IUGR猪的生长与肠道发育及L-精氨酸和大豆卵磷脂的营养调控研究
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摘要
子宫内发育迟缓(IUGR)对胎儿生理机能和后期代谢产生深远影响,在猪生产上IUGR发生率高(15%-20%),导致仔猪生后生长速度、养分利用率、肉品质和健康状况低下,对养猪生产效益影响巨大。本研究选用新生IUGR仔猪和正常体重(NBW)仔猪,研究IUGR对猪出生后生长和肠道发育的影响及相关机制；并在仔猪哺乳和断奶后,补充L-精氨酸(Arg)和大豆卵磷脂(SL),研究其对IUGR猪生长和肠道发育的营养调控,为养猪生产和人类医学研究提供科学依据和调控技术。
1IUGR对猪出生后生长的影响
选用40头初生IUGR仔猪(IUGR组)和40头全同胞NBW仔猪(NBW组),每组4个重复,每个重复10头,仔猪于21d龄断奶,饲养至160d龄。测定各阶段猪的生产性能,并分别于1d、7d、21d、28d、66d和160d龄时,每组随机选取4头猪(1头/重复)进行屠宰取样,测定器官指数、血清常规指标、血清激素和HSP70水平。数据分析调用SAS的GLM过程,采用LSMEAN过程进行最小二乘分析,结果发现：IUGR导致猪出生后体重(NBW21.26kg vs. IUGR15.96kg, SEM0.23)和各阶段平均日增重(ADG)显著降低(P<0.05),断奶后各阶段平均日采食量(ADFI)亦显著降低(P<0.05),料重比(F/G)显著升高(P<0.05),表明IUGR损害猪出生后的生长；1-20d、1-160d和67-160d龄内IUGR猪的相对生长率(FGR)分别比NBW猪高36.04%、46.51%和28.06%(P<0.05),提示IUGR猪表现出“补偿生长”现象；与NBW猪相比,IUGR猪出生后血清总蛋白(TP)水平下降9.73%(P<0.05),尿素氮(UN)升高42.75%(P<0.05),表明IUGR对猪蛋白质代谢和利用效率产生不利影响；IUGR对猪出生后血清葡萄糖(Glu)无显著影响(P>0.05),而胰岛素(Ins)水平降低23.45%(P<0.05)；IUGR猪QUICKI、HOMA-IS和G/I指数与NBW猪相比显著升高(P<0.05), HOMA-IR降低(P<0.05),表明IUGR可改善猪的Ins敏感性;IUGR导致猪出生后血清胰岛素样生长因子I (IGF-I)和雌二醇(E2)分别降低12.97%和18.99%(P<0.05),瘦素(+15.38%)显著升高(P<0.05)；IUGR猪出生后血清皮质醇和HSP70水平分别比NBW猪高24.18%和6.11%(P<0.05),提示IUGR对猪产生明显应激影响。总之,IUGR对猪出生后的生长发育产生不利影响。
2IUGR对猪出生后肠道发育的影响
试验设计同1。分离猪的小肠,测定小肠及其黏膜重量、小肠形态学指标、黏膜中二糖酶和碱性磷酸酶(1AP)活性、抗氧化指标、激素和HSP70水平、小肠上皮细胞凋亡和增殖状况及Akt、mTOR、S6K1和FoxO4的磷酸化水平。数据分析同1,结果发现：IUGR显著降低猪出生后小肠(-30.07%)、小肠黏膜(-28.75%)和非黏膜(-30.53%)绝对重量(P<0.05),以及小肠单位长度肠段(-21.87%)和单位长度黏膜(-22.34%)重量(P<0.05),从日龄变化来看,此不利影响至少延续到66d龄；IUGR导致猪十二指肠、空肠前段和后段、回肠的总黏膜厚度(TMT)、绒毛高度(VH)、绒毛高度/绒毛宽度(HWR)、绒毛高度/隐窝深度(VCR)和绒毛表面积(VS)均显著降低(P<0.05),且影响至少持续到160d；IUGR显著降低猪出生后小肠黏膜乳糖酶(-20.31%)、麦芽糖酶(-30.73%)和IPA(-23.74%)活性(P<0.05); IUGR导致猪出生后肠道黏膜组中MDA(+26.98%)和H202水平(+12.68%)显著升高(P<0.05),而T-AOC (-17.28%)、GPx (-17.22%)和SOD (-11.62%)显著降低(P<0.05),表明IUGR导致小肠黏膜抗氧化能力低下,发生氧化应激(OS); IUGR猪出生后,小肠黏膜组织中NOS活性(-15.00%)和NO水平(-22.16%)显著降低(P<0.05),肠道黏膜屏障功能受损；免疫组织化学分析显示,肠道绒毛破损处的HSP70表达增多,IUGR猪黏膜HSP70水平在66d和160d龄时显著降低(P<0.05),但在哺乳期和断奶前后显著升高(P<0.05),表现出机体应激适应性反应。IUGR导致猪出生后小肠上皮细胞凋亡指数(AI,+46.06%)、AI/PI(+52.06%)和黏膜Caspase-3比活性(+14.11%)显著升高(P<0.05),增殖指数(PI,-6.29%)显著降低(P<0.05),提示肠道上皮细胞凋亡和增殖失衡,进而导致肠道形态结构发生改变,肠道生长和功能受损。IUGR导致猪出生后小肠黏膜组织中Ins (-31.34%)、IGF-I (-25.73)和E2(-11.58%)水平均显著下降(P<0.05),肠道黏膜Akt (-49.49%, NBW0.580vs. IUGR0.293, SEM0.018)、mTOR (-31.27%, NBW0.673vs. IUGR0.438, SEM0.020)、S6K1(49.10%, NBW0.269vs. IUGR0.151, SEM0.013)和FoxO4(-50.81%, NBW0.615vs. IUGR0.302, SEM0.023)磷酸化水平降低(P<0.05),这可能是IUGR导致肠道上皮细胞增殖和凋亡稳态发生紊乱,肠道生长发育受损的原因之一。其中,小肠黏膜中E2介导的Akt-FoxO4信号通路可能在猪66d和160d时发挥作用。总之,IUGR损害猪出生后肠道发育,导致猪生长因子分泌减少,肠道黏膜Akt、mTOR和FoxO4活性降低,肠细胞凋亡增加,有丝分裂减少,此可能是导致肠道发育受损的重要原因。
3Arg和SL对哺乳阶段IUGR猪生长和肠道发育的调控
选取18头IUGR仔猪和6头NBW仔猪,自然哺乳至7d龄,将所有IUGR仔猪随机分成三组,分别饲喂基础人工乳(IUGR组)、基础人工乳+0.6%Arg (IUGR+Arg组)和基础人工乳+1.5%SL(IUGR+SL组),所有NBW仔猪饲喂基础人工乳(NBW组),试验期7d。于结束时(14d龄)每组选取4头仔猪进行屠宰取样,测定生长性能和肠道发育相关指标(同1),以及血清和肠道黏膜中游离氨基酸水平。数据分析调用SAS的GLM过程,采用LSMEAN进行最小二乘分析,并进行两两比较。结果发现：
