丁酸钠对坏死性小肠结肠炎小鼠脑损伤的保护作用

张玉妮; 张兴道; 贺雨; 艾青; 史源

doi:10.16016/j.2097-0927.202211032

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丁酸钠对坏死性小肠结肠炎小鼠脑损伤的保护作用

基础医学 | 更新时间：2026-01-09

- 丁酸钠对坏死性小肠结肠炎小鼠脑损伤的保护作用
- Protective effect of sodium butyrate on brain injury in mice with necrotizing enterocolitis
- 陆军军医大学学报 2023年45卷第13期页码：1388-1396
- 作者机构：
  
  400014 重庆，重庆医科大学附属儿童医院新生儿科，国家儿童健康与疾病临床医学研究中心，儿童发育疾病研究教育部重点实验室，儿童感染免疫重庆市重点实验室
- 作者简介：
  
  [ 史源，E-mail：shiyuan@hospital.cqmu.edu.cn SHI Yuan, E-mail: shiyuan@hospital.cqmu.edu.cn
- 基金信息：
  
  国家重点研发计划项目(2022YFC2704802)
- DOI：10.16016/j.2097-0927.202211032
  中图分类号： R725.7;R322.81;R914.4
- 收稿：2022-11-06，
  
  修回：2023-02-25，
  
  纸质出版：2023-07-15
- 稿件说明：
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张玉妮, 张兴道, 贺雨, 等. 丁酸钠对坏死性小肠结肠炎小鼠脑损伤的保护作用[J]. 陆军军医大学学报, 2023,45(13):1388-1396.

Yuni ZHANG, Xingdao ZHANG, Yu HE, et al. Protective effect of sodium butyrate on brain injury in mice with necrotizing enterocolitis[J]. Journal of Army Medical University, 2023, 45(13): 1388-1396.
张玉妮, 张兴道, 贺雨, 等. 丁酸钠对坏死性小肠结肠炎小鼠脑损伤的保护作用[J]. 陆军军医大学学报, 2023,45(13):1388-1396. DOI： 10.16016/j.2097-0927.202211032.

Yuni ZHANG, Xingdao ZHANG, Yu HE, et al. Protective effect of sodium butyrate on brain injury in mice with necrotizing enterocolitis[J]. Journal of Army Medical University, 2023, 45(13): 1388-1396. DOI： 10.16016/j.2097-0927.202211032.

摘要

目的

探究丁酸钠对坏死性小肠结肠炎(necrotizing enterocolitis，NEC)小鼠脑损伤的影响。

方法

137只3 d龄C57BL/6新生鼠分为：对照组(CON组，

=40，不与母鼠分离)、NEC+PBS灌胃组(NP组，

=57)和NEC+丁酸钠灌胃组(NB组，

=40)，NP组和NB组分别从3 d龄开始予PBS或丁酸钠灌胃，干预7 d后与母鼠分离，采用人工喂养联合缺氧冷刺激的方法连续3 d刺激建立NEC模型。分析各组小鼠存活率，肠组织病理损伤情况，脑组织TNF-α、IL-6 mRNA水平以及活化的小胶质细胞和星形胶质细胞的表达情况。采用水迷宫实验和透射电镜检测各组成年小鼠学习记忆能力和髓鞘微结构改变。Western blot检测肠组织HMGB1和脑组织TLR4、NF-κB蛋白表达水平。

