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Alkaline phosphatase (ALP) is abundant in raw milk. Because of its high heat resistance, ALP negative is used as an indicator of successful sterilization. However, pasteurized milk loses its immune protection against allergies. Clinically, ALP is also used as an indicator of organ diseases. When the activity of ALP in blood increases, it is considered that diseases occur in the viscera and organs. Oral administration or injection of ALP will not cause harm to the body and has a variety of probiotic effects. For infants with low immunity, ALP intake is a good prebiotic, which can protect the infant's intestine from potential pathogens. In addition, ALP has a variety of probiotic effects on any age group, including the prevention and treatment of intestinal diseases, allergies, hepatitis, acute kidney injury (AKI), diabetes, and even the prevention of aging.
- ALP
- infant intestinal health
- raw milk
1. Introduction
Alkaline phosphatase (ALP) is an enzyme that catalyzes the hydrolysis of phosphate under alkaline conditions. ALP widely exists in various mammalian tissues and plays an important role in biological processes. However, human tissues can also synthesize ALP, including tissue nonspecific alkaline phosphatase (TNAP), placental alkaline phosphatase (PLAP), germ cell alkaline phosphatase (GCALP), and intestinal alkaline phosphatase (IAP) [1]. However, for infants with incomplete immune development, ALP gene expression is still low, and exogenous ALP supplementation is very necessary [2]. At the same time, ALP protects the health and stability of tissues and bodies at all life stages. When diseases occur, ALP is used as an important biomarker for the diagnosis of many diseases [3][4][5].
2. Important Health Indicators
碱性磷酸酶（According to clinical diagnosis, abnormal ALP activity in blood is related to various diseases—for example, bone-specific ALP and bone disease [3], breast cancer diagnosis [4], and diabetes [5]. In the case of diagnosis, ）是一种在碱性条件下催化磷酸盐水解的酶。ALP广泛存在于各种哺乳动物组织中，在生物学过程中发挥着重要作用。然而，人体组织也可以合成碱性磷酸酶，包括组织非特异性碱性磷酸酶（TNALP measured in serum is used as a diagnostic tool for liver disease [6] and testicular cancer [7][8]. In patients with chronic liver disease, blood AL）、胎盘碱性磷酸酶（P increased in the order of chronic hepatitis (CH), liver cirrhosis (LC), and hepatocellular carcinoma (HCC) with pathological progress [9]. At the same time, ALP in the patient’s blood will be detected before and after a medical process. The change in ALP in blood can affect the therapeutic effect and survival rate of patients, such as metastatic prostate cancer [10], metastatic breast cancer [11], clear cell chondrosarcoma [12], and metastatic nasopharyngeal carcinoma [13].
3. Factors Affecting ALP Activity
）、生殖细胞碱性磷酸酶（GCALP）和肠道碱性磷酸酶（IAP has an important protective effect on the infant intestine. I。但是，对于免疫发育不完全的婴儿，AP is a homodimer, and each subunit consists of two Zn2+ and one Mg2+ ion [14]. The activity of ILP基因表达仍然很低，补充外源性AP was the highest at pH 9.7 [15]. IAP is generally secreted in the duodenum, followed by less expression in the jejunum, ileum, and colon [16][17][18]. IAP is largely absent in the stomach in an acidic environment [18][19]. IAP mainly exists in lumen vesicles secreted by intestinal cells on the brush edge of microvilli. At the same time, a small amount of IAP will also be bidirectionally released into the blood and lumen and then spread throughout the intestine [20]. The investigation found that the level of IAP activity in human intestinal tract varies with blood type. The level of IAP in human intestinal tract of type O and type B is the highest, while the activity in human intestinal tract of type A blood is the lowest [21]. In the gut, IAP is a mucosal defense factor that restricts bacteria from crossing the mucosal barrier into mesenteric lymph nodes [22][23]. In addition to the local activity of IAP in intestinal mucosa, about 1–2% of IAP is released into the blood or gastrointestinal cavity to treat and prevent systemic infection and sepsis [24].
IAP activity is related to dietary nutrition and dietary frequency. Food intake can regulate the activity of IAP. Intake of omega-3 fatty acids can reduce the level of LPS and improve intestinal permeability by increasing the activity of intestinal I是非常必要的。同时，AP in transgenic mice [25]. In addition, a protein diet may reduce the activity of IAP. When feeding calves before rumination with a soybean diet, the activities of intestinal enzymes such as IAP in the intestine are reduced [26]. Another study found that the intestinal IAP activity of pigs increased significantly in the short term after using wheat or barley instead of a milk-based high protein diet [27]. After the protein structure of milk is destroyed by fermentation, intake of yogurt can increase the activity of IAP [28]. In addition, glucomannan, oligosaccharide, and vitamin D supplementation are associated with increased intestinal IAP activity [29][30][31]. Some phytochemical components, such as curcumin, black pepper, red pepper, ginger, piperine, and capsaicin, have also been found to be associated with increased IAP activity [32]. When mice were fasted for two days, IAP expression in the intestine decreased significantly, resulting in a decrease in the ability of intestinal LPS dephosphorylation [23]. Because starvation leads to the downregulation of I在生命的各个阶段保护组织和身体的健康和稳定。当疾病发生时，AP, the host’s sensitivity to pathogens increases. Therefore, for the treatment and prognosis stage of patients, intake of diet that can increase IAP is of positive significance for the recovery of patients’ health [23] because IAP is associated with limiting the speed of fatty acid transmembrane transport to intestinal cells [33][34]. HFD feeding increases IAP stress-induced secretion in the intestine, thereby maintaining host weight stability [35]. On the other hand, some studies have found that HFD feeding can reduce IAP activity and increase TLR4 activity in the intestine of obese rats [36]. Similarly, when present in food ω- 3 PUF被用作诊断许多疾病的重要生物标志物。
根据临床诊断，血液中A will also lead to a decrease in IAP expression and activity [37]. IAP-KO mice fed HFD were more likely to gain weight [33]. Therefore, for different individuals, the effect of HFD feeding on intestinal IAP is not stable, and further research is needed. In addition, protein intake may also be related to the regulation of IAP. The activity of ALP in the intestine of rats fed a protein-free diet decreased by 36–38% [38]. In conclusion, the intake of food nutrition is related to the activity of 活性异常与多种疾病有关，如骨特异性ALP.与骨病、乳腺癌诊断、糖尿病等。在诊断的情况下，血清中的 Reasonable dietary intake is helpful for regulating the activity of intestinal ALP.
