Boron (B) is considered a prebiotic chemical element with a role in both the origin and evolution of life ^{[1][2][3][4][5]}[1,2,3,4,5], as well as an essential micronutrient (meaning that life cannot be sustained without it) in plants ^[6][7][6,7], some bacteria ^[8][9][8,9], fungi, and algae [10]. Moreover, B is considered beneficial in human and animal nutrition ^[11][12][11,12]. B has not been classified as an essential micronutrient for humans and animals because its biological role has not been clearly identified ^[13][14][15][13,14,15]. However, B has beneficial effects on the biological functions of humans and animals, such as reproduction, growth, calcium metabolism, bone formation, energy metabolism, immunity, brain function, and steroid hormones, including vitamin D and estrogen ^{[12][16][17][18]}[12,16,17,18].

As a scientific term, the word “prebiotic” has two meanings: (i) in the origin and evolution of life, “prebiotic” means either the chemical molecules essential for the evolution of life or the raw constituents from which these molecules were formed ^[3][19][3,19]; (ii) in nutrition, “prebiotic” today means “a substrate that is selectively utilized by host microorganisms (thereby) conferring a health benefit” [20]. The latest data on the accepted definition of prebiotics from nutrition and regulations have been well reviewed [21]. Currently, prebiotics are based on microbiota-accessible carbohydrates (MACs) [22] but also on other natural phytochemicals, such as polyphenols ^[23][24][23,24], polyunsaturated fatty acids (PUFAs) ^[25][26][25,26], lactose, and lactose derivatives [27]. The effects of prebiotics on human/animal health are increasingly being investigated, with many scientific papers published in this field [28]. Presently, the demonstrated prebiotic effects on health mainly involve benefits for the gastrointestinal (GI) tract, innate and adaptive immune homeostasis, cardiovascular metabolism, mental health, and bone health ^[29][30][31][29,30,31].

The MACs are some of the most important carbon sources for colon bacteria, as they promote the growth of healthy bacteria and the production of short-chain fatty acids (SCFAs) that can have multiple interactions with the host tissues [32]. A diet that is low in MACs favors bacteria that degrade the mucus and results in the decreased diversity of bacteria with a loss of beneficial bacterial strains. The MACs also contribute to the decreased epithelial integrity of the colon, favoring increased mortality and disease development, as proven within various preclinical and clinical research works [33]. The MAC class also includes some microbiota-accessible naturally organic B (NOB) species, which naturally occur in plants [34] and are present in fruits, vegetables, herbs, nuts, and seeds that are essential to human nutrition ^[35][36][35,36].

Various studies ^[37][38][39][37,38,39] have shown that sugar-alcohol B esters (SBEs), as NOB species, are crucial in plant development. More recently, SBEs have been proven to be potential modulators of health in humans as well ^{[34][40][41][42]}[34,40,41,42]. The identification of the health benefits of SBEs and the further clinical recognition of their importance have become an important direction of research into the science of NOB compounds.

To date, out of all SBEs, only fructoborate (FB) has been clinically tested, proving to have beneficial and quantifiable activity in humans ^[18][34][35][18,34,35]. The main physiologically stable phyto-SBE compounds are B pectic polysaccharides rhamnogalacturonan II (RG-II) [43], glucose- and fructose-borate esters, bis-sucrose esters, and borate polyalcohols containing minimally digestible carbohydrates, such as sorbitol, mannitol, and dulcitol ^{[42][44][45][46]}[42,44,45,46], and the recently discovered chlorogenoborate diester complex (CBDC) [47]. In the future, all of these compounds may be promising novel prebiotic candidates [47]. SBEs and CBDC (detected in green coffee beans) are found in numerous vegetables and fruits ingested by humans and animals, and from a biochemical point of view, they are indigestible but microbiota-accessible ^[34][47][34,47].

Recent studies have shown that, since the pK_a of SBEs is approximately 4.0, their indigestibility is at a maximum above the pH (4.5) of the postprandial stomach ^[18][34][18,34]. In human cells, there are no known biochemical mechanisms or biomolecules that require B, and therefore, B has yet no specific status among nutraceuticals. As the mechanism of action (MoA) of B has not been identified in human/animal cellular metabolism, the market for B nutraceuticals does not yet distinguish between NOB compounds (e.g., SBEs, CBDC) and naturally inorganic B compounds (boric acid (BA), borates).

