CN120860036A - Plant sterol and plant sterol ester complexing agent and application thereof - Google Patents
Plant sterol and plant sterol ester complexing agent and application thereofInfo
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Abstract
本发明公开了一种植物甾醇和植物甾醇酯复合剂及其应用，其中，所述复合剂包括质量比为1：10的植物甾醇与植物甾醇酯。本发明旨在通过植物甾醇和植物甾醇酯二者复配，改善植物甾醇水溶性和生物利用度，实现协同增效；从多靶点出发，在干扰球虫脂质获取的同时，上调盲肠紧密连接蛋白表达以修复肠道屏障，抑制血清及盲肠促炎因子释放缓解炎症反应，调控脂质合成与脂肪酸氧化相关基因表达重塑脂代谢稳态；进而有效抑制球虫生长发育，显著改善球虫感染肉鸡生长性能。
This invention discloses a phytosterol and phytosterol ester compound and its application, wherein the compound comprises phytosterol and phytosterol ester in a mass ratio of 1:10. This invention aims to improve the water solubility and bioavailability of phytosterols through the combination of phytosterol and phytosterol ester, achieving synergistic effects; from multiple target perspectives, while interfering with coccidia lipid acquisition, it upregulates the expression of cecal tight junction proteins to repair the intestinal barrier, inhibits the release of serum and cecal pro-inflammatory factors to alleviate inflammatory responses, and regulates the expression of lipid synthesis and fatty acid oxidation-related genes to reshape lipid metabolism homeostasis; thereby effectively inhibiting coccidia growth and development and significantly improving the growth performance of coccidia-infected broilers.
Description
Technical Field
The invention relates to the technical field of feed additives, in particular to a plant sterol and plant sterol ester complexing agent and application thereof.
Background
Coccidiosis is a global parasitic disease caused by Eimeria coccidium (Eimeria), causing serious economic loss to the poultry farming industry. By taking chicken as an example, after coccidian infection, intestinal mucosa injury, nutrition absorption disorder, immune function inhibition and secondary infection can be caused, the morbidity can reach more than 50 percent, and the mortality can reach up to 25 percent. The coccidium has complex life history, the sporulated oocysts have long survival time in the external environment, have extremely strong resistance to the conventional disinfectant, and can be transmitted through multiple ways such as feces, instruments, insects and the like. At present, the prevention and control of coccidiosis mainly dependent on chemical synthetic drugs (such as ionophores, sulfonamides and quinolines) and vaccines. However, long-term use of chemical drugs causes rapid spread of drug-resistant insect strains, and drugs such as decoquinate are liable to induce coccidium to produce drug resistance, and periodic alternation of the drugs is required. Meanwhile, the problem of drug residue and environmental pollution are increasingly prominent. Although the vaccine can induce the host to generate immune protection, the vaccine has the defects of short immune period, unstable protective power, easy interference by environmental factors and the like, and virulent vaccine can cause recessive infection.
The invention patent application with the prior patent publication number of CN106420769A discloses an application of beta-sitosterol in preparing an anti-eimeria tenella medicine, wherein the beta-sitosterol and auxiliary materials are prepared into powder, added into feed, mixed uniformly and fed to chickens according to daily feed amount, or the beta-sitosterol is prepared into beta-sitosterol water-soluble powder which is dissolved in water and fed to chickens according to daily water intake, although animal infection experiments prove that the anti-coccidia index (ACI) of the beta-sitosterol can reach more than 180, the anti-eimeria tenella medicine has better anti-eimeria tenella effect, but intestinal tract absorption rate, blood concentration and the like are not tested, and whether the anti-eimeria is directly killed or indirectly acted through host immune adjustment cannot be determined.
Disclosure of Invention
The invention mainly aims to provide a plant sterol and plant sterol ester complexing agent and application thereof, and aims to solve the technical problem that the existing coccidiosis prevention and control cannot meet expectations.
The invention provides a plant sterol and plant sterol ester complexing agent, which comprises plant sterols and plant sterol ester in a mass ratio of 1:10, wherein the plant sterols mainly comprise 40% -60% of beta-sitosterol, 15% -30% of oleyl sterols, 10% -25% of stigmasterols, 10% -10% of brassica oleifera sterols and 5% -other sterols, the plant sterol ester comprises 40% -55% of beta-sitosterol oleate, 10% -20% of campesterol oleate, 5% -15% of stigmasterol oleate, 5% -brassica oleifera oleate, 5.0% of free phytosterols, 3.0% of oleic acid and 2.0% of other impurities.
In addition, in order to achieve the aim, the invention also provides an application of the plant sterol and plant sterol ester complexing agent in preparing the anti-eimeria tenella medicine.
In addition, in order to achieve the aim, the invention also provides the application of the plant sterol and plant sterol ester complexing agent in preparing the diet additive for up-regulating the expression of cecum tight junction protein.
In addition, in order to achieve the aim, the invention also provides the application of the plant sterol and plant sterol ester complexing agent in preparing the diet additive for inhibiting the release of serum and cecum pro-inflammatory factors and relieving inflammatory response.
In addition, in order to achieve the aim, the invention also provides the application of the plant sterol and plant sterol ester complexing agent in preparing a diet additive for down-regulating HMGCR.
Optionally, the plant sterol and plant sterol ester complex can be added to the diet in an amount of from 50 to 200mg/kg for any of the above applications.