(1)IUGR猪在7-14d龄内补充0.6%的Arg,14d龄体重比IUGR猪提高21.78%(P<0.05),但仍低于NBW猪(P<0.05)；与IUGR猪相比,IUGR+Arg猪ADG和干物质采食量(DMI)分别提高47.30%和21.41%(P<0.05),腹泻率降低61.46%(P<0.05);补充Arg后,IUGR猪血清皮质醇,血清和肠道黏膜中HSP70水平均显著降低(P<0.05),提示IUGR应激减弱；与IUGR猪相比,IUGR+Arg猪血清和小肠黏膜中Arg代谢相关AA (Arg、Orn、Cit和Pro),NO含量和NOS活性显著升高(P<0.05),血清中UN显著降低(P<0.05),Ins水平显著升高(P<0.05),但Glu、 TP、IGF-I、瘦素和E2水平无显著变化(P>0.05),表明Arg对IUGR猪蛋白质代谢和内分泌功能具有一定程度的改善。
日粮中补充Arg,可显著提高7-14d龄内IUGR猪小肠肠重、黏膜和非黏膜的绝对重量和相对重量(P<0.05),以及肠重/长度(P<0.05),提高乳糖酶和麦芽糖酶活性(P<0.05),提高T-AOC和GPx (P<0.05),降低黏膜MDA含量(P<0.05),改善肠道抗氧化功能；IUGR猪补充Arg后,空肠和回肠VH显著升高(P<0.05),回肠TMT和HWR显著升高(P<0.05),空肠和回肠各形态学测量指标与NBW猪相比均无显著差异(P>0.05),表明IUGR猪补充Arg后,可改善IUGR猪小肠肠道形态和消化吸收功能;与IUGR猪相比,14d龄IUGR+Arg猪肠道黏膜Ins水平显著升高(P<0.05), IGF-I也有升高趋势(P>0.05),黏膜Akt和mTOR磷酸化水平分别升高47.09%和60.34%(P<0.05),但S6K1升高不显著(P>0.05)；同时,IUGR+Arg猪肠上皮细胞AI和AI/PI分别比IUGR猪降低42.86%和44.08%(P<0.05)。
(2) IUGR猪在7-14d龄内补充1.5%的SL,仔猪体重和ADG分别升高20.46%和53.32%(P<0.05),但对DMI无显著影响(P<0.05),提示SL可能通过提高养分消化率来改善IUGR仔猪生长性能。与Arg类似,SL可降低IUGR猪血清皮质醇和HSP70水平,缓解IUGR应激；与IUGR猪相比,IUGR+SL猪小肠组织生长加快,形态结构得到改善,黏膜麦芽糖酶和乳糖酶活性显著升高(P<0.05),黏膜T-AOC、 GPx和SOD显著升高(P<0.05), MDA显著下降(P<0.05),提示氧化应激得到缓解；与IUGR猪相比,SL可提高IUGR猪小肠黏膜中Akt(+38.84%)和mTOR(+36.12%)信号通路转导(P<0.05),减少肠细胞凋亡(-24.340%,P<0.05),但Caspase-3比活性无显著变化(P>0.05)；补充SL后,IUGR猪小肠黏膜和血清中AA浓度、黏膜中Ins和IGF-I水平未出现升高(P>0.05),表明Arg和SL对肠道发育的调控机制不同。
总之,在7-14d龄IUGR猪日粮中补充Arg和SL,可促进IUGR猪个体和小肠组织生长,改善肠道形态和功能,这与能与补充Arg和SL后,IUGR猪Ins分泌增加,肠道黏膜Akt和mTOR信号增强,肠细胞凋亡减少有关。
4SL对IUGR猪断奶后生长和肠道发育的调控
选取32头IUGR仔猪和16头NBW仔猪,自然哺乳至21d龄断奶。随后将IUGR仔猪随机分成两组,分别饲喂基础日粮(IUGR组)和基础日粮+1.5%SL (IUGR+SL组),所有NBW仔猪饲喂基础日粮(NBW组),每组4个重复(4头/重复),试验期140d。分别于仔猪28d、66d和160d龄时屠宰取样,生长性能和肠道发育相关指标测定同1,数据分析调用SAS的GLM程序,采用LSMEAN过程进行最小二乘分析,分析日粮添加SL对IUGR的调控效应,并进行两两比较,并与IUGR和NBW猪进行比较,数据结果表明：
(1) IUGR断奶仔猪补充SL后,体重比IUGR猪高14.86%(P<0.05),比NBW猪低10.36%(P<0.05)；SL可显著改善IUGR猪生长性能,加快“补偿生长”,在160d时体重达到NBW仔猪水平(NBW86.14kg vs. IUGR+SL81.05kg, SEM2.41, P>0.05);与IUGR猪相比,IUGR+SL猪血清Ins和E2水平升高(P<0.05),皮质醇水平下降(P<0.05),应激得到缓解；IUGR+SL猪断奶后血清和小肠黏膜中HSP70均高于IUGR猪(P<0.05),提示SL可提高IUGR猪免疫功能和抗应激能力。
(2)与在猪哺乳阶段调控结果类似,SL促进IUGR断奶猪小肠组织生长,缓解氧化应激,对黏膜中NO和NOS无显著影响(P>0.05)；补充SL后,66d和160d龄IUGR猪肠道黏膜Akt磷酸化水平分别升高56.89%和33.56%(P<0.05),IUGR断奶仔猪肠道上皮细胞AI和AI/PI分别下降21.58%和24.00%(P<0.05),小肠各段VH、TMT和VS均显著升高(P<0.05),而肠道黏膜Caspase-3活性、mTOR和FoxO4活性无显著变化(P>0.05)。
总之,在IUGR断奶猪日粮中补充SL,对IUGR猪个体和小肠发育有明显改善,这与能肠道黏膜Akt信号增强,肠细胞凋亡减少有关。
Intrauterine growth retardation (IUGR), a serious problem among human fetuses and polyembryony animals, has long-term adverse effects on fetal physiological function and metabolism. Pig fetuses are born with a high occurrence of15%to20%, and these IUGR piglets show a lower postnatal growth rate, nutrient utilization, meat quality, and health condition. In this study, IUGR piglets and piglets with normal body weight (NWB) were used to investigate the difference of body growth and development of small intestine (SI) from birth to slaughter age (160d) and study the related mechanism. Meanwhile, diet supplemented with L-arginine (Arg) and Soya lecithins (SL) were involved to evaluate the nutrition regulation of the postnatal development in IGUR piglets. This study will further provide evidences of IUGR on growth and SI development in long term and theoretical basis on research in pig production and human medicine.