There is currently a major scientific gap between the use of B compounds in human and animal diets and the MoA of B and its target in the body [12]. However, more recent investigations have shown that in bacteria, the signaling molecule containing B (a furanosyl borate diester or autoinducer-2-borate (AI-2B)) contributes to the animal host’s health (via intestinal flora) and protection against pathogens ^[18][34][48][18,34,48]. Since SBEs are similar to AI-2B, it has been claimed [34] that SBEs can also increase the beneficial capabilities in some bacteria and reduce virulence in others. Considering the above-mentioned developments, new insights into the essentiality of B species in humans and animals are emerging. 

2. New Insights into the Essentiality of B Species in Symbiosis across Life Kingdoms

Symbiosis is described as “the close relationship between two organisms of different species, with benefits for one or both individuals” [49]. Symbiosis is any kind of long-term and close biological interaction between two different biological organisms, be it parasitic, commensalic or mutualistic. These close interactions between species are often long term and, for the most part, beneficial to the symbionts [50]. B plays an essential role in several symbioses between plants or animals and bacteria, including the following: (i) Rhizobium-legume symbioses: In micromole concentrations, B has been recognized as a key element (essential micronutrient) in the formation of a symbiosis between legumes and nitrogen-fixing bacteria, such as Rhizobium, Azorhizobium and Bradyrhizobium ^[51][52][51,52]. Although, admittedly, B was not found to be essential for these bacteria, these findings show that when B is lacking, the rhizobia-legume “dialogue” is depressed, and the bacterium is identified as a pathogen agent by the plant with disastrous consequences for the symbiosis. The unanimously accepted MoA is that arabinogalactan-protein extensin (AGPE), a hydroxyproline-rich glycoprotein, forms a B complex, while rhizobia cells are separated from it by an exopolysaccharide capsule ^[8][53][8,53]. The existence of a bacterial exopolysaccharide capsule is necessary to prevent the attachment of the AGPE glycoprotein matrix to the surface of the bacterium [54]. (ii) Arbuscular mycorrhizal (AM) symbiosis: It is well known that a considerable natural accumulation of B in certain plant parts (especially roots and leaves) is controlled by the presence of several mycorrhizal and saprotrophic species [55]. Recently, mycorrhizal symbiosis has been shown to be essential for many plant species to acquire nutrients from soil [56]. Although B does not play a key role in fungi, some of them are carriers for organic B species; consequently, fungal species have been proposed to function as agents for ameliorating B toxicity and for regulating the amount of B species in plants [57]. An interesting fact is that some fungal species accumulate B, while other species exclude it, suggesting that B has specific functions among fungi as well [10]. Recent research has revealed the useful effect of AM symbiosis by diminishing B toxicity in roots and leaves in a citrus rhizome. AM symbiosis improves the tolerance of Carrizo citrus to excessive sources of B by reducing the concentration and toxicity of B in leaves and roots [58]. It is believed that mushrooms do not require B for their own metabolism; the first hypotheses about B in fungi indicated that B could be sequestered as SBEs in forms that are unavailable to fungi. At present, not much information is available about the role of organic B species in AM symbiosis, but future research may demonstrate that the essentiality of B in plants extends beyond the role of B in mycorrhizae/plant symbioses [59]. (iii) Actinorhizal symbiosis: A nitrogen-fixing bacterium with structure and functionality similar to heterocystous cyanobacteria is Frankia spp., an actinomycete symbiont of actinorhizal plants. The following mechanism of action was suggested: B may be necessary for maintaining the envelope of the heterocyst of cyanobacteria ^[60][61][60,61], the envelope of filaments and vesicles of Frankia spp. [53], and for activation of the quorum sensing (QS) autoinducer-2 (AI-2) signaling molecule [62]. Actinomyces spp. are ubiquitous in the soil and in animal microbiota, including human microbiota [53]. Certain species are commensal in the skin microflora, in the oral flora, intestinal flora and the vaginal flora of humans and animals, and it has been assumed that these microorganisms need B for symbiosis with the host (human/animal) [63]. (iv) Algal-bacterial symbiosis: B-vibrioferrin (a borate-siderophore complex) was separated from the specific environment of a bacterial “symbiont” from a toxic marine dinoflagellate, although this does not necessarily mean that B plays the role of algal partner [64]. (v) Animal kingdom-bacterial symbiosis: At present, although there is scarce scientific evidence to show that B deficiency adversely affects the symbiosis between an animal host and its microbiota, studies still provide strong and sufficient arguments for B’s importance in the microbiota’s health, such as the following: (a) In microbiome bacteria, the signaling molecule with B, AI-2B, contributes to the health of the host (via intestinal