Optionally, the plant sterol and plant sterol ester complex is added to the basal diet in the form of a premix.
Optionally, the addition amount of the plant sterol and plant sterol ester complex in the diet is 100mg/kg
The beneficial effects are that:
According to the invention, the water solubility and the bioavailability of the plant sterol are improved through the compounding of the plant sterol and the plant sterol ester, so that the synergistic effect is realized, the expression of the cecum tight junction protein is up-regulated to repair intestinal barriers, the release of serum and cecum pro-inflammatory factors is inhibited to relieve inflammatory reaction, the lipid synthesis and fatty acid oxidation related gene expression is regulated and remodelling lipid metabolism steady state is regulated, the growth and development of coccidian are effectively inhibited, and the growth performance of coccidian infected broiler is remarkably improved.
Drawings
FIG. 1 is a graph comparing the pathological sections of cecum tissue from different experimental groups 21 d;
fig. 2 is a graph comparing the crypt depth of cecal tissue of broiler chickens from different experimental groups 21 d.
The achievement of the objects, functional features and advantages of the present invention will be further described with reference to the accompanying drawings, in conjunction with the embodiments.
Detailed Description
It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
The invention provides a plant sterol and plant sterol ester complexing agent, which comprises plant sterol and plant sterol ester with the mass ratio of 1:10, wherein the plant sterol mainly comprises beta-sitosterol (40% -60%), oleyl sterol (15% -30%), stigmasterol (about 10% -25%), brassicasterol (less than or equal to 10%) and other trace sterols (such as sitostanol, campestanol and the like, and the content is less than or equal to 5%). The plant sterol ester is an oleic acid esterified product, and the component is mainly oleic acid ester of various plant sterols, and comprises beta-sitosterol oleic acid ester (content 40% -55%), campesterol oleic acid ester (content 10% -20%), stigmasterol oleic acid ester (content 5% -15%), brassicasterol oleic acid ester (content less than or equal to 5%), free plant sterols (content less than or equal to 5.0%), oleic acid (free or residual) (content less than or equal to 3.0%) and other impurities (content less than or equal to 2.0%).
Further, the invention also discloses an anticoccidial feed, which is prepared by adding the plant sterol and plant sterol ester complexing agent into basic diet in the form of premix, and taking chicken feeding as an example, the addition amount of the plant sterol and plant sterol ester complexing agent is 50-200mg/kg, preferably 100mg/kg. And the complexing agent of the plant sterol and the plant sterol ester can indirectly influence the coccidian infection process and inflammatory reaction by adjusting the intestinal flora structure. The action mechanism is that the free phytosterol can be used as a nutrition substrate of intestinal beneficial bacteria (such as lactobacillus and bifidobacterium) to promote the proliferation of the intestinal beneficial bacteria, beneficial bacteria metabolites (such as short chain fatty acids) can enhance the barrier function of intestinal mucosa (such as up-regulating the expression of ZO-1 and Occludin), reduce the adhesion and invasion of coccidian to intestinal epithelium, and the phytosterol ester can inhibit the sterol synthesis pathway of the coccidian (the coccidian needs to acquire sterols from a host to maintain a cell membrane structure, and esterified sterols can competitively inhibit the uptake of the sterols) and simultaneously be converted into a free state through flora metabolism to synergistically activate host immune cells (such as macrophages and Treg cells). Meanwhile, coccidian infection can disturb host lipid metabolism (such as abnormal cholesterol synthesis and enhanced lipid peroxidation), and the phytosterol and sterol ester can realize dual effects of anticoccidial and anti-inflammatory by targeted regulation of lipid signal molecules. Specifically, the plant sterol ester can reduce excessive cholesterol synthesis of a host by downregulating HMGCR (cholesterol synthesis rate-limiting enzyme), inhibit key enzymes of the host cholesterol to synthesize self cell membranes by coccidian and block the material basis of the proliferation of the coccidian, the free plant sterol can inhibit the activation of NF-kappa B inflammatory channels by regulating nuclear receptors such as PPAR-gamma and reduce the release of pro-inflammatory factors such as IL-6, IL-17 and the like, and the esterified state can penetrate the coccidian cell membranes more easily through the fat-soluble advantage and directly destroy the lipid steady state of the coccidian. Meanwhile, coccidian infection can induce the metabolism of host immune cells to be converted into a 'pro-inflammatory phenotype' (such as glycolysis enhancement and mitochondrial dysfunction), and plant sterols and sterol esters can improve the anti-inflammatory efficiency by remodelling the metabolism state of immune cells. The phytosterol can promote the beta-oxidation of mitochondria of immune cells, enhance ATP generation, maintain the immunosuppressive function of Treg cells and reduce excessive inflammation, and the phytosterol ester can inhibit the excessive activation of effector T cells by regulating and controlling an AMPK/mTOR signal path, promote the release of anti-inflammatory metabolites (such as adiponectin) at the same time, realize the dynamic balance of metabolism and immunity and avoid the aggravation of intestinal damage caused by immune metabolism disorder.
To further illustrate the efficacy, the following is a detailed description of specific examples of applications.
1. Raw material preparation
The corn, the bean pulp, the corn protein powder, the soybean oil, the lysine, the DL-methionine, the calcium hydrophosphate, the stone powder and the vitamins used in the test are all conventional commercial products.
The phytosterol and phytosterol esters used in the experiments of the present invention were purchased from south bearded grass prebiotic biotechnology limited.
