Existence of phytase genes in bacteria.
Phosphorus plays vital roles in human health and nutrition. In nature, phosphorus exists as phosphate, either inorganic or organic. The major form of phosphate in plant-derived diets is phytate that cannot be degraded by monogastric animal, as well as humans. Initially, this chapter reviews current research of phosphorus in human nutrition and health. Subsequently, problems of phytate degradation and phosphorus utilization in plant-derived diet are outlined. Next, as the main part, the enzymes of phytase, which catalyze the release of inorganic phosphorus from phytate, are compared, especially those produced by gut microbiota. Meanwhile, how probiotic bifidobacteria can be used for producing phytase and therefore enhance their beneficial effects are discussed. Phytase-producing bifidobacteria can be either isolated rarely in nature or constructed by genetic cloning of phytase genes from other well-characterized enzymes. The combination of bifidobacteria and highly active phytase may improve human health and nutrition especially as supplementary probiotic foods. Therefore, potential application is prospected. Finally, other considerations related to industrial production and usage of phosphorus-enriched additives are remarked. In conclusion, improving and maintaining the phosphorus balance in food by bifidobacteria may be promising for a healthier life.
Phosphorus is an essential nutrient for the body and is routinely consumed through food. After consumption, phosphorus is usually bound with oxygen and exists as phosphate in the body. Both organic and inorganic forms of phosphate are present in regularly consumed foods. The amount of total phosphate ingestion can be significantly influenced by processed food. Following a meal, inorganic phosphate can be rapidly absorbed across the small intestine and enter the bloodstream causing an elevation in serum phosphate levels. An increase in serum levels of inorganic phosphate usually reduces serum levels of ionic calcium by forming a calcium phosphate complex. High ratio of phosphate to calcium usually leads to hypophosphatemia. In contrast, dietary phosphate deficiency, mostly due to malnutrition, can also impair the bone mineralization process and eventually lead to the development of rickets . Nevertheless, phosphorus homeostasis is important for versatile functions, especially skeletal growth, development, and maintenance .
Despite the essential role of phosphate in living cells and wide application of phosphate additives in kinds of food, humans cannot efficiently digest plant-derived phosphate, namely, phytate that is the main form in both cereals and vegetables . Degradation of phytate is catalyzed by phytases, which are predominately presented on bacteria and fungi. Bifidobacteria are the most frequently used microbial supplements in functional foods and probiotic formulations . Probiotics have many beneficial effects in human intestine . Phytase activity was detected in a few species of bifidobacteria [6,7]. Furthermore, heterologous secretion of phytases cloned from other bacteria was reported in bifidobacteria as well . These strains can be used in fermented foods for conversion of poorly digestible phytate enriched in plant materials, which serves an alternative approach for dietary phosphorus supplementation in humans, especially those health-compromised individuals.
2. Role of phosphorus in human nutrition and health
2.1. General biochemistry and distribution of phosphorus
In biological systems, phosphorus involves in many important reactions, including forming cell membrane and nucleic acids, generation of ATP, cell signaling through protein phosphorylation or dephosphorylation, urinary buffering, and bone mineralization. In addition, phosphorus widely takes part in biochemical reactions, e.g., glucose and triacylglycerol (triglyceride) utilize phosphate to synthesize glucose 6-phosphate and glycerol 3-phosphate respectively. Phosphorus is the sixth abundant element in the human body and comprises approximately 1% of total body weight . In mammals, phosphorus is presented as phosphate, which is a predominantly intracellular anion. There is 85% phosphate in bone and teeth, 14% in other tissues, and 1% in extracellular fluid.
Under steady state, a regular Western diet provides approximately 20 mg/kg/day of phosphorus . Around 16 mg/kg/day is absorbed in the proximal intestine, mainly in the jejunum. The normal range of serum phosphate concentration is 4.5–8.3 mg/dl and higher in infants who require more of the mineral for bone growth and soft tissue buildup . At zero metabolic balance, about 13 mg/kg/day phosphorus is excreted in the urine in adults. Thus, under phosphate equilibrium state and normal renal function, the amount of urine phosphorus can be an indicator of the amount absorbed in the intestine . Reasonably, phosphate absorption and reabsorption decline along human aging, respectively, in both the intestinal tract and kidney. Meanwhile, expression of sodium-phosphate co-transporters decreases .