1Effect of IUGR on body growth in postnatal pigs
Forty NBW newborn piglets and forty IUGR littermates (Duroc×(Landrace×Yorkshire)) were selected to set two groups, each of which had4replicates of10pigs per replicates. The growth performance of piglets was measured. At1d,7d,21d,28d,66d, and160d of age,4pigs in each group with close body weight (BW) were chosen to slaughter and sample. The absolute and relative weight of visceral organs were weighted and calculated, the serum glucose and urea nitrogen were detected by commercial kits, the serum hormones (insulin, IGF-I, leptin, E2, and cortisol) and HSP70level were measured by commercial ELSIA kits. All data were analyzed by LSMEAN using the General Linear Model (GLM) procedures of SAS9.0. The factors of day and IUGR were involved in the statistic model. The results showed that, compared with NBW postnatal piglets, IUGR decreased (P<0.05) the BW (NBW21.26vs. IUGR15.96, SEM0.23) and ADG in postnatal piglets, as well as decreased (P<0.05) the ADFI and increased (P<0.05) the F/G in piglets from weaning to slaughter age. However, the FGR was increased (P<0.05) in IUGR piglets during1to20,1 to160, and67to160d of age by36.04%,46.51%, and28.06%, respectively, which suggested a dramatic catch-up growth. IUGR decreased (P<0.05) the serum total protein (TP) content by9.73%, enhanced (P<0.05) the serum urea nitrogen (UN) level by42.75%in postnatal piglets, which showed delayed protein metabolism and utility efficiency in IUGR postnatal piglets. The serum glucose level was not changed (P>0.05) by IUGR, however, the serum insulin level was decreased (P<0.05) by23.45%, which suggested impaired insulin secretion in postnatal IUGR piglets. In addition, IUGR decreased (P<0.05) the QUICKI, HOMA-IS, and G/I, as well as elevated (P<0.05) the HOMA-IR, these indicated that IUGR improved the insulin sensitive in IUGR postnatal piglets before mature. Compared with IUGR piglets, serum IGF-I and E2levels was decreased (P<0.05) by12.97%and18.99%in postnatal IUGR piglets. However, the serum cortisol and HSP70levels was increased (P<0.05) by24.18%and6.11%, which showed a significant stress of IUGR. In conclusion, IUGR impaired the growth and development of postnatal pigs.
2Effect of IUGR on SI development in postnatal pigs
The pigs used in this part were the same as part1. The absolute and relative weight of SI and its mucosa were weighted and calculated, the SI morphological measurements were measured using a Nikon ECLIPSE80i light microscope with a computer-assisted morphometric system, the mucosal disaccharides and intestinal alkaline phosphatase (IAP) activity, the mucosal anti-oxidation capacity, the mucosal hormones (insulin, IGF-I, leptin, E2, and cortisol) and HSP70level were measured by commercial ELSIA kits, the apoptosis and proliferation of enterocytes were measured by TUNEL kits and immunohistochemistry method, and the phosphorylation of Akt, mTOR, S6K1and FoxO4in SI mucosa were evaluated by Western Blot. All data were analyzed as described in part1. The results showed that, In postnatal piglets, IUGR decreased (P<0.05) the weight of SI by30.07%, mucosa by28.75%, and non-mucosa by30.53%, as well as the intestinal and mucosal weight per length of SI. This showed that IUGR impaired the growth and development of SI, and the adverse effect was persistent up to66d of age at least. The TMT, VH, HWR, VCR and VS of duodenum, proximal and distal jejunum, and ileum were decreased (P<0.05) by IUGR in postnatal piglets. The impaired structure of SI induced by IUGR continued to160d of age at least. IUGR impaired the enzymes mature in SI, the activity of mucosal lactase (-20.31%), maltase (-30.73%), and IPA (-23.74%) was decreased (P<0.05) by IUGR in postnatal piglets. IUGR increased (P<0.05) the content of mucosal MDA (26.98%) and H2O2(12.68%), as well as decreased (P<0.05) the T-AOC (-17.28%), GPx (-17.22%), and SOD (-11.62%), which showed a severe oxidant stress (OS). IUGR also impaired (P<0.05) the activity of NOS (-15.00%), and reduced (P<0.05) the content of NO (-22.16%) in SI mucosa of postnatal piglets. The IHC staining of HSP70showed that, the expression of HSP70was increased in broken villi. ELISA result showed that IUGR increased (P<0.05) the mucosal HSP70content during suckling period and early time after weaning, which HSP70represented the adaptation reaction. However, the content of HSP70was lower (P<0.05) in IUGR piglets compared with NBW piglets at66and160d of age, which HSP70may indicate the capacity of anti-stress. IUGR decreased (P<0.05) the proliferation index (PI) of enterocytes by6.29%, increased (P<0.05) the apoptosis index (AI) by46.06%, AI/PI by52.06%, as well as the mucosal Caspase-3relative activity by14.11%in postnatal piglets. This indicated that, IUGR changed the homeostasis between proliferation and apoptosis of enterocytes, which could impair the structure and growth of SI. The concentration of mucosal insulin (-31.34%), IGF-I (-25.73), and E2(-11.58%) was decreased (P<0.05) by IUGR in postnatal period. Compared with NBW piglets, the phosphorylation of mucosal Akt, mTOR, S6K1, and FoxO4was also reduced (P<0.05) in IUGR piglets by49.49%,31.27%,49.10%, and50.81%, respectively. These indicated that the Akt and mTOR signaling were involved in regulating SI development. In addition, the mucosal E2/Akt/FoxO4pathway might play important roles on SI development in piglets at66and160d of age. In conclusion, IUGR delayed the growth and intestinal development of postnatal piglets. These may due to the decreased growth factors secretion, mucosal Akt, mTOR, and FoxO4activity, as well as imbalanced enterocytes apoptosis and proliferation.