结果

与CON组相比，NP组小鼠大脑中TNF-α、IL-6 mRNA表达显著上调(1.51±0.20

0.67±0.14，

0.05；2.03±0.39

1.01±0.17，

0.05)，活化的小胶质细胞增加(751.00±82.35

284.70±52.01，

0.05)，星形胶质细胞数量增加(

0.05)，肠组织HMGB1和脑组织TLR4、NF-κB蛋白表达水平显著升高(1.76±0.19

0.73±0.06，

0.0

5；1.14±0.16

0.81±0.01，

0.05；1.21±0.19

0.60±0.15，

0.05)；NP组成年小鼠水迷宫逃避潜伏期延长(

0.05)，平台穿越次数减少(

＜0.05)，G-ratio显著升高(

0.05)。而与NP组相比，NB组小鼠大脑中TNF-α、IL-6 mRNA表达水平降低(0.81±0.12

1.51±0.20，

0.05；0.93±0.38

2.03±0.39，

0.05)，小胶质细胞活化减少(468.00±99.59

751.00±82.35，

0.05)，星形胶质细胞减少(

0.05)，肠组织HMGB1和脑组织TLR4、NF-κB蛋白表达降低(1.22±0.11

1.76±0.19，

0.05；0.88±0.06

1.14±0.16，

0.05；0.70±0.19

1.21±0.19，

0.05)；成年小鼠水迷宫逃避潜伏期缩短(

0.05)，平台穿越次数增加(

＜0.05)，髓鞘厚度增加(

0.05)。

结论

丁酸钠可通过抑制大脑中的TLR4-NF-κB通路减轻神经炎症反应，从而发挥对NEC远期相关脑损伤的保护作用。

Abstract

Objective

To explore the effect of sodium butyrate on brain injury in mice with necrotizing enterocolitis (NEC).

Methods

A total of 137 3-day-old C57BL/6 mice were randomly divided into Control group (CON group

=40

without maternal separation)

NEC+PBS group (NP group

=57) and NEC+butyrate group (NB group

=40). The mice from the NP and NB groups were separated maternally and given either PBS or sodium butyrate by gavage from postnatal day 3 for 7 consecutive days

then a NEC model was established by formula feeding combined with hypoxia and hypothermia for 3 consecutive days. Survival rate

histopathological injury of the intestine

mRNA expression of TNF-α and IL-6 in the brain

and number of activated microglia and astrocytes were observed and detected. Morris water maze and transmission electron microscopy were employed to

observe the long-term cognitive impairment and microstructure of myelin

respectively

for the adult mice (4 weeks old). Western blotting was used to measure the protein level of HMGB1 in the intestine and TLR4 as well as NF-κB in the brain.

Results

Compared with the CON group

the mice of the NP group showed increased mRNA expression of TNF-α(1.51± 0.20

0.67±0.14) and IL-6 (2.03±0.39

1.01±0.17) in the brain (both

0.05)

raised number of activated microglia (751.00±82.35

284.70±52.01

0.05) and astrocytes (

0.05) in the hippocampus

and elevated protein levels of HMGB1 (1.76±0.19

0.73±0.06) in the intestine as well as TLR4 (1.14±0.16

0.81±0.01) and NF-κB (1.21±0.19

0.60±0.15) in the brain (all

0.05). In addition

the adult mice in the NP group demonstrated the prolonged escape latency and decreased crossing-platform times

and increased G-ratio (all

0.05). After the administration of sodium butyrate

the mRNA expression levels of TNF-α(0.81±0.12

1.51±0.20) and IL-6 (0.93±0.38

2.03±0.39) in the brain were decreased

the activation of microglia was inhibited (468.00±99.59

751.00±82.35)

and the number of astrocytes was reduced (all

0.05). The decreased expression levels of HMGB1 (1.22±0.11

1.76±0.19) in the intestine and TLR4 (0.88±0.06

1.14±0.16) and NF-κB (0.70±0.19

1.21±0.19) in the brain were also marked in the NB group (all

0.05). The adult mice of the NB group showed shortened escape latency

and increased crossing-platform times and myelin thickness (all

0.05).

Conclusion

Sodium butyrate alleviates the neuroinflammation by inhibiting the activation of TLR4-NF-κB signal pathway in the NEC brain

and thus exerts protective effect against NEC-associated brain injury.

关键词

Keywords

references

NEU J, PAMMI M. Necrotizing enterocolitis: the intestinal microbiome, metabolome and inflammatory mediators[J]. Semin Fetal Neonatal Med, 2018, 23(6): 400-405. DOI: 10.1016/j.siny.2018.08.001.

NEU J, WALKER W A. Necrotizing enterocolitis[J]. N Engl J Med, 2011, 364(3): 255-264. DOI: 10.1056/NEJMra1005408.

STOLL B J, HANSEN N I, BELL E F, et al . Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012[J ] . JAMA, 2015, 314(10): 1039-1051. DOI: 10.1001/jama.2015.10244.

REES C M, EATON S, PIERRO A. National prospective surveillance study of necrotizing enterocolitis in neonatal intensive care units[J]. J Pediatr Surg, 2010, 45(7): 1391-1397. DOI: 10.1016/j.jpedsurg.2009.12.002.