2.2. Phosphorus for nutrition and health
Phosphorus can be supplied in two forms, namely, organic phosphate and inorganic phosphate. Inorganic phosphate additives have greater bioavailability than organic sources of phosphorus that are the main form of phosphate in plant-derived foods. Phosphorus serves vital roles in the human body and is essential component of nutrient. It is crucial for bone growth and mineralization. Both bench and clinical researches show that phosphate is one of the major factors in the maintenance of bone health, and its deficiency results in bone pathology and clinical illness, such as rickets and osteomalacia . Inorganic phosphorus is one of the two main ionic components required for hydroxyapatite formation during the mineralization of the extracellular matrix .
Roughly, 80–90% of the mineral content of bone is calcium and phosphorus, and 85% of the phosphorus is in the skeleton. Adequate phosphorus intake is essential for skeletal mineralization. Although calcium plays an important role in regulating chondrocyte maturation, apoptosis of hypertrophic chondrocytes is dependent upon circulating phosphate at normal levels . Diets high in phosphorus often lead to diminished intestinal calcium absorption, reducing serum calcium concentration, and stimulating parathyroid hormone (PTH) secretion . Phosphorus also directly regulates the production of 1,25(OH)2D by kidney cells. Furthermore, phosphorus is considered to be a major dietary source of acid .
2.3. Phosphate homeostasis and health
As more than 2000 chemical reactions in living cells use phosphate, optimal phosphate balance is essential for effective regulation. Generally, phosphate homeostasis is determined by both intestinal absorption from consumed food and renal excretion of the serum phosphate. Sodium-dependent phosphate (NaPi) transporters actively regulate the intestinal phosphate absorption and partially mediate renal phosphate excretion and reabsorption as well. Parathyroid hormone (PTH) facilitates urinary phosphate excretion because of strong inhibition of NaPi transporters function . Dietary phosphate restriction induces an adaptive increase of intestinal phosphate uptake, and prolonged restriction increases NaPi-2a activity, thereby attempting to restore the balance by increasing kidney phosphate reabsorption .
The maintenance of optimal phosphate balance is managed by complex interactions between the gut, kidney, and bone, as well as “phosphatonins” involving multiple regulators. More precisely, the duodenum and jejunum are responsible for phosphorus absorption in the diet via both passive diffusion and active sodium-dependent transportation . The kidney is the major organ involved in the regulation of phosphate homeostasis. A variety of factors along the proximal convoluted and straight tubule of the kidney, including serum PTH, calcium, 1,25(OH)2D3, and bicarbonate concentrations, take part in the regulation of phosphate. In animals with intact parathyroid glands, the phosphate concentration in the proximal tubules is 70% of the plasma level. There is little phosphate reabsorption in the proximal straight tubule in the presence of PTH. However, in the absence of PTH, phosphate is avidly reabsorbed along the proximal straight tubule. As previously reported, phosphate renal losses were enhanced by increasing fibroblast growth factor 23 (FGF-23).
2.4. Phosphate toxicity
Excessive retention of phosphate in the body is toxic to humans and can cause a wide range of cellular and tissue injuries; partial toxicities are shown in Figure 1 . Common toxicity of phosphate in humans includes impaired renal function, rhabdomyolysis, and tumor lysis syndrome . Occasionally, exogenous phosphate toxicity is also documented in patients when exposed to hypertonic phosphate enemas . Horribly, excessive exogenous phosphate administration can be fatal though the lethal dose in humans is unknown . Overall, it is convincingly demonstrated that phosphate accelerates various pathologies. Acute toxicity can provoke hypocalcemia and associated symptoms including tetany, hypotension, and tachycardia. Moderate toxicity leads to deposition of calcium phosphate crystals, including often fatal cardiovascular calcification that usually irreversible. For instance, phosphate toxicity has been implicated as independent risk factor for high mortality in chronic kidney disease patients . In an animal study, a 7–20-fold higher commercial phosphate-containing enema induced 100% mortality . In another study, the
3. Phytate in plant-derived diets
Phytate, the salt form of phytic acid, represents 60–80% of total phosphorus in plant seeds that can be hydrolyzed by phytase. Even milk and its related products are the richest phosphate sources in human diet; the major sources of phosphate in all natural foods are protein-rich foods and cereal grains. However, humans do not encode genes for phytase and hence can poorly digest phytate in plant-derived diets. Lacking of phytase causes three major problems in simple-stomached animals as well as humans: (1) environmental pollution from manure phosphorus, (2) dietary addition of inorganic phosphorus, and (3) depletion of rock phosphorus deposits. For instance, in a crossover trial with chronic kidney disease-suffering patients, the fasting serum phosphorus concentration was lower after the vegetarian diet than after the meat diet that contained identical phosphorus. More notably, secretion of plasma FGF-23 was about 40% lower in subjects treated with vegetarian diet after one week .