Eimeria (EIMERIA TENELLA) used in the test of the present invention was given benefit from the teaching of China university of agriculture Wang Zhong and used in the test of the present invention after propagation.
2. Preparation of feeds for different groups of broilers
Control (control group)
A broiler feed comprises basic ration and premix. According to the feeding stage and the nutrition requirement standard, the basic feed for broiler chickens (suitable for 1-21 days in the early growth stage) is prepared.
The early-stage basic diet comprises, by weight, 50.00% of corn, 34.00% of soybean meal, 6.40% of corn gluten meal, 5.00% of soybean oil, 0.42% of lysine, 0.29% of DL-methionine, 2.23% of calcium hydrophosphate, 1.00% of stone powder and 0.66% of premix.
The premix provides vitamins A8,000IU, D32,500IU, vitamin E20.0mg, vitamin K33.0mg, vitamin B13.0mg, vitamin B28.0mg, vitamin B67.0mg, vitamin B120.015mg, pantothenic acid 20.0mg, nicotinic acid 50.0mg, biotin 0.1mg, folic acid 1.5mg, iron 96mg, zinc 30mg, copper 7.5mg, manganese 75mg, iodine 0.4mg and selenium 0.35mg for each kilogram of diet.
The preparation method of the broiler feed comprises the following steps of uniformly stirring and mixing the components. The nutrition level of the broiler diet is calculated.
Model example (model group)
The composition, nutrition level and preparation method of the broiler diet used in the model example are the same as those of the control example.
Comparative example (Low esterification group)
A broiler diet comprises basic diet and phytosterol. According to the feeding stage and the nutrition requirement standard, the basic feed for broiler chickens (suitable for 1-21 days in the early growth stage) is prepared.
The early-stage basic diet comprises, by weight, 50.00% of corn, 34.00% of soybean meal, 6.40% of corn gluten meal, 5.00% of soybean oil, 0.42% of lysine, 0.29% of DL-methionine, 2.23% of calcium hydrophosphate, 1.00% of stone powder and 0.66% of premix. And adding the low-esterification-degree compound into the early-stage basic feed, wherein the adding amount is 100mg/Kg of the early-stage basic feed.
The premix provides vitamins A8,000IU, D32,500IU, vitamin E20.0mg, vitamin K33.0mg, vitamin B13.0mg, vitamin B28.0mg, vitamin B67.0mg, vitamin B120.015mg, pantothenic acid 20.0mg, nicotinic acid 50.0mg, biotin 0.1mg, folic acid 1.5mg, iron 96mg, zinc 30mg, copper 7.5mg, manganese 75mg, iodine 0.4mg and selenium 0.35mg for each kilogram of diet.
The preparation method of the broiler feed comprises the following steps of uniformly stirring and mixing the components. The nutrition level of the broiler diet is calculated.
Example 1 (high esterification group)
A broiler diet comprises basic diet and plant sterol ester with mass ratio of 1.08:9.88. According to the feeding stage and the nutrition requirement standard, the basic feed for broiler chickens (suitable for 1-21 days in the early growth stage) is prepared.
The early-stage basic diet comprises, by weight, 50.00% of corn, 34.00% of soybean meal, 6.40% of corn gluten meal, 5.00% of soybean oil, 0.42% of lysine, 0.29% of DL-methionine, 2.23% of calcium hydrophosphate, 1.00% of stone powder and 0.66% of premix. And adding the compound with high esterification degree into the early-stage basic feed, wherein the adding amount is 100mg/Kg of the early-stage basic feed.
The premix provides vitamins A8,000IU, D32,500IU, vitamin E20.0mg, vitamin K33.0mg, vitamin B13.0mg, vitamin B28.0mg, vitamin B67.0mg, vitamin B120.015mg, pantothenic acid 20.0mg, nicotinic acid 50.0mg, biotin 0.1mg, folic acid 1.5mg, iron 96mg, zinc 30mg, copper 7.5mg, manganese 75mg, iodine 0.4mg and selenium 0.35mg for each kilogram of diet.
The preparation method of the broiler feed comprises the following steps of uniformly stirring and mixing the components. The nutrition level of the broiler diet is calculated.
3. Test protocol and daily management
288 Yizhai white feather broilers with uniform weight and good health condition and 1 day old are selected, randomly divided into 4 groups (a control group, a model group, a low esterification group and a high esterification group), 6 repeats of each group are selected, 12 repeats (each male and female half) are selected, the control group and the model group are fed with basic diet, 100mg/kg of plant sterol is added in the low esterification group feeding basic diet, and 100mg/kg of plant sterol and plant sterol ester complexing agent is added in the high esterification group broiler feeding basic diet.
The test period was 21 days. The test refers to the feeding management and immunization program of white feather broilers, and has good ventilation, free drinking water and ingestion. And 14d, 8X 104 Eimeria (EIMERIATENELLA) sporulated oocysts were infused in the stomach except the control group, which was infused with an equal dose of physiological saline. On trial day 21, 1 broiler chicken (24 broiler chickens per treatment) with an average weight close to the average weight of the corresponding group was selected from each repetition for slaughter sampling. The specific formulas and nutrition levels of the test diets are shown in Table 1.