4. Infant Intestinal Health
InALP Table 1,被用作肝病和睾丸癌的诊断工具。在慢性肝病患者中，随着病理进展，血 the research on the prevention and treatment of diseases by ALP are summarized. Relevant studies were identified by searching Web Science, Google Scholar, and PubMed. If a study met the following criteria, it was included in the table: 1. Study and evaluate the effect of oral or injection ALP treatment; 2. Researches written in English until December 2021. All studies that met the requirements of direct ALP treatment of laboratory animals are listed按慢性肝炎 (CH)、肝硬化 (LC) 和肝细胞癌 (HCC) 的顺序升高。同时，将在医疗过程前后检测患者血液中的 ALP。血液中ALP的变化会影响转移性前列腺癌、转移性乳腺癌、透明细胞软骨肉瘤、转移性鼻咽癌等患者的治疗效果和生存率。
足月新生儿肠道中的高 in the table. It turns out that high IAP activity in the intestine of full-term newborns, coupled with the high ALP activity in breast milk in the first few days after birth, provides sufficient detoxification capacity for LPS of initially colonized bacteria [2]. After the onset of AP 活性，加上出生后最初几天母乳中的高 ALP 活性，为最初定植细菌的 LPS 提供了足够的解毒能力。婴儿 IBD in发病后，儿童炎症性结肠黏膜中 infants, TLR4 mRNA expression and protein levels in inflammatory colonic mucosa in children increased [39]. The increased expression of 表达和蛋白水平升高 。TLR4 may be related to the content of 表达升高可能与肠黏膜IAP in intestinal mucosa. IAP activity below normal level may lead to 含量有关。低于正常水平的 IAP 活性可能导致 IAP/TLR4 imbalance, resulting in increased sensitivity of mucosa to 失衡，从而导致黏膜对 LPS [17].的敏感性增加 After。治疗后肠黏膜的恢复对疾病的预后非常重要。恢复肠道菌群平衡的治疗可能对 treatment, the recovery of intestinal mucosa is very important for the prognosis of the disease. Therapeutic treatment to restore intestinal flora balance may have a significant impact on mucosal healing of IBD [40]. In an animal model的黏膜愈合产生显着影响。在由葡聚糖硫酸钠 of colitis induced by sodium dextran sulfate (DSS), exogenous administration of IAP improved the symptoms of colitis [41]. Compared with 诱导的结肠炎动物模型中，外源性 IAP 可改善结肠炎的症状。与野生型小鼠相比，DSS 诱导的 wild-type mice, IAP-KO mice had more severe colitis induced by DSS [24]. 小鼠结肠炎更为严重。在严重肠上皮损伤的情况下，口服 In the case of severe intestinal epithelial injury, oral IAP may have beneficial effects [42]. The results obtained in the pediatric population also demonstrate that oral 可能会产生有益的影响 。在儿科人群中获得的结果还表明，口服 IAP may be可能对 beneficial for children with IBD [17].儿童有益。
Early in life, the initial colonization of intestinal microorganisms will affect the development of intestinal host defense [43][44], and the appropriate development of intestinal tissue may have a far-reaching impact on immune health in infancy and even throughout life [45][46]. Because the intestinal immune tissue is immature at birth and develops with the initially colonized microorganisms, it has been suggested that the increase in allergy and autoimmune diseases may be caused by the interference of microbial colonization and development of intestinal host defense system [47]. It is worth noting that the host defense capacity of the intestine of preterm infants is particularly immature and that the initial colonization of intestinal microorganisms is not the same as that of normal-born infants [48]. Compared with mature human intestinal cells, infant intestinal cells are more likely to produce excessive inflammatory response when stimulated and even respond to some intestinal symbiotic bacteria with an inflammatory effect [49][50]. The imbalance in intestinal microbial ecology in the neonatal period of preterm infants may lead to excessive intestinal inflammation, resulting in 在生命早期，肠道微生物的初步定植会影响肠道宿主防御能力的发展，而肠道组织的适当发育可能对婴儿期乃至整个生命的免疫健康产生深远的影响。由于肠道免疫组织在出生时是不成熟的，随着最初定植的微生物一起发育，有人提出过敏和自身免疫性疾病的增加可能是由于微生物定植和肠道宿主防御系统发育的干扰。值得注意的是，早产儿肠道的宿主防御能力特别不成熟，肠道微生物的初始定植与正常出生的婴儿并不相同。与成熟的人体肠道细胞相比，婴儿肠道细胞在受到刺激时更容易产生过度的炎症反应，甚至对一些具有炎症作用的肠道共生菌产生反应。早产儿新生儿期肠道微生物生态失衡可能导致肠道过度炎症，导致NEC.。作为婴儿唯一的营养来源，母乳有助于健康的细菌在婴儿肠道内定植。研究指出，早产妈妈挤出的母乳可以保护婴儿的肠道免受 As the sole source of nutrition for infants, breast milk helps healthy bacterial colonization in the infant’s intestines [51]. Studies have pointed out that breast milk extruded by preterm mothers can protect the infant’s intestine from NEC [52][53]. Although breast milk contains many immune nutrients, such as 。虽然母乳含有许多免疫营养素，如IgA, oligosaccharides, lactoferrin, 、低聚糖、乳铁蛋白、ALP, etc., it may help to prevent intestinal inflammation and NEC. At the same time, breast milk may also play an active role in stimulating health-promoting bacteria, thus providing protection against NEC. Studies have pointed out that giving probiotics to preterm infants can also prevent NEC. The combination of probiotics (e.g., Lactobacillus acidophilus and Bifidobacterium bifidum) and human milk has a protective effect, but the combination of probiotics and infant formula has lost its protective effect [54][55].等，但它可能有助于预防肠道炎症和NEC。同时，母乳也可能在刺激促进健康的细菌方面发挥积极作用，从而为 NEC 提供保护。研究指出，给早产儿服用益生菌也可以预防NEC。益生菌（如嗜酸乳杆菌和双歧双歧杆菌）与人乳的组合具有保护作用，但益生菌与婴儿配方奶粉的组合已失去保护作用。
Compared with infant formula, breast milk has several unique factors to actively protect the intestine of newborns. First, oligosaccharides in breast milk provide an energy source for the intestinal microbiota, help the growth of infant intestinal probiotics, and are beneficial to the infant intestine [56][57]. Second, breast milk itself contains a variety of bacteria that actively colonize the intestine, providing protection for the infant’s primitive microbiota [58]. Third, breast milk contains immunobioactive factors, such as secretory IgA, which can change the colonization of infants’ intestines and protect infants from pathogens [59][60]. Fourth, gastrointestinal administration of exogenous IAP can improve intestinal inflammation and promote intestinal tissue regeneration, while intestinal and可以通过降低管腔 systemic IAP administration can reduce systemic inflammation [61]. In addition, oral IAP supplements may regulate intestinal metabolic homeostasis by stimulating intestinal IgA secretion [4]. In conclusion, breast milk not only can change the intestinal environment of infants to prevent pathogenic bacteria but also can promote the colonization of symbiotic bacteria, so as to promote the short-term and long-term immune health of the host.