3Dietary supplementation with Arg and SL on body growth and SI development in suckling IUGR piglets
A total of twenty-four piglets including six NBW piglets and eighteen IUGR piglets were selected. All piglets were weaned at7d of age. Then they were assigned equally to four groups:six NBW (Group NBW) and six IUGR piglets fed control diet (Group IUGR), six IUGR piglets fed Arg diet supplemented with0.60%Arg (Group IUGR+Arg), and six IUGR piglets fed Arg diet supplemented with1.50%SL (Group IUGR+SL), respectively from7to14d of age. All piglets were housed individually in plastic floored pens and free access to water. At14d of age,4pigs in each group with close BW were chosen to slaughter and sample. The content of serum AA was measured by HPLC. Other parameters measured were the same as part1. Data were analyzed by LSMEAN using the GLM procedures of SAS9.0. The results showed that,
(1) Dietary supplementation with0.60%Arg in IUGR piglets increased (P<0.05) the14d BW by21.78%, the ADG by47.30%and DMI by21.41%, and decreased (P<0.05) the diarrhea rate by61.46%compared with IUGR piglets fed control diet. However, the14d BW of piglets in IUGR+Arg group was still lower (P<0.05) than that of IUGR piglets. In IUGR piglets, Arg decreased (P<0.05) serum cortisol and HSP70level, and mucosal HSP70content, which indicated a reduced stress effect. Compared with IUGR piglets, diet supplemented by Arg increased (P<0.05) the serum and mucosal concentration of Arg, Orn, Cit, and Pro, the activity of NOS and the content of NO, the level of insulin, and decreased (P<0.05) the serum urea nitrogen in IUGR piglets at14d of age. However, the level of glucose, TP, IGF-I, leptin and E2was not changed (P>0.05) by Arg in IUGR piglets.
In group IUGR+Arg, the weight of SI, its mucosa and non-mucosa, as well as SI weight/length was higher (P<0.05) than that of IUGR piglets. The activity of mucosal lactase and maltase was also elevated (P<0.05) by Arg in IUGR piglets. Arg reduced the content of MDA, and increased the T-AOC and GPx of SI mucosa in IUGR piglets, which suggested improved the anti-oxidation of SI. Arg treated improved the structure of SI in IUGR piglets. The VH of jejunum and ileum, the TMR and HWR of ileum was increased by Arg in IUGR piglets at14d of age.
Dietary supplementation with Arg increased (P<0.05) the mucosal insulin, IGF-I, as well as the phosphorylation of Akt by47.09%and mTOR by60.34%compared with IUGR piglets. Meanwhile, Arg treated decreased (P<0.05) the AI and AI/PI by42.86%and44.08%, respectively, but did not affect the PI (P>0.05).(2) Dietary supplementation with SL in IUGR piglets during suckling period increased (P<0.05) the14d BW and ADG by20.46%and53.32%compared to IUGR piglets. However, the DMI was not changed (P>0.05) by SL supplementation, this indicated that SL improved the growth of IUGR piglets may via increasing the nutrients utility. Similarly as Arg supplementation, SL decreased (P<0.05) the serum cortisol and HSP70levels to reduce IUGR induced stress, increased (P<0.05) the mucosal T-AOC, GPx, and SOD levels and decreased (P<0.05) the content of MDA to relieve OS. The activity of mucosal lactase and maltase was also increased (P<0.05) by SL in IUGR piglets.
Compared with IUGR control piglets, dietary supplementation with SL enhanced (P<0.05) the signaling of Akt and mTOR by38.84%and36.12%, reduced (P<0.05) the AI by24.34%in IUGR piglets. However, the enterocytes PI, mucosal Caspase-3relative activity, AA concentrations, insulin and IGF-I level were not changed by SL supplemented in IUGR piglets. This suggested that the regulation mechanism of SL on body growth and SI development in IUGR piglets differed from Arg supplementation.
Conclusion, diet supplemented with Arg and SL increased the body and intestinal tissue grow, improved the morphology and function of SI. The elevated insulin level, Akt and mTOR activity, and decreased enterocytes apoptosis contributed to these benefit effects.
4Diet supplemented with SL on body growth and SI development in weaning piglets
At the time of birth, sixteen NBW piglets and thirty-two IUGR piglets were selected. All piglets were weaned at21d of age. Then they were assigned equally to three groups:16NBW (Group NBW) and16IUGR piglets fed control diets (Group IUGR), and16IUGR piglets fed Arg diet supplemented with1.50%SL (Group IUGR+SL), respectively from21to160d of age. Each groups had4replicates of4pigs per replicates. All piglets were housed by replicate with ad libitum feeding and drinking. At28d,66d, and160d of age,4pigs in each group with close BW were chosen to slaughter and sample. The indexes measured were the same as part1. Data were analyzed by LSMEAN using the GLM procedures of SAS9.0. The factors of day and SL were involved in the statistic model. The results showed that,
(1) Dietary supplementation with SL increased (P<0.05) the growth performance, improved the catch-up growth. The BW of IUGR+SL piglets at160d of age was not different (P<0.05) from that of NBW piglets. The level of serum insulin and E2was increased by SL in IUGR piglets after weaning. The increased insulin in IUGR+SL piglets was consistent with the increased serum glucose. The serum cortisol level was decreased (P<0.05) by SL supplementation in IUGR piglets after weaning. However, the serum and mucosal HSP70level was increased (P<0.05), which may indicated that SL improved the immune function and anti-stress capacity.
(2) Similarly as the regulation effect on SI of IUGR piglets during suckling period, SL supplemented improve the SI growth, increased (P<0.05) the activity of lactase, maltase and IAP, reduced the OS. However, the NO and NOS were not changed by SL in IUGR piglets after weaning. Dietary supplementation with SL increased (P<0.05) the activity of Akt, reduced (P<0.05) the enterocytes AI, increased (P<0.05) the VH, TMT and VS of SI. However, the mTOR and FoxO4activity was not change by SL supplementation in IUGR piglets after waning.