Table 1. Basal diet formula and nutrient level (air-dried basis)
The premix provides vitamins A8,000IU, VD32,500IU, vitamin VE20.0mg, vitamin VK33.0mg, vitamin VB13.0mg, vitamin VB28.0mg, vitamin VB67.0mg, vitamin VB120.015mg, pantothenic acid 20.0mg, nicotinic acid 50.0mg, biotin 0.1mg, folic acid 1.5mg, iron 96mg, zinc 30mg, copper 7.5mg, manganese 75mg, iodine 0.4mg and selenium 0.35mg for each kilogram of diet.
The calculated values are the metabolic energy and the available phosphorus, and the measured values are the crude protein, calcium and total phosphorus contents.
4. Sample collection
On trial day 21, 1 broiler chicken (24 broiler chickens per treatment) with an average weight close to the average weight of the corresponding group was selected from each repetition for slaughter sampling. Jugular blood was collected before slaughter, blood samples were collected into 10mL centrifuge tubes (about 2/3 of the tube volume), and after 15 minutes of oblique placement, centrifuged at 1000 Xg for 10 minutes, and the supernatant serum was collected and stored in a-80 ℃ refrigerator for testing. The chicken neck after blood collection is exsanguinated and killed, the cecum tissue is taken out after immediate dissection, the cecum section of about 1cm is rapidly sheared out, chyme in the intestinal tract is gently flushed by using 0.75% physiological saline, and then the section of the intestine is placed into 4% paraformaldehyde to be fixed for making slices. And (5) filling part of cecum tissues into a freezing tube, and storing at-80 ℃ for use after liquid nitrogen quick freezing.
5. Index measurement and test results
5.1 Analysis of growth Properties and test results
All test chickens were fasted on a fasting basis in each repeat unit for 12h of fasting at test 14, 21d, respectively. Feed intake was recorded for each group during the trial, and average body weight, average Daily Gain (ADG), average Daily Feed Intake (ADFI) and feed to meat ratio (F/G) were calculated for 1-21 d.
Average Daily Feed Intake (ADFI) = (total feed-residual feed)/(number of tested chickens x number of tested days);
average Daily Gain (ADG) = (total last weight-initial total weight)/(test days x number of test chickens);
Feed to meat ratio (F/G) =average daily gain/average daily feed intake.
The data of the different experimental groups in table 2 on the growth performance of eimeria tenella infected broilers were obtained according to the above formula.
TABLE 2 influence of different experimental groups on the growth performance of Eimeria tenella infected broilers
Note that the same column of the table above is marked with different letters to indicate significant differences (P < 0.05), and the tables are the same.
As shown in table 2, compared with the control group, the weight and average daily gain of the model group broiler 21d are significantly reduced, the feed conversion rate is significantly increased (P < 0.05), which indicates that coccidian infection has serious negative effects on the growth and development of broiler chickens, coccidian parasitizes and breeds in intestinal tracts, and influences the digestion and absorption of nutrients, thereby further causing the growth inhibition of broiler chickens, the reduction of feed conversion efficiency, and finally the slow weight increase and the increase of feed conversion rate.
Compared with the model group, the weight of 21-day-old broiler chickens and average daily gain of the low-esterification group chickens are obviously improved, the feed conversion ratio is obviously reduced (P is less than 0.05), and the inhibition effect of coccidium infection on the growth performance of the broiler chickens can be effectively relieved by the low-esterification treatment. The possible mechanism is that the low esterification treatment influences the physiological functions of the intestinal tracts of the coccidium infected broiler chickens, improves the absorption capacity of the intestinal tracts to nutrient substances, and can enhance the utilization efficiency of organisms to the nutrient substances by regulating the metabolic process in the broiler chickens, thereby promoting the growth of the broiler chickens and improving the feed conversion rate.
The weight and average daily gain of the broiler 21d in the high esterification group tended to increase, and the feed to meat ratio tended to decrease (P > 0.05), and it was found that the high esterification treatment had a certain effect on improving the growth performance of the broiler infected with coccidium, without significant difference from the low esterification group.
5.2 Fecal oocyst count and result analysis
And respectively collecting and uniformly mixing each repeated faeces every day after the coccidium infection is 5 th, 6 th and 7d, then taking 2g of faeces to be tested, placing the faeces into a beaker, adding saturated saline, fully and uniformly mixing, taking 1mL of faeces liquid, injecting the faeces liquid into a Micmarst counting plate, recording the number of eggs in two counting chambers under a microscope low-power microscope, taking an average value, and multiplying the average value by 200, wherein the obtained value is the number of faeces Oocysts Per Gram (OPG). Each sample was repeated 3 times and averaged to give the results shown in table 3.
TABLE 3 influence of different experimental groups on the oocyst count of Eimeria tenella infected broiler feces
Note that the same column of the table above labels different letters to indicate significant differences (P < 0.05).
As can be seen from table 3, coccidian infection in the model group resulted in a significant increase in OPG value (P < 0.05) in broiler chickens compared to the control group, and with increasing infection time, OPG increased, peaking at day 6, and coccidian oocysts were not seen in the feces of the broiler chickens in the control group, indicating that coccidian underwent a growth and reproduction process in broiler chickens. Coccidian continuously proliferates in a host body, oocysts produced by the coccidian are discharged out of the body through excrement, and the increase of OPG reflects mass proliferation of coccidian in intestinal tracts of broilers, so that serious threat is caused to health of broilers.