IAP can maintain intestinal immune balance and improve host tolerance to symbiotic microbiota by reducing lumen AATP concentration浓度和使细菌 and dephosphorylating bacterial LPS [62]. At the same time, 去磷酸化来维持肠道免疫平衡并提高宿主对共生微生物群的耐受性。同时，IAP knockout mice showed increased fat absorption and obesity, suggesting that intestinal lipid transport is related to the regulation of 基因敲除小鼠表现出脂肪吸收增加和肥胖，提示肠道脂质转运与IAP [28]. Both endogenous and oral 的调节有关。内源性和口服IAP supplementation can inhibit the absorption of 补充剂均能抑制膳食脂肪中LPS in dietary fat, and oral IAP supplementation can prevent and reverse metabolic syndrome. In addition, IAP supplementation improved the blood lipid status of mice fed standard low-fat food [28][63]. 的吸收，口服IAP补充剂可预防和逆转代谢综合征。此外，IAP 补充剂改善了喂食标准低脂食物的小鼠的血脂状况 。在肠损伤动物模型中，口服 In animal models of intestinal injury, oral IAP reduces intestinal epithelial injury and inflammation [42]. The dynamic transformation of the form of 可减少肠上皮损伤和炎症 。ALP isozyme is related to the maturation of fetal intestine [64], suggesting that 同工酶形式的动态转化与胎儿肠道的成熟有关，表明ALP活性可能在人类胎儿发育过程中发生变化。在新生幼鼠肠道中补充 activity may change during human fetal development. Supplementation of ALP in the intestine of newborn rat pups has a protective effect on experimentally induced ALP 对实验诱导的 NEC [65].具有保护作用 。ALP has a protective effect on the intestine of premature young rats against intestinal damage and inflammation caused by microbial 对早产幼鼠肠道具有保护作用，防止微生物 LPS [66].引起的肠道损伤和炎症。
Intestinal肠道碱性磷酸酶 alkaline phosphatase (IAP) can maintain intestinal health through a variety of mechanisms, including detoxification of lipopolysaccharide (LPS), flagellin, 可通过多种机制维持肠道健康，包括解毒脂多糖 (LPS)、鞭毛蛋白、CpG DNA and nucleotides; upregulation of the expression level of tight junction protein, thereby increasing intestinal barrier function; and regulation of intestinal microbiome homeostasis [67][68][69]. During lactation, infant intestinal 和核苷酸；上调紧密连接蛋白的表达水平，从而增加肠屏障功能；和肠道微生物群稳态的调节。在哺乳期间，婴儿肠道 ALP gene基因表达和酶活性仍然很低 expression and enzyme activity remain low [70]. Preterm birth and formula feeding are considered to be associated with the inhibition in 。早产和配方奶喂养被认为与抑制 IAP expression表达和活性有关，缺乏 and activity, and the lack of ALP may increase the risk of ALP 可能会增加 NEC [71].的风险 For infants, breast milk is。对于婴儿，母乳是 the only exogenous source of ALP [2],的唯一外源性来源，巴氏杀菌会破坏母乳中 and pasteurization destroys 99% of ALP in breast milk [72]. 的 ALP 。母乳中的 ALP in被认为是新生儿肠道中的抗炎因子，是抑制 breast milk is considered to be an anti-inflammatory factor in the neonatal intestine and a key component in inhibiting NEC [73][74].的关键成分 The lack of 。IAP activity will lead to neonatal intestinal ecological imbalance and bacterial translocation, resulting in a variety of diseases [75].活性的缺乏会导致新生儿肠道生态失衡和细菌易位，从而导致多种疾病。
In在之前的研究中，发现服用 previous studies, it was found that taking LPS can lead to weight gain and acute inflammation and eventually insulin resistance [76]. Similar effects can be seen in animal models fed LPS 会导致体重增加和急性炎症，并最终导致胰岛素抵抗。在喂食 HFD or或 LPS. Similarly, LPS can also lead to a pro-inflammatory response in the fetal brain after infecting the mother, thereby increasing anxiety and reducing social activities [77]. Therefore, researchers believe that the important roles of 的动物模型中可以看到类似的效果。同样，LPS 还可以在感染母亲后导致胎儿大脑中的促炎反应，从而增加焦虑并减少社交活动。因此，研究人员认为，HFD and和 LPS in the pathogenesis of ASD seem to be consistent between humans and animals. ALP is considered to be a drug that can protect the balance in the intestinal environment and reduce inflammation [78]. 在 ASD 发病机制中的重要作用似乎在人和动物之间是一致的。ALP 被认为是一种可以保护肠道环境平衡和减少炎症的药物。ALP has anti-inflammatory effects, prevents intestinal leakage, and promotes a healthy microbiota [62]. At the same time, recent studies have proved that oral supplementation of 具有抗炎作用，防止肠道渗漏，并促进健康的微生物群。同时，近期研究证明，孕妈妈口服补充IAP对婴儿健康具有积极意义。一项小鼠模型试验发现，母体 to pregnant mothers is of positive significance to the health of infants. A mouse model test found that maternal IAP treatment can alleviate some autism spectrum disorder (ASD)-like symptoms of offspring mice [79]. It is worth noting that the content of IAP 治疗可以缓解后代小鼠的一些自闭症谱系障碍 (ASD) 样症状。值得注意的是，母乳中 ALP in breast milk decreased with lactation time [80]. Therefore, the intake of 的含量随着哺乳时间的增加而降低。因此，为婴儿和母亲补充ALP supplementation for infants and mothers is of great significance for maintaining infant health. Unfortunately, 的摄入量对于维持婴儿健康具有重要意义。不幸的是，ALP does not exist in any infant formula.不存在于任何婴儿配方奶粉中。