flora or microbiota) and protection against pathogens [48]. Functionally, AI-2 has been linked to important bacterial processes, such as virulence and biofilm formation, suggesting the possibility of AI-2 reacting with B to produce AI-2B [65]. There is a growing body of work showing that the chemical language of bacteria using the AI-2 signaling molecule is a chemical language both between species and within the same species, as well as across kingdoms (e.g., bacteria and animals) ^[66][67][66,67]. (b) Oral administration of BA in toxic concentrations to Blattella germanica insects caused dysbiosis of the intestinal microbiota (IM) [68]. (c) B is essential for symbiosis between nematodes and mice microbiomes. Low or marginal dietary intake with B may affect the establishment and survival of parasites through its effects on the intestinal microflora [69]. (d) Significant induction of Xenopus laevis tadpole larval growth has been shown to be correlated with changes in the host’s intestinal microbial communities. These changes in the host’s physiology are due to indirect effects of B that could stimulate bowel maturation, with a beneficial effect on bacteria that promote the host metabolism ^[70][71][70,71]. (e) Tartrolon is a natural B compound found in some species of bacteria and has been detected in marine bivalve mollusks of the Teredinidae family (a group of saltwater shells found in symbiosis with the Teredinibacter turnerae bacterium). Together with the T. turnerae bacterium, marine bivalve mollusks achieve cellulose digestion and nitrogen fixation. The antibacterial tartrolon produced by mollusk gill symbionts helps to suppress pathogenic bacteria in the mollusk gut and allows the host to more efficiently absorb the glucose released from the breakdown of lignocellulose [72]. (f) For chickens, it was observed that B-based nutrition (as BA) helped to regulate the microbiota following the attack of pathological bacteria. In fact, the BA formed complexes with carbohydrates and phenolic acids from the regular chickens’ diet. A simple calculation shows that 0.1% BA used in the experiment can be totally complexed by fructose and phenolic acids from the diet. The study suggests that B maintains intestinal homeostasis and is effective in controlling Salmonella enteritidis infection through the microbiota [73]. (g) Dietary B addition proved an influence related to dose on protozoan abundance and rumen microbial fermentation in one-year-old rams. The higher B content in the feces could be explained by its availability for the microbiota; B is not accumulated in any internal organ but only in the intestine. The concentration of B in the rumen fluid has been found to be lower than that in the feces [74]. (h) Other animal tests showed that, after five days of feeding the sheep with B, the feces had a high concentration of B (250 ppm), higher than in the urine (140 ppm) [75]. This experiment demonstrated the large capacity of the large intestine to “sequester” B. Additionally, this does not necessarily mean that there is a relationship between B metabolism and the organ volume. (i) It has recently been found that when indigestible B in the nutrition ingested by African ostrich chicks reaches the colon, it interacts with the microbiota, thus stimulating apoptosis and cell proliferation. Here again, the proliferation of the intestinal cells is influenced by the relationship between B and microbiota [76]. (j) B in oral washes positively influences periodontal health. BA and calcium fructoborate (CaFB) hydrogels have shown their potential as a treatment option for gingivitis and periodontitis [77]. In another study, the B levels in non-carious teeth were also higher than in carious teeth, and a significant negative correlation was identified only in non-carious teeth group [78]. (k) Moderate supplementation with dietary B improved growth performance, the digestibility of crude protein, and the diarrhea index in weaned pigs, regardless of health status [79]. (l) In humans, a natural diet rich in B led to an improvement in the oral microbiota and, most importantly, to a decrease in thyroid-stimulating hormone (TSH), which is generally a consequence of dysbiosis [80]. At the same time, the ability to buffer saliva increased significantly after a diet rich in B, and the B level of decayed teeth was lower than that of healthy teeth [81]. Increased B in saliva has a positive effect on dental and oral health and may decrease the formation of cavities and show potential as a treatment option for gingivitis and periodontitis [77]. Important changes in salivary buffering capacity and TSH during a natural B-rich diet are of clinical importance, with dysbiosis being a common finding in thyroid disorders [81]. Recent work has also revealed that B-rich foods result in cardioprotective effects and longevity, improving long-term survival among patients with kidney transplantation (KTR) [77]. Another recent work showed that B-rich foods result in lower mortality risks and a more favorable cardiometabolic risk profile [82]. All these data presented above show that, differing from inorganic B species, B organic species mainly appear to be essential for the symbiosis among organisms from different kingdoms.

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