Compared with the model group, the OPG values of the low-esterification group and the high-esterification group broiler chickens are obviously reduced (P < 0.05), which shows that the low-esterification treatment and the high-esterification treatment have an inhibition effect on the reproduction of coccidia, influence the survival and reproduction environment of the coccidia in the intestinal tracts of the broiler chickens, reduce the reproduction capacity of the coccidia, and further reduce the number of oocysts discharged from the body. Meanwhile, the number of the faecal oocysts of the broiler chicken infected by the Eimeria tenella in the high esterification group is obviously lower than that of the faecal oocysts of the broiler chicken infected by the Eimeria tenella in the low esterification group, and the reason is that the addition of the plant sterol ester in the high esterification group on the basis of the low esterification group can realize the reduction of excessive cholesterol synthesis of a host by reducing HMGCR (cholesterol synthesis rate-limiting enzyme), and inhibit the key enzyme of the coccidium to synthesize own cell membranes by using the cholesterol of the host, and block the material basis of the proliferation of the coccidium.
5.3 Analysis of serum Biochemical indicators and results
The results of measuring Total Cholesterol (TC) (accession number: A111-1-1), triglyceride (TG) (accession number: A110-1-1), low-density lipoprotein cholesterol (LDL-C) (accession number: A113-1-1), and high-density lipoprotein cholesterol (HDL-C) (accession number: A112-1-1) in serum samples using the relevant kit from the Nanjing institute of biological engineering according to the specification are shown in Table 4.
TABLE 4 influence of different experimental groups on the biochemical index of the serum of Eimeria tenella infected broilers
Note that the same column of the table above labels different letters to indicate significant differences (P < 0.05).
As can be seen from table 4, the TC and HLD-C content values in the serum of the broiler chickens of the model group were significantly reduced (P < 0.05) compared to the control group, indicating that coccidian infection caused significant interference on the lipid metabolism of the broiler chickens. Coccidian infection may destroy the normal physiological functions of the intestinal tracts of broilers, affecting the processes of lipid absorption, synthesis and transport. For example, coccidian may damage intestinal epithelial cells, affect the absorption of lipids such as cholesterol, or interfere with the activity of lipid synthesis and metabolism related enzymes in the liver, resulting in reduced synthesis of TC and HDL-C. In addition, TG (triglyceride) content tends to decrease, although not significantly different, suggesting that coccidian infection may also have some effect on triglyceride metabolism, possibly involving changes in the breakdown, transport or utilization processes of fat.
The TC content values in the low and high esterified group broiler sera were significantly reduced (P < 0.05) compared to the model group, indicating that low and high esterification treatments further affected cholesterol levels in broiler sera. The possible reason is that both treatments alter the lipid distribution and metabolic pathways in the body. For example, they may promote the transport or conversion of cholesterol to other tissues, or inhibit the synthesis of cholesterol in the liver. The TG content also tends to decrease, suggesting that low and high esterification treatments have a certain regulatory effect on triglyceride metabolism, and may affect the processes of fat cell metabolism, beta-oxidation of fatty acids, etc., so that the TG content in serum tends to decrease. Meanwhile, aiming at the HDL-C content, the HDL-C value of the low esterification group is higher than that of the model group, and the HDL-C value of the high esterification group is lower than that of the model group, the accurate regulation and control of cholesterol metabolism can be realized by adding the plant sterol ester into the high esterification group, namely, the lipid available for coccidian is reduced by reducing serum TC, and the transportation and metabolism of the cholesterol to the liver are accelerated by the dynamic regulation of the HDL-C, so that the abnormal accumulation of the cholesterol at an intestinal infection part is avoided.
5.4 Serum inflammatory factor index and result analysis
The levels of interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-17 (IL-17) tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in serum were measured according to the specification using ELISA test kits of Shanghai enzyme-Linked Biotechnology Co., ltd, and the measurement results are shown in Table 5.
TABLE 5 influence of different experimental groups on oocyst count of Eimeria tenella infected broiler feces
Note that the same column of the table above labels different letters to indicate significant differences (P < 0.05).
As can be seen from Table 5, the levels of IL-2, IL-6, IL-17 and TNF- α in the serum of the broiler chickens of the model group were significantly increased (P < 0.05) compared to the control group, indicating that coccidian infection elicited immune responses in the broiler chickens. IL-2 is an important immunoregulatory factor, which can promote proliferation and differentiation of T cells and enhance cellular immune function of organisms, IL-6 can induce differentiation of B cells and secretion of antibodies and simultaneously participate in regulation of inflammatory response, IL-17 is mainly secreted by Th17 cells and plays an important role in inflammatory response and anti-extracellular pathogen infection, TNF-alpha has various biological functions, including activating immune cells, inducing apoptosis and the like, and when the organisms resist coccidian infection, the organisms release the cytokines to enhance immune defenses, but at the same time, can also trigger inflammatory response and cause a certain damage to the organisms.
Compared with the model group, the low-esterification group and the high-esterification group have obvious regulation effect on the immune overactivation caused by coccidian infection, but the regulation effect of the high-esterification group has more advantages:
In the low esterification group, the content of IL-2, IL-6, TNF-alpha and IFN-gamma is obviously reduced (P < 0.05) compared with that in the model group, which shows that the excessive release of proinflammatory factors can be effectively inhibited, but the content of IL-17 is not obviously different from that in the model group (P > 0.05), which shows that the regulation of Th17 cell mediated inflammatory pathways is limited.