In conclusion, diet supplemented with SL in weaning piglets improved the body growth and intestinal development. These were closely related to the elevated Akt signal transduction and decreased enterocytes apoptosis.
1IUGR对猪出生后生长的影响
选用40头初生IUGR仔猪(IUGR组)和40头全同胞NBW仔猪(NBW组),每组4个重复,每个重复10头,仔猪于21d龄断奶,饲养至160d龄。测定各阶段猪的生产性能,并分别于1d、7d、21d、28d、66d和160d龄时,每组随机选取4头猪(1头/重复)进行屠宰取样,测定器官指数、血清常规指标、血清激素和HSP70水平。数据分析调用SAS的GLM过程,采用LSMEAN过程进行最小二乘分析,结果发现：IUGR导致猪出生后体重(NBW21.26kg vs. IUGR15.96kg, SEM0.23)和各阶段平均日增重(ADG)显著降低(P<0.05),断奶后各阶段平均日采食量(ADFI)亦显著降低(P<0.05),料重比(F/G)显著升高(P<0.05),表明IUGR损害猪出生后的生长；1-20d、1-160d和67-160d龄内IUGR猪的相对生长率(FGR)分别比NBW猪高36.04%、46.51%和28.06%(P<0.05),提示IUGR猪表现出“补偿生长”现象；与NBW猪相比,IUGR猪出生后血清总蛋白(TP)水平下降9.73%(P<0.05),尿素氮(UN)升高42.75%(P<0.05),表明IUGR对猪蛋白质代谢和利用效率产生不利影响；IUGR对猪出生后血清葡萄糖(Glu)无显著影响(P>0.05),而胰岛素(Ins)水平降低23.45%(P<0.05)；IUGR猪QUICKI、HOMA-IS和G/I指数与NBW猪相比显著升高(P<0.05), HOMA-IR降低(P<0.05),表明IUGR可改善猪的Ins敏感性;IUGR导致猪出生后血清胰岛素样生长因子I (IGF-I)和雌二醇(E2)分别降低12.97%和18.99%(P<0.05),瘦素(+15.38%)显著升高(P<0.05)；IUGR猪出生后血清皮质醇和HSP70水平分别比NBW猪高24.18%和6.11%(P<0.05),提示IUGR对猪产生明显应激影响。总之,IUGR对猪出生后的生长发育产生不利影响。
2IUGR对猪出生后肠道发育的影响
试验设计同1。分离猪的小肠,测定小肠及其黏膜重量、小肠形态学指标、黏膜中二糖酶和碱性磷酸酶(1AP)活性、抗氧化指标、激素和HSP70水平、小肠上皮细胞凋亡和增殖状况及Akt、mTOR、S6K1和FoxO4的磷酸化水平。数据分析同1,结果发现：IUGR显著降低猪出生后小肠(-30.07%)、小肠黏膜(-28.75%)和非黏膜(-30.53%)绝对重量(P<0.05),以及小肠单位长度肠段(-21.87%)和单位长度黏膜(-22.34%)重量(P<0.05),从日龄变化来看,此不利影响至少延续到66d龄；IUGR导致猪十二指肠、空肠前段和后段、回肠的总黏膜厚度(TMT)、绒毛高度(VH)、绒毛高度/绒毛宽度(HWR)、绒毛高度/隐窝深度(VCR)和绒毛表面积(VS)均显著降低(P<0.05),且影响至少持续到160d；IUGR显著降低猪出生后小肠黏膜乳糖酶(-20.31%)、麦芽糖酶(-30.73%)和IPA(-23.74%)活性(P<0.05); IUGR导致猪出生后肠道黏膜组中MDA(+26.98%)和H202水平(+12.68%)显著升高(P<0.05),而T-AOC (-17.28%)、GPx (-17.22%)和SOD (-11.62%)显著降低(P<0.05),表明IUGR导致小肠黏膜抗氧化能力低下,发生氧化应激(OS); IUGR猪出生后,小肠黏膜组织中NOS活性(-15.00%)和NO水平(-22.16%)显著降低(P<0.05),肠道黏膜屏障功能受损；免疫组织化学分析显示,肠道绒毛破损处的HSP70表达增多,IUGR猪黏膜HSP70水平在66d和160d龄时显著降低(P<0.05),但在哺乳期和断奶前后显著升高(P<0.05),表现出机体应激适应性反应。IUGR导致猪出生后小肠上皮细胞凋亡指数(AI,+46.06%)、AI/PI(+52.06%)和黏膜Caspase-3比活性(+14.11%)显著升高(P<0.05),增殖指数(PI,-6.29%)显著降低(P<0.05),提示肠道上皮细胞凋亡和增殖失衡,进而导致肠道形态结构发生改变,肠道生长和功能受损。IUGR导致猪出生后小肠黏膜组织中Ins (-31.34%)、IGF-I (-25.73)和E2(-11.58%)水平均显著下降(P<0.05),肠道黏膜Akt (-49.49%, NBW0.580vs. IUGR0.293, SEM0.018)、mTOR (-31.27%, NBW0.673vs. IUGR0.438, SEM0.020)、S6K1(49.10%, NBW0.269vs. IUGR0.151, SEM0.013)和FoxO4(-50.81%, NBW0.615vs. IUGR0.302, SEM0.023)磷酸化水平降低(P<0.05),这可能是IUGR导致肠道上皮细胞增殖和凋亡稳态发生紊乱,肠道生长发育受损的原因之一。其中,小肠黏膜中E2介导的Akt-FoxO4信号通路可能在猪66d和160d时发挥作用。总之,IUGR损害猪出生后肠道发育,导致猪生长因子分泌减少,肠道黏膜Akt、mTOR和FoxO4活性降低,肠细胞凋亡增加,有丝分裂减少,此可能是导致肠道发育受损的重要原因。
3Arg和SL对哺乳阶段IUGR猪生长和肠道发育的调控
选取18头IUGR仔猪和6头NBW仔猪,自然哺乳至7d龄,将所有IUGR仔猪随机分成三组,分别饲喂基础人工乳(IUGR组)、基础人工乳+0.6%Arg (IUGR+Arg组)和基础人工乳+1.5%SL(IUGR+SL组),所有NBW仔猪饲喂基础人工乳(NBW组),试验期7d。于结束时(14d龄)每组选取4头仔猪进行屠宰取样,测定生长性能和肠道发育相关指标(同1),以及血清和肠道黏膜中游离氨基酸水平。数据分析调用SAS的GLM过程,采用LSMEAN进行最小二乘分析,并进行两两比较。结果发现：
(1)IUGR猪在7-14d龄内补充0.6%的Arg,14d龄体重比IUGR猪提高21.78%(P<0.05),但仍低于NBW猪(P<0.05)；与IUGR猪相比,IUGR+Arg猪ADG和干物质采食量(DMI)分别提高47.30%和21.41%(P<0.05),腹泻率降低61.46%(P<0.05);补充Arg后,IUGR猪血清皮质醇,血清和肠道黏膜中HSP70水平均显著降低(P<0.05),提示IUGR应激减弱；与IUGR猪相比,IUGR+Arg猪血清和小肠黏膜中Arg代谢相关AA (Arg、Orn、Cit和Pro),NO含量和NOS活性显著升高(P<0.05),血清中UN显著降低(P<0.05),Ins水平显著升高(P<0.05),但Glu、 TP、IGF-I、瘦素和E2水平无显著变化(P>0.05),表明Arg对IUGR猪蛋白质代谢和内分泌功能具有一定程度的改善。