5. Inhibition of Allergy
Children growing up on farms have a lower risk of asthma and allergies than children living in the same rural area but not on farms [81][82]. This protective 在农场长大的儿童患哮喘和过敏的风险低于生活在同一农村地区但在农场长大的儿童。这种保护性“farm effect农场效应” is recognized in many people until adulthood [83]. The farm exposure associated with this allergic protective effect appears to be eating unprocessed raw milk [84][85].在许多人中得到认可，直到成年。与这种过敏保护作用相关的农场暴露似乎是食用未加工的生牛奶。尤其是生奶的消费和生奶的保护作用与农场条件无关，因此可以保护普通非农业人口。许多研究表明，食用未经处理的生牛奶可以预防哮喘和过敏性疾病的风险。这些流行病学研究结果最近证实了生物奶可以预防小鼠模型中由家庭尘螨和 In particular, the consumption of raw milk and the protective effect of raw milk have nothing to do with farm conditions, so it can protect the ordinary non-agricultural population [86][87]. Many studies have shown that eating untreated raw milk can prevent the risk of asthma and allergic diseases [84][85][86][87][88]. These epidemiological findings recently confirmed the causal evidence that biological milk can prevent allergic asthma caused by household dust mites and OVA-induced food allergy in mouse models [89][90].引起的食物过敏引起的过敏性哮喘的因果证据。
Pasteurization makes milk lose the ability to protect consumers from allergies. 巴氏杀菌使牛奶失去了保护消费者免受过敏的能力。生乳处理大鼠脾细胞CD4+The histone acetylation degree of Th1-, Th2-, and regulatory T cell-related genes in splenocyte CD4+ T cells of rats treated with raw milk was higher than that of mice treated with pasteurized milk. Compared with processed milk products, the histone acetylation degree of Th2 gene in rats treated with raw milk was lower. In the research of mice allergic to food, raw milk reduced allergic symptoms to food allergens other than milk. The activation of T cell-related genes is considered to be the cause of the observed tolerance induction, indicating that epigenetic modification helps raw milk protect the body from allergy [90]. On the other hand, some studies have shown that pasteurized milk lost its allergic protection, but pasteurized milk added with 细胞中Th1-、Th2-和调节性T细胞相关基因的组蛋白乙酰化程度高于巴氏杀菌乳处理的小鼠。与加工乳制品相比，生乳处理的大鼠Th2基因组蛋白乙酰化程度较低。在对食物过敏的小鼠的研究中，生牛奶减少了对牛奶以外的食物过敏原的过敏症状。T 细胞相关基因的激活被认为是观察到的耐受诱导的原因，表明表观遗传修饰有助于生乳保护身体免受过敏。另一方面，一些研究表明，巴氏杀菌牛奶失去了过敏保护作用，但添加 ALP restored的巴氏杀菌牛奶恢复了其过敏保护作用 its allergic protection [91]. Skimmed raw milk inhibited food allergy symptoms similar to raw milk and reduced acute skin allergy and lowered levels of 。脱脂生奶可抑制与生奶相似的食物过敏症状，减少急性皮肤过敏，并降低 OVA-specific 特异性 Ig-E- and Th-2-related cytokines. This indicates that the fat component is not an ingredient in raw milk that inhibits food allergy [91]. 和 Th-2 相关细胞因子的水平。这表明脂肪成分不是生乳中抑制食物过敏的成。
ALP可以调节肠道菌群结构，保护消费者免受过敏诱导。生乳处理除了增加毛螺菌科 can regulate the structure of intestinal microbiota and protect consumers from allergy induction. Raw milk treatment increased the relative abundance of butyrate producing bacteria in mouse intestine, in addition to increasing Lachnospiraceae ucg-001, Lachnospiraceae ucg-001、毛螺菌科 ucg-008, and Ruminiclostridium 5 ( 和瘤胃梭菌 5（Clostridium clusters xiva and IV), and decreased the relative abundance of bacterial Proteus that can promote inflammation. Clostridium clusters xiva and IV can decompose nondigestible oligosaccharides to produce acetic acid, propionic acid, and butyric acid. These organisms are usually close to host epithelial cells, which have a great impact on the host immune balance [92][93]. In a study of mice intestinal microorganisms, 和 IV）外，还增加了小鼠肠道中产生丁酸盐的细菌的相对丰度，并降低了能够产生丁酸盐的细菌的相对丰度。促进炎症。梭状芽胞杆菌簇 xiva 和 IV 可以分解不易消化的寡糖以产生乙酸、丙酸和丁酸。这些生物通常靠近宿主上皮细胞，对宿主免疫平衡有很大影响。在一项对小鼠肠道微生物的研究中，Clostridium clusters xiva and和 IV can help induce the accumulation and differentiation of 可以帮助诱导 Foxp3 + Treg cells in mouse colon. Clostridium can induce colon epithelial cells to release active TGF-β and other Treg inducing factors, which can induce Treg differentiation by regulating 细胞在小鼠结肠中的积累和分化。梭菌可诱导结肠上皮细胞释放活性TGF-β等Treg诱导因子，通过调节CD103+ DC. In addition, Clostridium has also been shown to induce DC诱导Treg分化。此外，梭状芽胞杆菌也被证明可以在结肠中诱导表达 IL-10 expressing的 Treg cells in the colon.细胞。增加肠道梭状芽孢杆菌的定植可以增加身体对过敏的抵抗力。这些微生物在喂食巴氏杀菌牛奶的老鼠的肠道中消失了。然而，在巴氏杀菌牛奶中添加 ALP 后，在生乳处理组中观察到的肠道益生菌群变化再次出现，并减少了过敏反应 。