The regulation and control effect of the high-esterification group is more comprehensive and the intensity is higher, IL-2 is slightly higher than that of the low-esterification group but is still obviously lower than that of the model group, IL-6 is reduced by 20.27 percent and is obviously lower than that of the low-esterification group, IL-17 is obviously reduced to 134.79 +/-3.03 pg/mL (P < 0.05) which is the only group capable of effectively regulating the index downwards, TNF-alpha is higher than that of the low-esterification group but is reduced by 10.41 percent and is compared with that of the model group and the difference between the IL-2 and the control group is smaller than that of the low-esterification group, and IFN-gamma is slightly higher than that of the low-esterification group but is still obviously lower than that of the model group.
The high esterification group balances the relation between the immunity of the organism against coccidian and the inflammation injury more accurately through multidimensional regulation and control of a pro-inflammatory factor network (particularly strong inhibition of IL-6 and IL-17), so that moderate immune response is reserved to resist coccidian infection, the damage of excessive inflammation to intestinal tissues is avoided, the regulation and control effect is obviously superior to that of the low esterification group, and the key effect of synergy of the plant sterol ester is embodied.
5.5 Cecal histomorphology and results analysis
And (3) carrying out treatments such as dehydration, transparency, wax dipping, embedding and the like on the fixed cecum tissue, cutting wax blocks by using a slicing machine, enabling the slicing thickness to be 5-6 mu m, covering the slices containing the whole intestinal section on warm water, then placing the slices on a glass slide, and drying and storing the glass slide by using a slice baking machine. And dewaxing and rehydrating the intestinal tract slice on the glass slide, then dyeing with hematoxylin-eosin, and drying the surface dyeing liquid of the eluted slice. Neutral gum is dripped into the glass slide, and the glass slide is covered with a cover glass for sealing and then dried. A plurality of discontinuous visual field observations are randomly selected under a microscope, 5 or more representative photographs are selected, the representative photographs are taken, the representative photographs are observed through K-viewer software, the heights of the crypts are measured, the results are shown in fig. 1-2, fig. 1 is a graph of pathological sections of the cecum tissue of different experimental groups 21d, a is a control group, b is a model group, c is a low esterification group, d is a high esterification group, fig. 2 is the depths of the crypts of the cecum tissue of the broilers of different experimental groups 21d, the data are expressed as average values of six replicates of each treatment, the same letters of a and b indicate that the difference is not significant (P > 0.05), and the different letters indicate that the difference is significant (P < 0.05). Magnification of 100×, scale of 100 μm.
As can be seen from fig. 1-2, the coccidian oocysts and cecal tissue destruction were clearly seen in the HE sections of the model group compared to the control group, which intuitively indicates that coccidian successfully infects the cecum of broilers and causes substantial damage to the tissues. Coccidia parasitize in the cecum, and various stages in its life history (such as schizogenesis, gametogenesis, etc.) cause damage to the cecum mucosal cells, resulting in destruction of tissue integrity. There are a large number of inflammatory cells in the crypt, and the cecal crypt depth is significantly increased (P < 0.05), which is an inflammatory response manifestation of the body to coccidian infection. Inflammatory cells aggregate to combat coccidian invasion and proliferation, but excessive inflammatory responses may further exacerbate tissue damage. The increased crypt depth may be due to the fact that coccidian infection stimulates proliferation of intestinal stem cells in an attempt to repair damaged mucosal tissue, but this repair process may not be entirely normal, resulting in a change in crypt structure.
Compared with the model group, the number of cecum coccidian oocysts of the low-esterification group and the high-esterification group broilers is reduced, the tissue damage of the cecum is reduced, and the depth of the cecum crypt is not changed remarkably (P is more than 0.05). The two treatment modes are described to have an inhibitory effect on the parasitic and reproductive activities of coccidia in the cecum. The low and high esterified phytosterol/alcohol esters may reduce the number of coccidian in the cecum by affecting the coccidian's living environment, nutrient intake or interfering with its metabolic processes, thereby reducing the extent of coccidian infection. The reduction of cecum tissue destruction suggests that low and high esterification helps to alleviate the damage of coccidian infection to cecum tissue, and the combination of the change of cytokines in the serum in the front, the low and high esterification group serum has significantly reduced content of pro-inflammatory cytokines (such as IL-6, TNF-alpha, etc.), which is consistent with the reduction of cecum tissue destruction and the reduction of inflammatory cell infiltration. The two treatment modes are proved to reduce the damage of inflammation to cecum tissues by regulating immune response, stabilize the structure of the cecum tissues to a certain extent, help to restore the normal digestion and absorption functions of intestinal tracts, provide sufficient nutrition for organisms, promote the growth of broilers, and explain the reason of improving the growth performance.
