductions in body weight, fat, and oxidative stress; fewer cancerous tumors; and increased insulin sensitivity. One of the effects of SCAA restriction in food is to inhibit growth, leading to healthier, longer-lived but smaller animals. SCAA restriction could be a new dietary approach to health and longevity for adults [70,71].

S is present in foods rich in the methionine and cysteine amino acids, including beef, lamb, pork, and poultry meat, and unfermented cow’s milk. Also, foods preserved with sulfites should be reduced in the diet. Vegetables and fruits such as bell pepper, carrot, spinach, zucchini, cucumber, lettuce, tomato, banana, watermelon, apple, kiwi, melon, berries, oranges, pineapple, and cereals such as rice, quinoa, and oats have low S and high B content.

4.1.2. Low Iron-Containing Foods

Keeping Fe in the blood at optimal levels can contribute to better health, longer life, and longevity. In Fe overload, Fe is deposited in body tissues including the heart, liver, pancreas, and joints. This can lead to heart failure, liver disease, high blood sugar, and arthritis. Too much Fe in the blood can contribute to the development of age-related health conditions, such as Parkinson’s disease (PD), liver disease, and a reduced ability to fight infections. Too little Fe can also cause problems such as low energy, decreased muscle strength, and cognitive decline. Recent scientific findings have shown that genes involved in metabolizing Fe in the blood are linked to a longer and healthier life [72,73].

It has been shown that humans become less efficient at incorporating Fe into red blood cells as they age, and as a result, more Fe is released to create prooxidant free radicals, which are known to damage deoxyribonucleic acid (DNA) and accelerate cell aging. In animal studies, this damage has been associated with signs of aging, such as muscle loss, brain tissue damage, and short lifespan. Fe accumulation in the brain, e.g., can contribute to conditions such as PD and Alzheimer’s disease (AD). In order to optimize Fe intake, a balanced diet of foods rich in non-heme Fe should be applied. Non-heme Fe is found in plant foods, the richest sources being quinoa, chickpeas, lentils, dried apricots, and salad greens. Fe absorption can be increased from non-heme plant sources by combining them with foods rich in vitamin C, such as broccoli, bell peppers, and oranges [74,75].

There are two main forms of Fe: heme and non-heme. Plant-based foods, as well as Fe dietary supplements, usually contain non-heme Fe. Meat and seafood contain both heme and non-heme Fe. Heme Fe tends to be absorbed by the human body at a higher level. Legumes, whole grains, nuts, and seeds all contain phytic acid, which has been shown to inhibit the absorption of non-heme Fe. Soy protein and calcium can also affect Fe absorption. Also, polyphenolic compounds found in coffee, black tea, and herbal infusions can also inhibit the absorption of non-heme Fe [76].

4.1.3. Reduced Gluten Foods

Celiac disease (CD) is an autoimmune condition occurring in individuals with a genetic predisposition due to an inadequate immune response to gluten, proteins found in grain products called gliadins. Exposure to gluten in genetically predisposed individuals results in gut inflammation and reduced gut barrier function due to the immune response to gluten-related antigens. CD often presents gastrointestinal (GI) symptoms such as malabsorption, steatorrhea, and abdominal pain, as well as extraintestinal symptoms like dermatitis herpetiformis, Fe-deficiency anemia, metabolic bone disease, infertility, and liver disease. Untreated CD is associated with DYS characterized by elevated levels of Escherichia coli and Staphylococcus aureus, which normalize after treatment with a gluten-free diet. Nowadays, there is an increasing incidence of the diagnosis of CD in adults, particularly in the elderly. The incidence of CD in the over-65 age group has gradually increased from 4% to 19–34% [77]. Recently, a study showed a small but statistically significant increase in mortality rate in those who consume gluten. People with CD may experience joint pain, osteopenia or osteoporosis, bone fractures, skin rashes, and psychiatric symptoms such as anxiety and depression. The dietary trigger for CD, gluten, is well known. When people with CD eliminate gluten (a protein found in wheat, rye, and barley) from their diet, they show an improvement or resolution of symptoms. Increased mortality in CD patients has been linked to CVDs, cancer, respiratory diseases, and other unspecified causes [78]. Thus, people with CD should consume a diet rich in gluten-free whole grains, such as oats, quinoa, and amaranth (a South American pseudocereal, once essential in the diet of the Aztecs) [79].