日粮中补充Arg,可显著提高7-14d龄内IUGR猪小肠肠重、黏膜和非黏膜的绝对重量和相对重量(P<0.05),以及肠重/长度(P<0.05),提高乳糖酶和麦芽糖酶活性(P<0.05),提高T-AOC和GPx (P<0.05),降低黏膜MDA含量(P<0.05),改善肠道抗氧化功能；IUGR猪补充Arg后,空肠和回肠VH显著升高(P<0.05),回肠TMT和HWR显著升高(P<0.05),空肠和回肠各形态学测量指标与NBW猪相比均无显著差异(P>0.05),表明IUGR猪补充Arg后,可改善IUGR猪小肠肠道形态和消化吸收功能;与IUGR猪相比,14d龄IUGR+Arg猪肠道黏膜Ins水平显著升高(P<0.05), IGF-I也有升高趋势(P>0.05),黏膜Akt和mTOR磷酸化水平分别升高47.09%和60.34%(P<0.05),但S6K1升高不显著(P>0.05)；同时,IUGR+Arg猪肠上皮细胞AI和AI/PI分别比IUGR猪降低42.86%和44.08%(P<0.05)。
(2) IUGR猪在7-14d龄内补充1.5%的SL,仔猪体重和ADG分别升高20.46%和53.32%(P<0.05),但对DMI无显著影响(P<0.05),提示SL可能通过提高养分消化率来改善IUGR仔猪生长性能。与Arg类似,SL可降低IUGR猪血清皮质醇和HSP70水平,缓解IUGR应激；与IUGR猪相比,IUGR+SL猪小肠组织生长加快,形态结构得到改善,黏膜麦芽糖酶和乳糖酶活性显著升高(P<0.05),黏膜T-AOC、 GPx和SOD显著升高(P<0.05), MDA显著下降(P<0.05),提示氧化应激得到缓解；与IUGR猪相比,SL可提高IUGR猪小肠黏膜中Akt(+38.84%)和mTOR(+36.12%)信号通路转导(P<0.05),减少肠细胞凋亡(-24.340%,P<0.05),但Caspase-3比活性无显著变化(P>0.05)；补充SL后,IUGR猪小肠黏膜和血清中AA浓度、黏膜中Ins和IGF-I水平未出现升高(P>0.05),表明Arg和SL对肠道发育的调控机制不同。
总之,在7-14d龄IUGR猪日粮中补充Arg和SL,可促进IUGR猪个体和小肠组织生长,改善肠道形态和功能,这与能与补充Arg和SL后,IUGR猪Ins分泌增加,肠道黏膜Akt和mTOR信号增强,肠细胞凋亡减少有关。
4SL对IUGR猪断奶后生长和肠道发育的调控
选取32头IUGR仔猪和16头NBW仔猪,自然哺乳至21d龄断奶。随后将IUGR仔猪随机分成两组,分别饲喂基础日粮(IUGR组)和基础日粮+1.5%SL (IUGR+SL组),所有NBW仔猪饲喂基础日粮(NBW组),每组4个重复(4头/重复),试验期140d。分别于仔猪28d、66d和160d龄时屠宰取样,生长性能和肠道发育相关指标测定同1,数据分析调用SAS的GLM程序,采用LSMEAN过程进行最小二乘分析,分析日粮添加SL对IUGR的调控效应,并进行两两比较,并与IUGR和NBW猪进行比较,数据结果表明：
(1) IUGR断奶仔猪补充SL后,体重比IUGR猪高14.86%(P<0.05),比NBW猪低10.36%(P<0.05)；SL可显著改善IUGR猪生长性能,加快“补偿生长”,在160d时体重达到NBW仔猪水平(NBW86.14kg vs. IUGR+SL81.05kg, SEM2.41, P>0.05);与IUGR猪相比,IUGR+SL猪血清Ins和E2水平升高(P<0.05),皮质醇水平下降(P<0.05),应激得到缓解；IUGR+SL猪断奶后血清和小肠黏膜中HSP70均高于IUGR猪(P<0.05),提示SL可提高IUGR猪免疫功能和抗应激能力。
(2)与在猪哺乳阶段调控结果类似,SL促进IUGR断奶猪小肠组织生长,缓解氧化应激,对黏膜中NO和NOS无显著影响(P>0.05)；补充SL后,66d和160d龄IUGR猪肠道黏膜Akt磷酸化水平分别升高56.89%和33.56%(P<0.05),IUGR断奶仔猪肠道上皮细胞AI和AI/PI分别下降21.58%和24.00%(P<0.05),小肠各段VH、TMT和VS均显著升高(P<0.05),而肠道黏膜Caspase-3活性、mTOR和FoxO4活性无显著变化(P>0.05)。
总之,在IUGR断奶猪日粮中补充SL,对IUGR猪个体和小肠发育有明显改善,这与能肠道黏膜Akt信号增强,肠细胞凋亡减少有关。
Intrauterine growth retardation (IUGR), a serious problem among human fetuses and polyembryony animals, has long-term adverse effects on fetal physiological function and metabolism. Pig fetuses are born with a high occurrence of15%to20%, and these IUGR piglets show a lower postnatal growth rate, nutrient utilization, meat quality, and health condition. In this study, IUGR piglets and piglets with normal body weight (NWB) were used to investigate the difference of body growth and development of small intestine (SI) from birth to slaughter age (160d) and study the related mechanism. Meanwhile, diet supplemented with L-arginine (Arg) and Soya lecithins (SL) were involved to evaluate the nutrition regulation of the postnatal development in IGUR piglets. This study will further provide evidences of IUGR on growth and SI development in long term and theoretical basis on research in pig production and human medicine.