5.6 Cecum tissue Gene expression detection
About 100mg of cecal tissue sample was rapidly removed from the-80℃refrigerator, transferred to an autoclaved 2mL crushing tube, added with 1mLTRIzo1, placed in a high throughput tissue crusher, set at 5000rpm for 15s/2 times, and allowed to stand at room temperature for 5min. 200. Mu.L of chloroform reagent was added to the lysate and the solution was thoroughly mixed by vortexing with an oscillator. After mixing, the liquid was allowed to stand for 10min, transferred to a centrifuge pre-cooled to 4℃in advance, and centrifuged at 12000rpm for 5min. Sucking 500 mu L of supernatant to a new autoclave 2mLEP tube, adding an equal volume of precooled isopropanol, fully shaking and uniformly mixing, and standing at room temperature for 10min to promote RNA aggregation. Centrifuging the mixed solution at 12000rpm for 10min at 4 ℃, discarding the supernatant, and precipitating to obtain crude RNA. To the pellet was added 1mL of pre-chilled 75% ethanol (formulated with DEPC water, pH 5.2) and centrifuged at 8000rpm for 15min at 4 ℃. The supernatant was discarded and the obtained pellet was the purer RNA, and the RNA was purified by repeating the above steps. The cover is opened and placed in an ultra-clean bench to be dried for 5-8min at room temperature to make the precipitate transparent, 30-50 mu LDEPC of water is added and mixed uniformly, and the solution is promoted by incubation for 10min at 55-60 ℃. Finally, the concentration and purity of RNA are measured by an ultra-micro spectrophotometer, the ratio A260/A280 is 1.8-2.1, and the ratio A260/A230 is 1.9-2.1.
RNA was reverse transcribed into cDNA using a high capacity cDNA reverse transcription kit (AG, hunan, china) on a reverse transcription apparatus thermal cycler, the parameters of which were as follows, heating at 37℃for 15min, denaturing at 85℃for 5s, and storing the obtained cDNA in a-80℃refrigerator to be tested when the temperature was reduced to 4 ℃.
The PCR primer sequences used to detect gene expression are shown in Table 6 and were reacted on a fluorescent quantitative real-time PCR apparatus (LightCycler 480 II, roche, switzerland) using SYBR Green Pro Taq HS kit (AG, hunan, china).
TABLE 6 Gene primer sequence number
The reaction conditions were 50℃for 2 minutes, 95℃for 10 minutes initially, followed by 40 cycles of amplification, each cycle comprising 95℃for 15 seconds and 60℃for 1 minute of annealing extension. Each sample was subjected to 3 replicates, and the target gene expression level was calculated by using beta-actin as a reference gene using 2 −ΔΔCT methods.
5.7 Cecal tight junction protein expression level results analysis
TABLE 7 influence of different experimental groups on the expression level of Tight-junction protein of Eimeria tenella infected broiler chickens
Note that the same column of the table above labels different letters to indicate significant differences (P < 0.05).
As can be seen from table 7, the expression levels of cecal ZO-1 and Occludin were significantly reduced in the model group broilers (P < 0.05) compared to the control group. This suggests that coccidian infection severely damages the tight junction structure of cecal epithelial cells, resulting in impaired intestinal mucosal barrier function. Coccidian directly breaks down the structure of the tight junction proteins during the parasitic and reproductive processes in the cecum, or interferes with their synthesis and transport processes, thereby reducing their expression levels in the cecum tissue.
Compared with a model group, the low-esterification group and the high-esterification group show differential regulation and control effects in the aspect of repairing the cecum tight connection structure, wherein the action characteristics of the high-esterification group have the more targeted advantage that in the low-esterification group, the ZO-1 expression quantity is obviously improved and has no obvious difference with a control group, and the Occludin expression quantity is obviously improved, so that the expression of two key tight connection proteins can be comprehensively recovered, and intestinal barrier damage caused by coccidian infection can be effectively repaired.
The regulation and control of the high esterification group shows the accurate targeting characteristic that although the expression quantity of ZO-1 is lower than that of the low esterification group, the difference between the high esterification group and the control group is smaller than that of the model group, and the expression quantity of the core skeleton protein ZO-1 is recovered preferentially in three types of proteins, wherein the expression quantity of Occludin is not up to a significant level (P > 0.05), but is still improved by 65.91 percent compared with the model group and is closer to the physiological level of the control group, and the expression quantity of Claudin-1 is basically consistent with that of the control group, so that the expression quantity of Claudin-1 is the only group which does not cause abnormal elevation of the protein.
Therefore, the high esterification group can restore the intestinal barrier and avoid over-expression or unbalance of the tight junction protein by preferentially restoring the expression of ZO-1 and maintaining the physiological level of Claudin-1, thereby being more in line with the physiological requirement of steady state regulation of the intestinal barrier. Although the lifting amplitude of the accurate targeted repair mechanism is slightly inferior to that of a low-esterification group in Occludin, the structural integrity of the physical barrier of the intestinal tract can be more effectively reconstructed, a better repair mode is provided for blocking coccidium invasion and reducing leakage of intestinal contents, and the differential advantage of the plant sterol ester in the repair of the intestinal barrier is reflected.
5.8 Analysis of results of expression of cecal cholesterol metabolism-related Gene
TABLE 8 influence of different experimental groups on expression of genes related to cholesterol metabolism in Eimeria tenella infected broilers
Note that the same column of the table above labels different letters to indicate significant differences (P < 0.05).
As can be seen from table 8, the expression levels of cecal SREBP2 and LDLR were significantly up-regulated (P < 0.05) and the expression levels of ACAT1 and ACAT2 were significantly down-regulated (P < 0.05) in the model group broiler compared to the control group. SREBP2 is a key transcription factor that regulates cholesterol synthesis and uptake, and its up-regulation of expression may promote cholesterol synthesis and LDLR-mediated cholesterol uptake to meet the increased lipid demand for cholesterol and the like that the body may have after coccidian infection, as the processes of coccidian growth, proliferation or immune response of the body to infection may require more lipid participation. ACAT1 and ACAT2 are mainly responsible for converting free cholesterol into cholesterol esters for storage, and down-regulation of their expression may lead to reduced cholesterol ester synthesis, and more cholesterol exists in free form, which may affect the metabolic balance of intracellular cholesterol and the stability of membrane structures, and thus affect the normal function of cecal cells.