4.2. Nutrients That Need to Be High in the Food

4.2.1. Prebiotic Boron-Rich Foods

Recent studies have shown that the nutritional intake of B can moderate or mitigate various pathological conditions associated with aging, including cognitive decline, cancer, bone health, and sarcopenia. These results suggest that a B-rich diet supports healthy aging and promotes longevity. Raising prebiotic B intake by dietary means may contribute to beneficial effects on thyroid metabolism, obesity, and lipid metabolism, and may be used in dentistry as a cariostatic agent. The major sources of prebiotic B are nuts, dried fruits, legumes, fresh vegetables, raisins, and GCB [80,81]. Also, from another point of view, in a study that specifically examined the toxicity of B on the population, the mortality rate in communities with a high amount of B in drinking water was lower than that of the general population of France as a reference area (p < 10⁻³). The results of this study do not support the idea of a harmful effect of the B level of water on human health in this specific region. There is even a trend toward a beneficial effect following exposure to low doses of environmental B (less than 1 mg/L B in drinking water) [82]. The dietary intake of plant-based B-containing molecules could play an important role in extending human lifespan [16,62].

4.2.2. High Omega-3 Fatty Acid Foods

A deficiency of omega-3 FAs causes dry skin, fatty deposits in the liver, and developmental and growth problems in children; induces central nervous system dysfunction; and impairs vision, while an omega-3 FA-enriched diet has a protective role in CVDs. Omega-3 FAs are polyunsaturated FAs that occur widely in nature and occur in certain foods. A new study explored whether or not there is a link between omega-3 FAs and human life expectancy. Researchers found that higher levels of omega-3 FAs in the blood could predict a lower mortality rate in people over 65 [83]. Three main types of omega-3 FAs exist: alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). People usually take DHA supplements during pregnancy because they may help the developing fetus. Apart from supplements, some sources of omega-3 FAs include soybean oil, rapeseed oil, certain fishes (salmon, tuna, and sardines), and seeds (chia and nuts). People who eat nuts (high in monounsaturated FAs) five times a week have a 50% reduction in the incidence of CVDs, and it has been suggested that diets rich in omega-3 FAs are linked to lower rates of cancer, reduced risk of AD, and a reduction in the symptoms of rheumatoid arthritis. The findings suggest that higher circulating levels of marine EPA and DHA are associated with a lower risk of premature death. People with high blood levels of omega-3 FAs who did not smoke had the highest survival estimate [84]. People with high omega-3 FA levels who smoked and those with low omega-3 FA levels who did not smoke were almost identical in survival estimates. In addition, people with low omega-3 FA blood levels who smoked had the lowest survival estimate. These results indicate that lipids play a crucial role in regulating aging and longevity [85,86].

4.2.3. Foods Rich in SCFAs and MCFAs

An FA is a simple lipid molecule with a carboxylic group on one end and a hydrocarbon chain on the other. Based on the chain length of the C atoms, FAs are classified into the following three groups: SCFAs with <6 C atoms, MCFAs with 6–12 C atoms, and long-chain fatty acids (LCFAs) containing >12 C atoms, respectively. MCFAs are mainly of food origin, while SCFAs are mostly produced by gut bacteria through the fermentation of fibrous foods but can be found directly in fermented foods. Lauric acid (LA; C:12) is an MCFA and is present in high amounts in coconut oil and palm kernel oil, about 45 g/100 g edible portion. Plant oils, seeds, fruits, and breast milk contain also LA. Caprylic acid, also called octanoic acid, is saturated FA. It is found naturally in the milk of various mammalians, and as a minor constituent of coconut oil and palm kernel oil, along with two other FAs, caproic acid (C:6) and capric acid (C:10). Together, these three FAs comprise 15% of the FAs in goat’s milk fat [87]. Furthermore, MCFA has a pathogen-suppressive effect because its supplementation has been shown to reduce the growth of enteropathogenic bacteria such as Vibrio cholerae, Salmonella typhi, and E. coli in mice diet when given upon the induction of disease, resulting in decreased gut inflammation and improved gut health and integrity [88,89]. Numerous reports have been published on the anticarcinogenic properties of LA in vitro. Of the MCFAs, LA has been shown to be a very active treatment for cancer. Specific blood profiles of sphingolipids and phospholipids have been shown to change with age and are linked to exceptional human longevity. These findings suggest that lipid-related interventions could enhance human health and longevity and that blood lipids are likely to serve as a valuable source of biomarkers of human aging [90].