1Effect of IUGR on body growth in postnatal pigs
Forty NBW newborn piglets and forty IUGR littermates (Duroc×(Landrace×Yorkshire)) were selected to set two groups, each of which had4replicates of10pigs per replicates. The growth performance of piglets was measured. At1d,7d,21d,28d,66d, and160d of age,4pigs in each group with close body weight (BW) were chosen to slaughter and sample. The absolute and relative weight of visceral organs were weighted and calculated, the serum glucose and urea nitrogen were detected by commercial kits, the serum hormones (insulin, IGF-I, leptin, E2, and cortisol) and HSP70level were measured by commercial ELSIA kits. All data were analyzed by LSMEAN using the General Linear Model (GLM) procedures of SAS9.0. The factors of day and IUGR were involved in the statistic model. The results showed that, compared with NBW postnatal piglets, IUGR decreased (P<0.05) the BW (NBW21.26vs. IUGR15.96, SEM0.23) and ADG in postnatal piglets, as well as decreased (P<0.05) the ADFI and increased (P<0.05) the F/G in piglets from weaning to slaughter age. However, the FGR was increased (P<0.05) in IUGR piglets during1to20,1 to160, and67to160d of age by36.04%,46.51%, and28.06%, respectively, which suggested a dramatic catch-up growth. IUGR decreased (P<0.05) the serum total protein (TP) content by9.73%, enhanced (P<0.05) the serum urea nitrogen (UN) level by42.75%in postnatal piglets, which showed delayed protein metabolism and utility efficiency in IUGR postnatal piglets. The serum glucose level was not changed (P>0.05) by IUGR, however, the serum insulin level was decreased (P<0.05) by23.45%, which suggested impaired insulin secretion in postnatal IUGR piglets. In addition, IUGR decreased (P<0.05) the QUICKI, HOMA-IS, and G/I, as well as elevated (P<0.05) the HOMA-IR, these indicated that IUGR improved the insulin sensitive in IUGR postnatal piglets before mature. Compared with IUGR piglets, serum IGF-I and E2levels was decreased (P<0.05) by12.97%and18.99%in postnatal IUGR piglets. However, the serum cortisol and HSP70levels was increased (P<0.05) by24.18%and6.11%, which showed a significant stress of IUGR. In conclusion, IUGR impaired the growth and development of postnatal pigs.
2Effect of IUGR on SI development in postnatal pigs
The pigs used in this part were the same as part1. The absolute and relative weight of SI and its mucosa were weighted and calculated, the SI morphological measurements were measured using a Nikon ECLIPSE80i light microscope with a computer-assisted morphometric system, the mucosal disaccharides and intestinal alkaline phosphatase (IAP) activity, the mucosal anti-oxidation capacity, the mucosal hormones (insulin, IGF-I, leptin, E2, and cortisol) and HSP70level were measured by commercial ELSIA kits, the apoptosis and proliferation of enterocytes were measured by TUNEL kits and immunohistochemistry method, and the phosphorylation of Akt, mTOR, S6K1and FoxO4in SI mucosa were evaluated by Western Blot. All data were analyzed as described in part1. The results showed that, In postnatal piglets, IUGR decreased (P<0.05) the weight of SI by30.07%, mucosa by28.75%, and non-mucosa by30.53%, as well as the intestinal and mucosal weight per length of SI. This showed that IUGR impaired the growth and development of SI, and the adverse effect was persistent up to66d of age at least. The TMT, VH, HWR, VCR and VS of duodenum, proximal and distal jejunum, and ileum were decreased (P<0.05) by IUGR in postnatal piglets. The impaired structure of SI induced by IUGR continued to160d of age at least. IUGR impaired the enzymes mature in SI, the activity of mucosal lactase (-20.31%), maltase (-30.73%), and IPA (-23.74%) was decreased (P<0.05) by IUGR in postnatal piglets. IUGR increased (P<0.05) the content of mucosal MDA (26.98%) and H2O2(12.68%), as well as decreased (P<0.05) the T-AOC (-17.28%), GPx (-17.22%), and SOD (-11.62%), which showed a severe oxidant stress (OS). IUGR also impaired (P<0.05) the activity of NOS (-15.00%), and reduced (P<0.05) the content of NO (-22.16%) in SI mucosa of postnatal piglets. The IHC staining of HSP70showed that, the expression of HSP70was increased in broken villi. ELISA result showed that IUGR increased (P<0.05) the mucosal HSP70content during suckling period and early time after weaning, which HSP70represented the adaptation reaction. However, the content of HSP70was lower (P<0.05) in IUGR piglets compared with NBW piglets at66and160d of age, which HSP70may indicate the capacity of anti-stress. IUGR decreased (P<0.05) the proliferation index (PI) of enterocytes by6.29%, increased (P<0.05) the apoptosis index (AI) by46.06%, AI/PI by52.06%, as well as the mucosal Caspase-3relative activity by14.11%in postnatal piglets. This indicated that, IUGR changed the homeostasis between proliferation and apoptosis of enterocytes, which could impair the structure and growth of SI. The concentration of mucosal insulin (-31.34%), IGF-I (-25.73), and E2(-11.58%) was decreased (P<0.05) by IUGR in postnatal period. Compared with NBW piglets, the phosphorylation of mucosal Akt, mTOR, S6K1, and FoxO4was also reduced (P<0.05) in IUGR piglets by49.49%,31.27%,49.10%, and50.81%, respectively. These indicated that the Akt and mTOR signaling were involved in regulating SI development. In addition, the mucosal E2/Akt/FoxO4pathway might play important roles on SI development in piglets at66and160d of age. In conclusion, IUGR delayed the growth and intestinal development of postnatal piglets. These may due to the decreased growth factors secretion, mucosal Akt, mTOR, and FoxO4activity, as well as imbalanced enterocytes apoptosis and proliferation.