Compared with the model group, the expression level of HMGCR in the cecum of the broiler in the high esterification group is obviously reduced (P < 0.05), and the expression level of LDLR in the cecum of the broiler in the low esterification group and the broiler in the high esterification group is obviously reduced (P < 0.05). HMGCR is a key rate-limiting enzyme in cholesterol synthesis, whose down-regulation of expression inhibits cholesterol synthesis, which may be that the highly esterified group regulates cholesterol synthesis pathways by some mechanism, reducing unnecessary cholesterol synthesis to maintain the balance of body lipid metabolism. The low-esterified group and the high-esterified group broiler cecum LDLR expression levels are significantly down-regulated, which means that both treatments may reduce cholesterol uptake mediated by LDLR, help to avoid excessive cholesterol uptake caused by coccidian infection, and have significance in maintaining cholesterol homeostasis in cecum cells.
In conclusion, the broiler feed added with the phytosterol and phytosterin complexing agent can obviously up-regulate the expression of cecum tight junction protein (ZO-1, occludin), inhibit the release of serum pro-inflammatory factors and the over-expression of cecum pro-inflammatory factors, down-regulate lipid synthesis key genes (SREBP 1, FASN, SCD, DGAT 2) and activate fatty acid oxidation pathway (PPARalpha), so as to achieve the purposes of improving the growth performance of coccidian infected broiler, relieving the overimmune activation and remodelling the lipid metabolism steady state, and the broiler feed can be used for regulating and controlling metabolic disorder and inflammatory injury caused by coccidian infection through multiple targets.
The test results show that the low esterification group and the high esterification group have equivalent effects in improving the production performance of the coccidium infected broiler chickens. The high esterification group has obvious advantages in the aspects of coccidian inhibition, immunoregulation, lipid metabolism regulation and intestinal repair, namely, firstly, the method can remarkably reduce the OPG of broilers, effectively inhibit the intestinal canal propagation of coccidian, reduce the discharge of coccidian and reduce the group infection risk, secondly, the method can remarkably reduce the levels of serum IL-2, IL-6, TNF-alpha and INF-gamma, relieve inflammatory reaction, particularly, remarkably reduce the effect of key inflammatory factors IL-17, and highlight the precise immunoregulation advantage, thirdly, the method can remarkably reduce the cholesterol synthesis speed limiting step through remarkably reducing the expression of cecum HMGCR, simultaneously, and cooperatively reduce the expression of LDLR to reduce the uptake of cholesterol, realize the bidirectional regulation of lipid metabolism, more comprehensively regulate the low esterification group of LDLR, fourthly, remarkably reduce the number of the eggs of the cecum, lighten tissue injury, and strengthen the barrier function of intestinal mucosa through up-regulating the expression of ZO-1, thereby playing an important role in intestinal tissue repair.
It should be noted that, in this document, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or system that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or system. Without further limitation, an element defined by the phrase "comprising one does not exclude the presence of other like elements in a process, method, article, or system that comprises the element.
The foregoing embodiment numbers of the present invention are merely for the purpose of description, and do not represent the advantages or disadvantages of the embodiments.
The foregoing description is only of the preferred embodiments of the present invention, and is not intended to limit the scope of the invention, but rather is intended to cover any equivalents of the structures or equivalent processes disclosed herein or in the alternative, which may be employed directly or indirectly in other related arts.
Claims (8)
1. The plant sterol and plant sterol ester complexing agent is characterized by comprising plant sterol and plant sterol ester with a mass ratio of 1:10, wherein the plant sterol mainly comprises 40% -60% of beta-sitosterol, 15% -30% of oleanolic acid, 10% -25% of stigmasterol, 10% -10% of brassicasterol and 5% -other impurities, the plant sterol ester comprises 40% -55% of beta-sitosterol oleic acid ester, 10% -20% of campesterol oleic acid ester, 5% -15% of stigmasterol oleic acid ester, 5% -5% of brassicasterol oleic acid ester, 5.0% of free phytosterol, 3.0% of oleic acid and 2.0% of other impurities.
2. Use of a phytosterol and phytosterol ester complex as claimed in claim 1 in the manufacture of a medicament against eimeria tenella.
3. Use of a phytosterol and phytosterol ester complexing agent as claimed in claim 1 in the manufacture of a diet additive for upregulating cecum claudin expression.
4. Use of a phytosterol and phytosterol ester complex as claimed in claim 1 in the manufacture of a diet additive for inhibiting the release of serum and cecum pro-inflammatory factors to reduce inflammatory response.
5. Use of a phytosterol and phytosterol ester complexing agent as claimed in claim 1 in the manufacture of a diet additive for down-regulating HMGCR.
6. The use according to any one of claims 3 to 5, wherein the plant sterol and plant sterol ester complex is added to the diet in an amount of 50-200mg/kg.
7. The use according to claim 6, wherein the plant sterol and plant sterol ester complex is added to the basal diet in the form of a premix.
8. The use according to claim 6, wherein the plant sterol and plant sterol ester complex is added to the diet in an amount of 100mg/kg.
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