4.2.4. Polyphenol-Rich Foods

Polyphenols have long been recognized for their high levels of antioxidants, attributed to their interaction with the GM. Research indicates that the association between sedentary lifestyles and increased mortality is observed only among adults who do not consume coffee, but not among those who do [91]. Natural polyphenols are identified as essential plant compounds with anti-aging properties, found in sources such as blueberry polyphenols, procyanidins from apples, theaflavins from black tea, epigallocatechin gallate (EGCG), curcumin, and resveratrol [92].

Recent studies demonstrate that polyphenols can modulate several processes central to aging. Evidence suggests that polyphenols, due to their antioxidant and anti-inflammatory capacities, may influence telomere length and help prevent telomere shortening. The antioxidant effects of diet on telomere function substantiate the significance of diet in determining telomere length status. Specifically, EGCG and quercetin are noted for their potent antioxidant effects, potentially preventing the apoptosis of cardiac myocytes by inhibiting telomere shortening. Thus, research supports the idea that polyphenols, with their antioxidant and anti-inflammatory properties, may positively affect telomere length and exhibit strong anti-aging capabilities [92].

The key dietary sources of polyphenols include fruits (plums, apples, apricots, peaches, pomegranates, sweet cherries, and grapes), berries (black elderberries, black aronia, blueberries, raspberries, blackcurrants, wild strawberries, and blackberries), vegetables (artichoke, broccoli, chicory, spinach, red onion, and curly endives), nuts (almonds, hazelnuts, walnuts, chestnuts, and pecans), fruit juices (blood orange juice and lemon juice), soy products (tofu, tempeh, soy flour, soy yogurt, and soy sprouts), green tea, red wine, cereals, chocolate, black tea, and coffee [92].

The most important food products with a high content of polyphenols are, among others:

(i)

Blueberries (656 mg polyphenols/100 g) [93].

(ii)

Strawberries are rich in anthocyanidins (289.20 mg/100 g) and especially flavonols (fisetin) [94].

(iii)

Apples are rich in phytochemicals; mainly, they are abundant in polyphenols, such as rutin, CA, catechin, epicatechin, proanthocyanidin, and vitamin B₂ [95].

(iv)

Black rice has been consumed for centuries in Asian countries, including China, Japan, and Korea. It is regarded as a functional food due to its high content of ferulic acid, various phytosterols, and other bioactive compounds such as anthocyanins and other polyphenols [96,97].

(v)

Tea is the most widely consumed beverage in the world after water. The polyphenol content in tea varies based on the fermentation type (61.86 mg/100 mL for green tea infusion; 104.48 mg/100 mL for black tea infusion); green tea primarily consists of catechins, while black tea contains a significant amount of tannins. Evidence suggest that polyphenols in green tea confer actions against accelerated ultraviolet (UV)-induced skin aging with anti-wrinkle, anti-melanogenic, antioxidant, and anti-inflammatory effects [98,99,100,101].

4.2.5. Functional Probiotic Foods Produced by Fermentation

From a health perspective, fermented dairy products such as yogurt and cheese are recognized for their content of beneficial microbes. These foods provide microbes that can transiently populate the human gut. Hippocrates, 2500 years ago, suggested “Let food be medicine and medicine be food” to underscore the potential role of bioactive food compounds in preventing or treating chronic diseases. Probiotic fermentation combines the benefits of fermented foods with probiotics by increasing the number of bioactive peptides released. Furthermore, due to high levels of lactic acid, butyric acid, citric acid, and acetic acid in products like cream, cheese, yogurt, Acidophilus–Bifidus milk, koumiss, kefir, and fermented beverages, these products are considered suitable matrices for probiotic microorganisms. Functional fermented foods offer additional health benefits beyond their nutrient content, representing significant potential for the dairy industry. Research indicates that fermented dairy products positively impact GI health and may enhance the immune system [102].