3Dietary supplementation with Arg and SL on body growth and SI development in suckling IUGR piglets
A total of twenty-four piglets including six NBW piglets and eighteen IUGR piglets were selected. All piglets were weaned at7d of age. Then they were assigned equally to four groups:six NBW (Group NBW) and six IUGR piglets fed control diet (Group IUGR), six IUGR piglets fed Arg diet supplemented with0.60%Arg (Group IUGR+Arg), and six IUGR piglets fed Arg diet supplemented with1.50%SL (Group IUGR+SL), respectively from7to14d of age. All piglets were housed individually in plastic floored pens and free access to water. At14d of age,4pigs in each group with close BW were chosen to slaughter and sample. The content of serum AA was measured by HPLC. Other parameters measured were the same as part1. Data were analyzed by LSMEAN using the GLM procedures of SAS9.0. The results showed that,
(1) Dietary supplementation with0.60%Arg in IUGR piglets increased (P<0.05) the14d BW by21.78%, the ADG by47.30%and DMI by21.41%, and decreased (P<0.05) the diarrhea rate by61.46%compared with IUGR piglets fed control diet. However, the14d BW of piglets in IUGR+Arg group was still lower (P<0.05) than that of IUGR piglets. In IUGR piglets, Arg decreased (P<0.05) serum cortisol and HSP70level, and mucosal HSP70content, which indicated a reduced stress effect. Compared with IUGR piglets, diet supplemented by Arg increased (P<0.05) the serum and mucosal concentration of Arg, Orn, Cit, and Pro, the activity of NOS and the content of NO, the level of insulin, and decreased (P<0.05) the serum urea nitrogen in IUGR piglets at14d of age. However, the level of glucose, TP, IGF-I, leptin and E2was not changed (P>0.05) by Arg in IUGR piglets.
In group IUGR+Arg, the weight of SI, its mucosa and non-mucosa, as well as SI weight/length was higher (P<0.05) than that of IUGR piglets. The activity of mucosal lactase and maltase was also elevated (P<0.05) by Arg in IUGR piglets. Arg reduced the content of MDA, and increased the T-AOC and GPx of SI mucosa in IUGR piglets, which suggested improved the anti-oxidation of SI. Arg treated improved the structure of SI in IUGR piglets. The VH of jejunum and ileum, the TMR and HWR of ileum was increased by Arg in IUGR piglets at14d of age.
Dietary supplementation with Arg increased (P<0.05) the mucosal insulin, IGF-I, as well as the phosphorylation of Akt by47.09%and mTOR by60.34%compared with IUGR piglets. Meanwhile, Arg treated decreased (P<0.05) the AI and AI/PI by42.86%and44.08%, respectively, but did not affect the PI (P>0.05).(2) Dietary supplementation with SL in IUGR piglets during suckling period increased (P<0.05) the14d BW and ADG by20.46%and53.32%compared to IUGR piglets. However, the DMI was not changed (P>0.05) by SL supplementation, this indicated that SL improved the growth of IUGR piglets may via increasing the nutrients utility. Similarly as Arg supplementation, SL decreased (P<0.05) the serum cortisol and HSP70levels to reduce IUGR induced stress, increased (P<0.05) the mucosal T-AOC, GPx, and SOD levels and decreased (P<0.05) the content of MDA to relieve OS. The activity of mucosal lactase and maltase was also increased (P<0.05) by SL in IUGR piglets.
Compared with IUGR control piglets, dietary supplementation with SL enhanced (P<0.05) the signaling of Akt and mTOR by38.84%and36.12%, reduced (P<0.05) the AI by24.34%in IUGR piglets. However, the enterocytes PI, mucosal Caspase-3relative activity, AA concentrations, insulin and IGF-I level were not changed by SL supplemented in IUGR piglets. This suggested that the regulation mechanism of SL on body growth and SI development in IUGR piglets differed from Arg supplementation.
Conclusion, diet supplemented with Arg and SL increased the body and intestinal tissue grow, improved the morphology and function of SI. The elevated insulin level, Akt and mTOR activity, and decreased enterocytes apoptosis contributed to these benefit effects.
4Diet supplemented with SL on body growth and SI development in weaning piglets
At the time of birth, sixteen NBW piglets and thirty-two IUGR piglets were selected. All piglets were weaned at21d of age. Then they were assigned equally to three groups:16NBW (Group NBW) and16IUGR piglets fed control diets (Group IUGR), and16IUGR piglets fed Arg diet supplemented with1.50%SL (Group IUGR+SL), respectively from21to160d of age. Each groups had4replicates of4pigs per replicates. All piglets were housed by replicate with ad libitum feeding and drinking. At28d,66d, and160d of age,4pigs in each group with close BW were chosen to slaughter and sample. The indexes measured were the same as part1. Data were analyzed by LSMEAN using the GLM procedures of SAS9.0. The factors of day and SL were involved in the statistic model. The results showed that,
(1) Dietary supplementation with SL increased (P<0.05) the growth performance, improved the catch-up growth. The BW of IUGR+SL piglets at160d of age was not different (P<0.05) from that of NBW piglets. The level of serum insulin and E2was increased by SL in IUGR piglets after weaning. The increased insulin in IUGR+SL piglets was consistent with the increased serum glucose. The serum cortisol level was decreased (P<0.05) by SL supplementation in IUGR piglets after weaning. However, the serum and mucosal HSP70level was increased (P<0.05), which may indicated that SL improved the immune function and anti-stress capacity.
(2) Similarly as the regulation effect on SI of IUGR piglets during suckling period, SL supplemented improve the SI growth, increased (P<0.05) the activity of lactase, maltase and IAP, reduced the OS. However, the NO and NOS were not changed by SL in IUGR piglets after weaning. Dietary supplementation with SL increased (P<0.05) the activity of Akt, reduced (P<0.05) the enterocytes AI, increased (P<0.05) the VH, TMT and VS of SI. However, the mTOR and FoxO4activity was not change by SL supplementation in IUGR piglets after waning.
In conclusion, diet supplemented with SL in weaning piglets improved the body growth and intestinal development. These were closely related to the elevated Akt signal transduction and decreased enterocytes apoptosis.
引文
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