Phosphate interacts with several dietary minerals, such as calcium, sodium, and magnesium. Therefore, deficiency of these minerals is more common than deficiency of phosphate when its bioavailability is low. It was noted that the phosphorus bioavailability of natural foods is variable. Particularly, the bioavailability of phosphorus in phosphate-rich plant foods such as whole grains, legumes, peas, nuts, and seeds is relatively low, because a high proportion of it is tied up in poorly absorbed phytates. Considering many studies link high phosphorus intakes that are mainly supplied by inorganic phosphate additives to increased morbidity and mortality, natural plant foods may favorite health outcomes as their relatively low bioavailability of phosphorus.
4. Phytases and gut microbiota
Phytases (myoinositol hexakisphosphate phosphohydrolase) are enzymes that catalyze the stepwise removal of phosphates from phytic acid (myoinositol hexakisphosphate) or its salt phytate. Until now, a plenty of phytases were discovered and they show different catalytic mechanisms. The first and most extensively studied group of phytases, such as
The gut, especially the jejunum, is the most active site, responsible for the absorption of two thirds of phosphate intake in humans. However, as mentioned above, gut cannot absorb organic phosphorus presented as phytate in plant-derived diets. We know that human gut consists of a complex community of microorganisms, namely, gut microbiota. One main role of gut microorganisms is they benefit the host by fermentation of human readily undigested substrates to absorbable nutrients. Some gut microorganisms produce kinds of enzymes and many of these enzymes are deficient in host, thereby symbiotic relationship is developed. Such a case is phytase producing microbe, like Escherichia coli, Streptomyces coelicolor, Clostridium spp., and so on. Search of “phytase” in the NCBI gene database yielded 198 genes annotated as bacterial phytase. A detailed presence of phytase genes in bacteria is demonstrated in Table 1. Among them, Proteobacteria and Actinobacteria are the most predominating groups that are also natural habitants of human gut.
5. Phytate degradation by bifidobacteria
5.1. Phytase-encoding genes
As shown in Table 1, there is only one gene in
|Organism||Protein name||Accession||Locus_tag||Length (aa)|
||Histidine acid phosphatase||WP_003838654||BIFDEN_01159||637|
||Histidine acid phosphatase||WP_003843340||HMPREF0168_2166||631|
||Histidine acid phosphatase||WP_012902513||BDP_1985||643|
||Histidine acid phosphatase||WP_010081042||Blon03000750||617|
||Histidine acid phosphatase||WP_012472023||BLD_1202||622|
||Histidine acid phosphatase||WP_011068470||BL0400||606|
||Histidine acid phosphatase||WP_015713264||BLIF_0216||622|
||Histidine acid phosphatase||WP_012576702||Blon_0263||623|
||Histidine acid phosphatase||WP_014484530||BLIJ_0267||618|
||Histidine acid phosphatase||WP_007051528||BLIG_00414||617|
||Histidine acid phosphatase||WP_007057720||HMPREF1314_0451||572|
||Histidine acid phosphatase||WP_007056476||HMPREF1312_1349||617|
||Histidine acid phosphatase||WP_013410389||BBMN68_1139||622|
||Histidine acid phosphatase||WP_015512490||BIL_17170||617|
||Histidine acid phosphatase||WP_007054753||BLLJ_0234||617|
||Histidine acid phosphatase||WP_014485906||BLNIAS_02473||617|
||Histidine acid phosphatase||WP_004222312||BIFPSEUDO_03792||639|
|Histidine acid phosphatase||WP_008783259||HMPREF0177_01170||561|
Available from http://www.ncbi.nlm.nih.gov/proteinclusters/?term=BIFPSEUDO_03792.