Consuming fermented dairy products may improve health conditions such as diarrhea, obesity, high cholesterol, CV functionality, and more. Fermentation enhances the presence of beneficial bioactive peptides, vitamins, and other elements produced by bacteria, contributing to overall health. Probioactives are bioactive compounds linked to the food matrix and probiotic microorganisms in food. Consuming fermented dairy, with or without probiotic bacteria, supports human health by helping to prevent or manage inflammatory diseases, as demonstrated by various strains in preclinical and clinical studies that promote health. As a result, fermented dairy products have the potential to serve as “functional food packages” with extended shelf-life and improved sensory qualities. Various foods have been fermented, and the current scientific focus on polyphenol-rich fermented foods has not yet gained full attention [103]. This might partly be due to the traditional antimicrobial nature of polyphenols. Polyphenolic fermented foods offer dual benefits: polyphenols can suppress various pathogens while promoting probiotic growth, and probiotics can biotransform polyphenols during fermentation, leading to increased bioavailability and enhanced phenolic profile content. This approach holds considerable potential for developing novel functional food products. Investigating the synergy between probiotics and polyphenols in food is recommended as it represents an underexplored area of research that could contribute significantly to the next generation of functional foods [104,105].

5. MAB Diet for Healthy Life: The Future of Personalized Nutrition

Prebiotic B as MABs is essential for the synthesis of AI-2: AI-2 is one of the QS systems of microorganisms and affects the collective behavior of bacteria. Structurally, AI-2 can exist bound to B (AI-2B). When AI-2 is linked to ingested prebiotic B, it automatically decreases the level of AI-2 and increases the proliferation of bacteria producing AI-2 (feedback mechanism). Prebiotic B means those natural compounds with organic B content that reach the colon undigested from the borate–phenolic acid (i.e., DCB) composition of plants.

MABs in the diet are essential for an HS. The lack of prebiotic B (MABs) in the human diet causes DYS and the degradation of the colonic mucus and the mucus of the oral cavity [9]. Prebiotic B ingested as DCB forms a complex with 4,5-dihydroxypentane-2,3-dione (DPD; pro-AI-2 signaling molecule) in the colon, resulting in AI-2B (a B-containing QS signal) and consequently: (i) AI-2B stimulates the growth of BPB; (ii) AI-2B transfers borate anion to BUT-stimulated mucins; (iii) AI-2B increases host impermeability to the microbiome; (iv) high levels of AI-2B inhibit pathogenic bacteria; (v) AI-2B is a marker of DYS process, and high level of AI-2B means eubiosis, i.e., HS [9,15].

The term “microbiota-accessible borates” used in this review is defined as natural OBS that can be used as a growth substrate by gut microorganisms [15]. These natural OBS include mainly BPP and BPE (the recently discovered DCB), which are resistant to digestion and absorption by the host and are metabolically available to the GM. The primary metabolite of MAB fermentation in the colon is BUT, which is predominantly produced by the Firmicutes phylum. MABs are the primary source of B for AI-2, which promotes the colonization of BPB to improve gut barrier function and reverse antibiotic-induced GM DYS, and, in addition, the abundance of MABs promotes the rejuvenation of the mucus of the colonic gel of the host gut [9,15] (Figure 3).

Consequently, for personalized nutrition with B, we will have to define the known concept of “nutrient density”. Nutrient density identifies the ratio of beneficial nutrients to calories in food [106]. Boron nutrient density (BND) reflects the ratio of nutrient content to the total energy content of food. BND is, therefore, expressed in terms of the amount of a specific nutrient (by weight) per 1000 calories, as can be seen from Equation (1):

$$BND={\displaystyle \frac{{\left[B\right]}_{\mathrm{m}\mathrm{g}/100\mathrm{g}}}{{\left[CAL\right]}_{100\mathrm{g}}}}\times 1000$$

(1)

BND is of two types: total BND (BND_T), which is the total B contained in an ingested food, and essential (microbiota-accessible) BND (BND_MA), which is the indigestible B accessible to the microbiota. In general, for plant-based foods, about 10% of the BND_T is accessible to the microbiota and therefore, indigestible. BDN_MA varies from one food to another and is increased in polyphenol-rich foods and, in particular, in foods rich in phenolic acids. This percentage of 10% of the BDN_T for vegetables is calculated from the existence on average of a quantitative ratio between B–carbohydrates and B–polyphenols (10:1, on average); the indigestibility of B–carbohydrates is on average 1%, while B–polyphenols have an average indigestibility of 90%.