补充碱性磷酸酶不仅对婴儿有益生元作用，对老年人甚至免疫力较弱的成年人也有积极作用。一项内分泌疾病研究发现，补充ALP可能有助于预防2型糖尿病（T2DM）。T2DM是一种重要的全球代谢疾病。由于2型糖尿病患者血糖浓度高且症状易并发，T2DM对医疗费用、发病率和死亡率的影响很大。T2DM的高血糖浓度类似于将器官浸入高葡萄糖培养基中。长期患病可导致眼睛、肾脏、神经、心脏和血管等器官长期受伤、功能障碍，甚至衰竭。从病因学的角度来看，许多因素被认为与T2DM的发生有关，如自身免疫水平、代谢综合征、饮食条件、体重、外部感染、遗传信息、药物使用、压力、怀孕等。最近，由血液中内毒素 Increasing(LPS) the colonization of intestinal Clostridium can increase the body’s resistance to allergy水平持续升高（代谢性内毒素血症）引起的低度全身炎症被认为是 T2DM 的一个原因 。研究表明，高水平的 IAP 对 T2DM 患者（无论是否肥胖）都有保护作用。具有高水平 IAP（约 65 U/g [94].粪便）的肥胖患者通常不会发展为 These2DM。当粪便中 microbes disappeared in the intestines of mice fed pasteurized milk. However, after the addition of ALP to pasteurized milk, the changes in the intestinal probiotic microbiota observed in the raw milk treatment group reappeared and reduced allergic reactionsALP 的活性降低 25 U/g 时，患糖尿病的风险增加 35%。粪便排泄的 IAP 活性反映了肠道中 IAP 产生、消化和降解的水平。IAP 活动可能受不同因素的调节，尤其是饮食条件 。一项调查发现，超过 65% 的健康人患有“早期代谢综合征”。口服 IAP 补充剂是一种早期预防和治疗早期糖尿病和/或其他主要或早期代谢疾病的治疗方法。研究人员认为，任何治疗目标至少应维持或恢复粪便中 IAP 的健康水平（约 65.0 U/g 粪便。其他治疗可能涉及上调 [95].
6. Other Diseases
IALP supplementation has a probiotic effect on multiple organs of the body, including the treatment of intestinal-,以提高免疫水平，例如短链脂肪酸（如丁酸钠和丙酸钠）、甲状腺激素、姜黄素 ω-3脂肪酸等。此外，食用玉米油可增加大鼠体内 liver-,IAP and kidney-related diseases [96][97]. 的分泌。这可能是身体通过分泌 IAP 来预防与高脂饮食相关的内毒素血症的生理反应。因此，进一步研究IAP缺乏的机制对于了解T2DM的病理生理具有重要意义。肠道菌群失衡可能与代谢综合征和糖尿病的发生有关。IAP在肠道细菌环境中起着两个非常重要的生理作用：第一，IAP可以帮助维持肠道菌群的正常结构；其次，IAP具有解毒细菌毒素的能力。IALP supplementation can detoxify a variety of proinflammatory mediators in the intestinal cavity. Among them, ALP has the most significant detoxification function on LPS (also known as endotoxin). In recent years,基因敲除小鼠的细菌少于野生型同窝小鼠。IAP 可以降低三磷酸核苷酸的浓度，保护肠道细菌，促进肠道生长。IAP 可以解毒 LPS 毒素并通过去磷酸化（磷酸水解）破坏毒素靶标。此外，IAP 可以限制脂肪吸收，从而维持肠黏膜的完整性 。口服 IAP 补充剂可降低肠道对抗生素诱导的鼠伤寒沙门氏菌和艰难梭菌的敏感性，并维持肠道健康的体内平衡 。
发现 LIAPS has been proved to be one of the key mediators connecting the development of intestinal and liver diseases and many other systemic diseases. LPS consists of core polysaccharide, O-antigen, and lipid A. ALP can remove the phosphate 缺陷小鼠（akp3 基因敲除，akp3 -/-）被诊断为代谢综合征，随后出现 T2DM 症状。同时，由于 IAP 可以解毒 LPS，减少代谢性内毒素血症，研究人员使用 IAP 对小鼠进行口服补充。结果表明，口服补充 IAP 不仅可以预防而且可以治疗野生型小鼠代谢综合征和高脂饮食 (HFD) 诱导的 T2DM。HFD引起的代谢综合征的病因被认为与内毒素进入血液引起的代谢性内毒素血症有关。其他研究发现，HFD 可能破坏肠道菌群平衡并导致屏障功能障碍，然后内毒素通过肠上皮进入血液并转运至全身循环。当发生内毒素血症时，IAP 可用作预防或治疗内毒素血症的有效口服补充剂，从而保护宿主免受代谢综合征的影响。此外，IAP 还可以预防小鼠使用抗生素引起的糖尿病和代谢综合征。肠道 ALP 的保护作用也已在转基因小鼠中得到证实。IAP 在胃肠道中的过表达可以通过改善肠道屏障来降低 HFD 诱导的糖尿病表型。
ALP group补充剂对身体的多个器官具有益生菌作用，包括治疗肠道、肝脏和肾脏相关疾病。补充 on LPS lipid ALP 可以解毒肠腔中的多种促炎介质。其中，ALP对LPS（又称内毒素）的解毒作用最为显着。近年来，LPS已被证明是连接肠道和肝脏疾病以及许多其他全身性疾病发展的关键介质之一。LPS由核心多糖、O-抗原和脂质A组成。ALP可以通过去磷酸化去除LPS脂质A by dephosphorylation, so as to relieve the toxicity of 上的磷酸基团，从而减轻LPS的毒性。在一项关于肝脏炎症的研究中，发现 [98][99][100]. In a study of liver inflammation, it was found that LPS induced通过刺激组织细胞中 chronic inflammation by stimulating the expression of TLR4 in tissue cells [101][102]. When the TLR4 的表达来诱导慢性炎症。当 IAP gene基因被敲除后，小鼠肠道环境对 was knocked out, the tolerance of mouse intestinal environment to LPS decreased significantly and was more vulnerable to intestinal validation [41][63]. When intestinal injury occurs, LPS 的耐受性显着降低，更容易受到肠道验证。当肠道损伤发生时，LPS is more likely to enter the blood, causing liver injury and even serious diseases. When disease occurs, 更容易进入血液，引起肝损伤甚至严重疾病。当疾病发生时，IAP supplementation—whether oral or injection—has been widely used to prevent and treat inflammatory diseases. For example, oral administration of recombinant ALP can prevent alcohol-induced hepatic steatosis and chronic liver failure [103][104]. Although 补充剂（无论是口服还是注射）已被广泛用于预防和治疗炎症性疾病。例如，口服重组 ALP 可以预防酒精引起的肝脂肪变性和慢性肝功能衰竭 。虽然 IAP may可能在胃中部分降解，但在饮用水中混合 be partially degraded in the stomach, oral administration after mixing IAP in drinking water is a very simple route of administration. A large number of experiments have proved that oral ALP supplementation can effectively increase the concentration of IAP in the intestinal cavity [69][78]. At the same time, after IAP 后口服给药是一种非常简单的给药途径。大量实验证明，口服 ALP 补充剂可以有效提高肠腔内 IAP 的浓度。同时，饮水中补充IAP supplementation in drinking water, the concentration of serum 后，肠腔静脉和门静脉中血清LPS in intestinal vena cava and portal vein decreased significantly, which will greatly reduce the harm of LPS translocation to the liver, so as to further protect the liver and reduce the development of malignant inflammatory circulation and liver fibrosis [105]. 浓度明显下降，将大大降低LPS易位对肝脏的危害，从而进一步保护肝脏，降低恶性炎症循环和肝纤维化的发展。在人体临床研究中，对严重溃疡性结肠炎患者进行了十二指肠和肠内 In human clinical studies, duodenal and enteral IAP was administered to patients with severe ulcerative colitis for 7 days, and no human safety problems, adverse events, or side effects of ALP were reported [106].治疗 7 天，没有报告 ALP 的人体安全问题、不良事件或副作用。