BLAST searches revealed that (1) BBPR_1292-like proteins are exclusively presented on the genomes of all
5.2. Phytase enzyme activities
Initially, it was believed that bifidobacteria are phytase negative, as very low level activity may be because of unspecific release by phosphatase, except
Although two novel phytases from
6. Potential application of phytase-producing bifidobacteria in foods
Despite phytase’s main application in animal feeds, its applications in human foods can be equally important, if not exceed. To a large extent, using phytase in human foods is not primarily the target to improve phosphorus consumption, because depletion of phytate is more important as it chelates essential minerals, including iron, zinc, and calcium, contributing to deficiencies of these nutrients. It was estimated that there are approximately two to three billion people around the world suffering from mineral deficiency. The application of phytase in human health may be more exciting but need further in-depth study of potential adverse effects. Because certain inositol phosphates are beneficial to human health, phytase and phytase-producing cells can be immobilized as cost-effective bioreactors for large-scale production of these compounds . There are many successful attempts to use phytase in brewing, baking, and dephytination of soy milk .
In fact, application of phytase or phytase-producing bacteria in food has already been illustrated. For example,
7. Advantages of using phytase-producing bifidobacteria
One of the most important advantages of using phytase-producing bifidobacteria is safety. As widely known, several species of bifidobacteria are generally regarded as safe (GRAS) or qualified presumption of safety (QPS). The GRAS status made these strains particularly attractive for application in both food and pharmaceutical industries. Currently, probiotic bifidobacteria are widely used as micro-ecological reagent in many countries. These micro-ecological reagents had been added into both foods and pharmaceuticals without additional toxicity test.
Secondly, as important as the safety issue, many beneficial effects of bifidobacteria made them promising in industry especially ameliorating gastrointestinal disorders (both bacterial- and viral-induced gastroenteritis), allergic diseases, antibiotic-associated diarrhea, lactose intolerance, constipation, and irritable bowel disease. Let alone increasing iron accessibility, phytase-producing bifidobacteria has expanded nutrition profile [41,42]. In the gut of human eating plant-derived diets, phytase-producing bifidobacteria can degrade phytate-based components, therefore improving their adaptability or cross-feeding other symbiotic inhabitants in the same niche.
Thirdly, intake of phytase-producing bifidobacteria is superior to eating inorganic phosphate additives for human. In one aspect, phosphorus homeostasis can be easily disturbed after eating external inorganic phosphate additives. In another aspect, phytase-producing bifidobacteria can improve organic phytate-originated phosphorus. Thereby, supplementation of external inorganic phosphate additives becomes unnecessary. This is particularly significant for avoiding excessive phosphate, resulting in different kinds of toxicities that are largely caused by phosphate-containing additives in foods and drinks. For example, phosphorus-based food additives may pose high risk in people suffering chronic kidney disease, as this made dietary management of hyperphosphatemia practically difficult. In dialysis patients, managing hyperphosphatemia may require using phosphate binder other than restricting protein intake as this allows patients to eat more protein-rich foods . In addition, a study evaluated 93 premature infants with a mean gestational age of 27.5 ± 2.0 weeks. The result demonstrated that elevated serum phosphorus was inversely correlated to the day of life of the infant after receiving human milk-derived fortifier though the incidence of hyperphosphatemia was mild and transient in this population . For those health promised people, intake of phytase-producing bifidobacteria supplied a novel interventional approach.
Lastly but not least, bifidobacteria can produce phytase in human gut as microbial cell factories. They can be ingested as live cells and then colonized in the intestine to facilitate the degradation of plant-derived diets. The relatively constant replication of bifidobacteria in human intestine can either enlarge the bioavailability of organic phytate or downsize the toxicity of excessive phosphorus, hence maintaining the balance of phosphorus in a long term.
8. Final remarks
Phosphorus salts are added to foods as additives in many countries. Thus, dietary intake of phosphorus is higher than the recommended daily allowance in these countries and populations. For instance, phosphorus additives were particularly common in the categories of small goods, bakery goods, frozen meals, and biscuits in Australia . In the United States, it has been estimated that phosphorus additives may add as much as 1 g of phosphorus to the diet . However, high phosphorus intake has been shown to inhibit the increase in serum 1,25(OH)2D concentration in response to low dietary calcium intake .
Collectively, although long-term and large amount consumption of phosphorus additives, little is known about risk associated with dietary phosphorus intake. A prospective cohort study of healthy adults reveals that high dosage of dietary phosphorus intake is associated with increased mortality . Considering that the deleterious effects of chronic ingestion of unrestricted amounts of phosphate in individuals are not clear, consumption of high phosphate-containing processed foods and soft drinks should be alarming, particularly for health-compromised individuals [48,49]. Under those circumstances as mentioned above, using phytase-producing bifidobacteria may be a new way for increasing bioavailability of phosphorus from plant-derived diets, therefore avoiding supplementation of inorganic additives.
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