For example, the 10 mg of BDN_T needed to have a minimum of 1 mg of B in the stools is provided by a 90% diet rich in fruits, vegetables, seeds, fermented foods, and marine fish:

(i)

For fruits, if we have an average of 0.5 mg B/100 g of fruits, at an average of 40 calories/100 g, BND_T: 12.5 mg B/1000 calories and BND_MA: 1.25 mg B/1000 calories.

(ii)

For vegetables, if we have an average of 0.3 mg B/100 g of vegetables, at an average of 30 calories/100 g, BND_T: 10 mg B/1000 calories and BND_MA: 1.0 mg B/1000 calories.

(iii)

For seeds, if we have an average of 1.5 mg B/100 g of seeds, at an average of 600 calories/100 g, BND_T: 2.5 mg B/1000 calories and BND_MA: 0.25 mg B/1000 calories.

(iv)

For fermented foods, with an average of 0.15 mg B/100 g, at an average of 70 calories/100 g, BND_T: 2 mg B/1000 calories and BND_MA: 0.2 mg B/1000 calories.

(v)

For marine fish, with an average of 0.1 mg B/100 g, at an average of 150 calories/100 g, BND_T: 0.8 mg B/1000 calories and BND_MA: 0/08 mg B/1000 calories.

The fundamental principle of the MAB diet is that the density of digestible microbiota B should be a minimum of 1 mg of B in stools, which is provided by a minimum of 10 mg of B intake daily. In addition, the MAB diet should provide about 90% of the regular daily diet of 2000 calories/person and have a low Fe, S, and gliadin content, and high omega-3 FA and polyphenol content. The following categories of foods should be used in the MAB diet, in order of BND: fruits and vegetables (50%), seeds (10%), fermented foods (20%), and marine fish (10%), and be part of 90% of the daily diet. This is an edible MAB diet comprising high B foods with low levels of S, Fe, and gliadins that can provide B intakes of 10 mg/day to a maximum of 20 mg/day and a B level in the stool of a minimum of 1 mg/day.

Table 1. B content of some food groups recommended for a balanced B diet.