With regard to intestinal flora, it was found that the number关于肠道菌群，发现 of intestinal bacteria in IAP-ko mice decreased overall and that oral supplementation of IAP in WT mice could quickly restore the normal intestinal flora of mice affected by antibiotics [69]. 小鼠肠道细菌数量总体减少，WT 小鼠口服补充 IAP 可迅速恢复受抗生素影响小鼠的正常肠道菌群。IAP prevents通过调节肠道菌群来预防 HFD-induced metabolic endotoxemia by regulating intestinal flora [63]. 诱导的代谢性内毒素血症。在斑马鱼模型中，缺乏 In a zebrafish model, zebrafish lacking IAP are highly sensitive to LPS toxicity. IAP plays a crucial role in promoting mucosal tolerance to intestinal resident bacteria [98]. Knockout of the intestinal 的斑马鱼对 LPS 毒性高度敏感。IAP 在促进黏膜对肠道常驻细菌的耐受性方面发挥着至关重要的作用。敲除小鼠肠道 ALP gene基因 (AKP3) in mice leads to metabolic abnormalities, resulting in visceral fat accumulation and hepatic steatosis [107]. On the other hand, an investigation found that the endogenous 会导致代谢异常，导致内脏脂肪堆积和肝脏脂肪变性。另一方面，一项调查发现，大鼠的内源性 IAP level水平随着年龄的增长而下降，代谢综合征在老年动物中很常见 of rats decreased with age and that metabolic syndrome was common in older animals [108][109]. This suggests that 。这表明“IAP deficiency缺乏” may be an inducement leading to metabolic syndrome and that the oral supplementary IAP dose can be easily adjusted to achieve the purpose of preventing or treating metabolic syndrome [69].可能是导致代谢综合征的诱因，口服补充IAP剂量可以很容易地调整，以达到预防或治疗代谢综合征的目的。
Studies have demonstrated that研究表明，使用 the use of ALP in the treatment of sepsis-induced AKI is promising [110][111][112]. In the treatment of acute renal injury, high-dose ALP 治疗脓毒症引起的 AKI 是有希望的。在急性肾损伤的治疗中，大剂量 ALP (（75 U/kg + 25 U/kg/h intravenous injection) can significantly increase serum ALP activity, making serum ALP about 5 times higher than baseline [113]. In a sheep model of sepsis, 静脉注射）可显着提高血清 ALP 活性，使血清 ALP 比基线高约 5 倍。在脓毒症绵羊模型中，ALP can可以减轻炎症并改善肺功能而无不良反应。静脉内 reduce inflammation and improve lung function without adverse reactions [8]. Intravenous ALP is preferentially delivered to blood and to liver, kidney, and other abdominal organs at a lower dose. Therefore, in the treatment以较低的剂量优先输送到血液和肝脏、肾脏和其他腹部器官。因此，在肾损伤的治疗中，需要高浓度的血清 of renal injury, a high concentration of serum ALP level is required to increase the grade of renal tissue [114]. In addition, rodent model studies of isolated renal ischemia-reperfusion injury have shown that ALP 水平来提高肾组织的分级。此外，对孤立性肾缺血再灌注损伤的啮齿动物模型研究表明，ALP treatment can reduce renal tubular injury [115].治疗可以减少肾小管损伤。
For对于因 women at high risk of pregnancy complications due to LPS infection, the use of supplementary AP isozymes may be an attractive treatment option [116]. LPS 感染而存在妊娠并发症高风险的女性，补充 AP 同工酶可能是一种有吸引力的治疗选择。在一项小鼠模型研究中，In a mouse model study, IAP inhibited LPS to play an inflammatory role by upregulating the expression of autophagy-related genes (ATG5, ATG16, IRGM1, TLR4) in the mouse small intestine. Oral ALP can prevent the immune stimulation of LPS in blood to the liver. ALP can remove the phosphate group on LPS and eliminate the toxicity of LPS. At the same time, ALP can reduce TLR4, TNF-a, matured IL-1β, and通过上调小鼠小肠中自噬相关基因（ATG5、ATG16、IRGM1、TLR4）的表达来抑制LPS发挥炎症作用。口服ALP可防止血液中LPS对肝脏的免疫刺激作用。ALP可以去除LPS上的磷酸基团，消除LPS的毒性。同时，ALP 可以通过上调小鼠肝组织中 mir146a 的水平来降低 TLR4、TNF-a、成熟 IL-1β 和 NF-κB expression by upregulating the level of mir146a in mouse liver tissue, which in turn reduces the inflammatory response of the liver [117]. 的表达，进而降低肝脏的炎症反应 。发现肝纤维化过程中内源性It was found that endogenous IAP decreased during liver fibrosis, resulting in intestinal barrier dysfunction and fibrosis deterioration. Oral IAP can protect the intestinal barrier and further prevent the development of liver fibrosis through a TLR4-mediated mechanism下降，导致肠屏障功能障碍和纤维化恶化。口服 IAP 可以通过 TLR4 介导的机制保护肠道屏障并进一步预防肝纤维化的发展。虽然机制尚不清楚，但口服和静脉注射 [107]. Although the mechanism is unclear, oral and intravenous ALP play a renal protective role in various sepsis animal models [8][105][118][119].在各种脓毒症动物模型中发挥肾脏保护作用。
Table表 1. Preventive and therapeutic effects of alkaline phosphatase (ALP) on diseases.