Food Category	Food Group	Source	Calories/100 g	B Content (mg/100 g)	BND	Refs.
Plant-based products	Fruits	Apricots	44	2.11	47.95	[107,108]
		Avocado	161	2.06	12.80	[80,107]
		Blueberries	47	0.76	16.17	[107,109]
		Currants	40	1.74	43.50	[80,107]
		Dates	292	1.08	3.70	[80,107,108]
		Figs	65	1.26	19.38	[80,107]
		Peaches	39	0.52	13.33	[80,107,108]
		Prunes	50	1.88	37.60	[80,107,108]
		Raisins	310	4.51	14.55	[80,107,108]
		Raspberries	43	1.74	40.47	[107,110]
Plant-based products	Vegetables	Beet root (canned)	46	0.32	6.96	[80,107]
		Broccoli	34	0.31	9.12	[107,108]
		Carrot	38	0.30	7.89	[107,108]
		Celery	21	0.50	32.81	[107,108]
		Dill	11	0.38	34.55	[80,107]
		Lentils	333	0.74	2.22	[80,107,108]
		Mushrooms	25	0.16	6.40	[80,107]
		Olive	115	0.35	3.04	[107,108]
		Onion	33	0.20	6.06	[107,108]
		Parsley	36	0.59	16.39	[80,107]
		Potato (sweet)	116	0.18	1.55	[107,108]
		Spinach	22	0.13	5.90	[107,111]
Plant-based products	Nuts, seeds, and cereals	Almond	576	2.82	4.90	[80,107,108]
		Amaranth seeds	400	0.53	1.33	[80,107,108]
		Black rice	362	0.32	0.88	[80,107,108]
		Brazil nuts	656	1.72	2.62	[80,107]
		Cashew nuts	553	1.15	2.08	[80,107]
		Hazelnuts	628	2.77	4.41	[107,108]
		Oat	350	0.35	1.00	[80,107,108]
		Peanuts	567	1.49	2.63	[107,112]
		Pistachio nuts	562	1.20	2.14	[80,107]
		Quinoa seeds	366	0.85	2.32	[80,107,108]
		Walnuts	654	1.63	2.49	[80,107]
Dairy products	Functional probiotic foods produced by fermentation	Cottage cheese	103	0.05	0.49	[80,107]
		Cow’s yogurt	61	0.10	1.64	[80,107,108]
		Donkey’s cheese	350	0.12	0.43	[80,107,108]
		Fermented soy (natto)	212	0.10	0.47	[80,107,108]
		Goat’s cheese	347	0.08	0.23	[80,107,108]
		Goat’s yogurt	97	0.15	1.55	[80,107,108]
		Kefir	52	0.10	1.92	[80,107,108]
		Sheep’s cheese	288	0.05	0.17	[80,107,108]
		Skyr	48	0.10	2.08	[80,107,108]
Aquatic products	Marine fish	Barracuda	211	0.10	0.47	[107,113]
		Salmon	181	0.12	0.66	[107,113]
	Seafood	Clams	89	0.10	1.12	[107,113]
		Crabs	97	0.13	1.34	[107,113]
		Oysters	63	0.40	6.35	[107,113]
		Shrimps	91	0.12	1.32	[107,113]
Beverages	Natural beverages	Coffee	2	0.03	15.00	[107,114]
		Green tea	1	0.01	10.00	[107,114]
		Shiraz Cabernet wine	83	0.86	10.36	[107,108]

B: boron; BND: boron nutrient density; Refs.: References.

lists all the food categories that are permitted to provide the requirement of MAB diet to be able to maintain the host–microbiota HS.

6. Conclusions

The MAB diet has a special meaning in personalized nutrition via GM in the future. By the consideration of BND in nutrition, more effective interventions could be developed for improving public health. H/A cells do not have a metabolic pathway to synthesize OBS and these must be taken from plants. Subsequently, MABs such as BPP and BPE become novel prebiotic candidates and are targeting the colon as novel colonic foods.

The effects of the MAB diet are as follows [8,9]:

(i)

Colonic mucus gel rejuvenation with far-reaching effects on the musculoskeletal system (bones, cartilages, and muscles) and the immune system (the brain, heart, and thyroid). The colonic mucus gel rejuvenation has a major meaning in the concept of healthy longevity. The MoA of MABs succeeds in rejuvenating the colonic mucus gel by stimulating BPB, stopping the growth of pathogenic bacteria, and strengthening the gel layer of the colonic mucus.

(ii)

Reversing DYS through MAB nutrition by reversing an aged microbiome into a younger one and the potential to provide healthy longevity to the aged host by supporting immunity and restoring HS in the GM system. Subsequently, reversing DYS slows aging.

(iii)

Essential nutritional adjuvants in antibiotic treatment applied in acute infections: stimulate commensal bacteria and stop the proliferation of pathogenic bacteria, thus regulating the GM during antibiotic treatment.

(iv)

Adjunct to periodontal therapy: MABs can be used effectively as an active ingredient in toothpastes and mouthwashes, as well as an adjuvant in the treatment of periodontal diseases (gingivitis and periodontitis).

The role of this high-MAB food diet is to ensure an HS of the GM with the host and to help the nutritional cocktail reverse the DYS due to the physiological dysfunctions of aging. The fundamental principle of the MAB diet is that BND_MA should be a minimum of 1 mg of B in stools, which is provided by a minimum of 10 mg of B daily intake of foods. In addition, the MAB diet should provide about 90% of the regulated daily diet of 2000 calories/person and have a low Fe, S, and gliadin content, and high omega-3 FA and polyphenol content. The following categories of foods should be used in the MAB diet, in order of BND: fruits, vegetables, seeds, fermented foods, and marine fish, and be part of 90% of the daily diet.