碱性磷酸酶 (ALP) 对疾病的预防和治疗作用。
| 动物 | 治疗方法 | 治疗剂量 | 治疗频率 | 期间 | 疾病 | 描述 | 参考 |
|---|---|---|---|---|---|---|---|
| 大鼠 | 口服 | 基础配方 | 喂养 | 4天 | NEC | 保护肠道 | [ 162 ] |
| 大鼠 | 口服 | 0.4、4 或 40 U/kg | 喂养 | 3天 | NEC | 保护肠上皮屏障功能 | [ 163 ] |
| 大鼠 | 口服 | 0.4、4 或 40 U/kg | 喂养 | 1天 | NEC | 降低亚硝化压力；降低肠道 TNF-α mRNA 表达；减少 LSP 易位到血清中 | [ 164 ] |
| 大鼠 | 口服 | 0.4、4 或 40 U/kg | 喂养 | 1天 | NEC | 降低全身性促炎细胞因子表达 | [ 165 ] |
| 大鼠 | 口服 | 700 单位/公斤 | 胃食管导管 | 6天 | 炎症性肠病 | 防止细菌易位 | [ 30 ] |
| 大鼠 | 口服 | 第1035章 | 饮用水 | 8天 | 炎症性肠病 | 降低 TNF-α、IL-1β、IL-6 和 iNOS 的 mRNA 水平 | [ 26 ] |
| 老鼠 | 口服 | 200 单位/公斤 | 灌胃 | 4小时 | 肝损伤 | 降低 LPS 毒性和预防肝损伤 | [ 141 ] |
| 老鼠 | 口服 | 6 单位/毫升 | 灌胃 | 8天 | 食物过敏 | 肠系膜淋巴结中 CD103+CD11b+ 树突状细胞和产生 TGF-β 的调节性 T 细胞减少 | [ 8 ] |
| 老鼠 | 口服 | 6 单位/毫升 | 灌胃 | 8天 | 食物过敏 | 肠道微生物群落结构的调控 | [ 102 ] |
| 老鼠 | 口服 | 100 或 300 U | 灌胃 | 2周 | 慢性结肠炎 | 抑制肠上皮细胞和腹腔巨噬细胞的活化，减轻慢性小鼠结肠炎 | [ 166 ] |
| 老鼠 | 口服 | 100 单位/毫升 | 饮用水 | 21 天 | 代谢综合征 | 肠道菌群组成的改变 | [ 118 ] |
| 老鼠 | 口服 | 150 或 300 U/mL | 饮用水 | 48 小时 | 肠道屏障功能障碍 | 肠连接蛋白表达减少和屏障功能受损 | [ 116 ] |
| 老鼠 | 口服 | 200 单位/毫升 | 饮用水 | 5天 | 细菌感染 | 保护小鼠免受抗生素相关细菌感染 | [ 117 ] |
| 老鼠 | 口服 | 100 单位/毫升 | 饮用水 | 11 周 | 代谢综合征 | 抑制膳食脂肪对内毒素的吸收；预防或逆转代谢综合征 | [ 71 ] |
| 老鼠 | 口服 | 300 单位/毫升 | 饮用水 | 7天 | 炎症性肠病 | 组织髓过氧化物酶活性和促炎细胞因子显着降低 | [ 49 ] |
| 老鼠 | 口服 | 200 单位/毫升 | 饮用水 | 4天 | 肝纤维化 | 通过 TLR4 介导的机制保护肠道屏障和肝纤维化的发展 | [ 129 ] |
| 老鼠 | 口服 | 100 单位/毫升 | 饮用水 | 寿命 | 老化 | 针对重要的肠道改变，包括肠道屏障功能障碍、微生物群失调和内毒素血症 | [ 86 ] |
| 老鼠 | 口服 | 200 单位/毫升 | 流质饮食 | 10天 | 肝脂肪变性 | 改善肝星状细胞的活化并阻止其对肝细胞的脂肪生成作用 | [ 129 ] |
| 人类 | 口服 | 30,000 单位 | 输液泵 | 7天 | 溃疡性结肠炎 | 降低 C 反应蛋白和粪便钙卫蛋白水平 | [ 130 ] |
| 大鼠 | 注射 | 1000 单位/公斤 | 腹腔内 | 4天 | 急性肝功能衰竭 | LPS 活性和肝脏 TLR4 表达降低 | [ 128 ] |
| 大鼠 | 注射 | 1000 单位/公斤 | 腹腔内 | 24 小时 | 急性肾损伤 | 减少肾脏炎症；ATP和LPS的去磷酸化 | [ 142 ] |
| 大鼠 | 注射 | 500 单位/公斤 | 腹腔内 | 5分钟 | 部分肝切除术 | 减轻肝和肺损伤 | [ 167 ] |
| 老鼠 | 注射 | 100 单位/毫升 | 肠袢 | 2小时 | 肠道菌群失调 | 抑制管腔三磷酸核苷酸的浓度 | [ 114 ] |
| 老鼠 | 注射 | 15 单位/毫升 | 静脉 | 1天 | 败血症 | 使体温正常化 | [ 168 ] |
| 老鼠 | 注射 | 150 U | 静脉 | 5分钟 | 妊娠并发症 | 保护早孕缺陷 | [ 140 ] |
| 老鼠 | 注射 | 150 单位/公斤 | 静脉 | 72 小时 | 继发性腹膜炎 | 减轻局部和全身的炎症反应，减少相关的肝和肺损伤 | [ 169 ] |
| 人类 | 注射 | 5.6 单位/公斤/小时 | 静脉 | 36 小时 | 心脏手术 | 内源性碱性磷酸酶释放 | [ 170 ] |
| 人类 | 注射 | 67.5 U/kg + 132.5 U/kg/24 小时 | 静脉 | 48 小时 | 急性肾损伤 | 全身标志物 C 反应蛋白、IL-6 和 LPS 结合蛋白以及肾损伤分子 1 和 IL-18 的尿排泄减少 | [ 135 ] |
| 小猪 | 注射 | 1、5 或 25 U/kg/h | 静脉 | 4小时 | 急性肾损伤 | 血清或肾组织 AP 活性增加 | [ 137 ] |
| 小猪 | 注射 | 1、5 或 25 U/kg/h | 静脉 | 4小时 | 心脏手术 | 肾脏和肝脏组织碱性磷酸酶活性增加 | [ 171 ] |
| Animal | Treatment Method | Treatment Dosage | Treatment Frequency | Duration | Disease | Description | Reference |
|---|---|---|---|---|---|---|---|
| Rats | Oral | Base formula | Feed | 4 days | NEC | Protect intestine | [120] |
| Rats | Oral | 0.4, 4,or 40 U/kg | Feed | 3 days | NEC | Preserving the intestinal epithelial barrier function | [121] |
| Rats | Oral | 0.4, 4, or 40 U/kg | Feed | 1 day | NEC | Decreased nitrosative stress; decreased intestinal TNF-α mRNA expression; decreased LSP translocation into the serum | [122] |
| Rats | Oral | 0.4, 4, or 40 U/kg | Feed | 1 day | NEC | Reduces systemic proinflammatory cytokine expression | [123] |
| Rats | Oral | 700 U/kg | Gastroesophageal catheter | 6 days | IBD | Protection against bacterial translocation | [22] |
| Rats | Oral | 1035 U | Drinking water | 8 days | IBD | Reduced mRNA levels for TNF-α, IL-1β, IL-6, and iNOS | [18] |
| Mice | Oral | 200 U/kg | Gavage | 4 h | Liver injury | Reducing LPS toxicity and preventing liver injury | [117] |
| Mice | Oral | 6 U/ml | Gavage | 8 days | Food allergic | Reduction in CD103+CD11b+ dendritic cells and TGF-β-producing regulatory T cells in the mesenteric lymph nodes | [91] |
| Mice | Oral | 6 U/ml | Gavage | 8 days | Food allergic | Regulation of intestinal microbial community structure | [95] |
| Mice | Oral | 100 or 300 U | Gavage | 2 weeks | Chronic colitis | Inhibit the activation of intestinal epithelial cells and peritoneal macrophages and attenuate chronic murine colitis | [124] |
| Mice | Oral | 100 U/mL | Drinking water | 21 days | Metabolic syndrome | Alterations in the composition of the gut microbiota | [125] |
| Mice | Oral | 150 or 300 U/mL | Drinking water | 48 h | Gut barrier dysfunction | Decreased expression of intestinal junctional proteins and impaired barrier function | [126] |
| Mice | Oral | 200 U/mL | Drinking water | 5 days | Bacterial infections | Protected mice from antibiotic-associated bacterial infections | [127] |
| Mice | Oral | 100 U/mL | Drinking water | 11 weeks | Metabolic syndrome | Inhibits absorption of endotoxin with dietary fat; prevents or reverses metabolic syndrome | [63] |
| Mice | Oral | 300 U/mL | Drinking water | 7 days | Inflammatory bowel diseases | Tissue myeloperoxidase activity and proinflammatory cytokines were significantly decreased | [41] |
| Mice | Oral | 200 U/mL | Drinking water | 4 days | Liver fibrosis | Protects the gut barrier and development of liver fibrosis via a TLR4-mediated mechanism | [105] |
| Mice | Oral | 100 U/mL | Drinking water | Lifetime | Aging | Targeting crucial intestinal alterations, including gut barrier dysfunction, microbiome dysbiosis, and endotoxemia | [78] |
| Mice | Oral | 200 U/mL | Liquid diet | 10 days | Hepatosteatosis | Ameliorated the activation of hepatic stellate cells and prevented their lipogenic effect on hepatocytes | [105] |
| Human | Oral | 30,000 U | Infusion pump | 7 days | Ulcerative colitis | Decrease the C-reactive protein and stool calprotectin levels | [106] |
| Rats | Injection | 1000 U/kg | Intraperitoneal | 4 days | Acute liver failure | Reduced LPS activity and hepatic TLR4 expression | [104] |
| Rats | Injection | 1000 U/kg | Intraperitoneal | 24 h | Acute kidney injury | Reduce renal inflammation; dephosphorylation of ATP and LPS | [118] |
| Rats | Injection | 500 U/kg | Intraperitoneal | 5 min | Partial liver resection | Attenuate both hepatic and pulmonary injury | [128] |
| Mice | Injection | 100 U/mL | Intestinal loop | 2 h | Intestinal flora disorder | Inhibiting the concentration of luminal nucleotide triphosphates | [129] |
| Mice | Injection | 15 U/mL | Intravenous | 1 day | Sepsis | Normalize body temperature | [130] |
| Mice | Injection | 150 U | Intravenous | 5 min | Pregnancy complications | Protects early pregnancy defects | [116] |
| Mice | Injection | 150 U/kg | Intravenous | 72 h | Secondary peritonitis | Attenuates the inflammatory response both locally and systemically and reduces associated liver and lung damage | [131] |
| Human | Injection | 5.6 U/kg/h | Intravenous | 36 h | Cardiac surgery | Endogenous alkaline phosphatase release | [132] |
| Human | Injection | 67.5 U/kg + 132.5 U/kg/24 h | Intravenous | 48 h | Acute kidney injury | Reductions in the systemic markers C-reactive protein, IL-6, and LPS-binding protein and in the urinary excretion of kidney injury molecule-1 and IL-18 | [111] |
| Piglet | Injection | 1, 5, or 25 U/kg/h | Intravenous | 4 h | Acute kidney injury | Increased serum or renal tissue AP activity | [113] |
| Piglet | Injection | 1, 5, or 25 U/kg/h | Intravenous | 4 h | Cardiac surgery | Increased kidney and liver tissue alkaline phosphatase activity | [133] |