ROBINSON J R, KENNEDY C, VAN ARENDONK K J, et al . Neurodevelopmental considerations in surgical necrotizing enterocolitis[J ] . Semin Pediatr Surg, 2018, 27(1): 52-56. DOI: 10.1053/j.sempedsurg.2017.11.010.

REES C M, PIERRO A, EATON S. Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis[J]. Arch Dis Child Fetal Neonatal Ed, 2007, 92(3): F193-F198. DOI: 10.1136/adc.2006.099929.

NIÑO D F, ZHOU Q J, YAMAGUCHI Y, et al . Cognitive impairments induced by necrotizing enterocolitis can be prevented by inhibiting microglial activation in mouse brain[J ] . Sci Transl Med, 2018, 10(471): eaan0237. DOI: 10.1126/scitranslmed.aan0237.

BIOUSS G, ANTOUNIANS L, LI B, et al . Experimental necrotizing enterocolitis induces neuroinflammation in the neonatal brain[J ] . J Neuroinflam, 2019, 16(1): 97. DOI: 10.1186/s12974-019-1481-9.

QIN C, ZHOU L Q, MA X T, et al . Dual functions of microglia in ischemic stroke[J ] . Neurosci Bull, 2019, 35(5): 921-933. DOI: 10.1007/s12264-019-00388-3.

DENG Y Y, XIE D, FANG M, et al . Astrocyte-derived proinflammatory cytokines induce hypomyelination in the periventricular white matter in the hypoxic neonatal brain[J ] . PLoS One, 2014, 9(1): e87420. DOI: 10.1371/journal.pone.0087420.

FURUSAWA Y, OBATA Y, FUKUDA S, et al . Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells[J ] . Nature, 2013, 504(7480): 446-450. DOI: 10.1038/nature12721.

PATNALA R, ARUMUGAM T V, GUPTA N, et al . HDAC inhibitor sodium butyrate-mediated epigenetic regulation enhances neuroprotective function of microglia during ischemic stroke[J ] . Mol Neurobiol, 2017, 54(8): 6391-6411. DOI: 10.1007/s12035-016-0149-z.

CHEN T, NOTO D, HOSHINO Y, et al . Butyrate suppresses demyelination and enhances remyelination[J ] . J Neuroinflammation, 2019, 16(1): 165. DOI: 10.1186/s12974-019-1552-y.

SUN Q, JI Y C, WANG Z L, et al . Sodium butyrate alleviates intestinal inflammation in mice with necrotizing enterocolitis[J ] . Mediators Inflamm, 2021, 2021: 6259381. DOI: 10.1155/2021/6259381.

李秋平, 余加林, 胡坤, 等. 丁酸对新生儿坏死性小肠结肠炎新生小鼠模型的保护作用[J]. 解放军医学杂志, 2018, 43(3): 201-205. DOI: 10.11855/j.issn.0577-7402.2018.03.04.

LI Q P, YU J L, HU K, et al . Protective effect of sodium butyrate on the neonatal mouse model of necrotizing enterocolitis[J ] . Med J Chin PLA, 2018, 43(3): 201-205. DOI: 10.11855/j.issn.0577-7402.2018.03.04.

YU X Y, RADULESCU A, ZORKO N, et al . Heparin-binding EGF-like growth factor increases intestinal microvascular blood flow in necrotizing enterocolitis[J ] . Gastroenterology, 20 09, 137(1): 221-230. DOI: 10.1053/j.gastro.2009.03.060.

ZHU F, WANG L Y, GONG Z Z, et al . Blockage of NLRP3 inflammasome activation ameliorates acute inflammatory injury and long-term cognitive impairment induced by necrotizing enterocolitis in mice[J ] . J Neuroinflammation, 2021, 18(1): 66. DOI: 10.1186/s12974-021-02111-4.

WADHAWAN R, OH W, HINTZ S R, et al . Neurodevelopmental outcomes of extremely low birth weight infants with spontaneous intestinal perforation or surgical necrotizing enterocolitis[J ] . J Perinatol, 2014, 34(1): 64-70. DOI: 10.1038/jp.2013.128.

MATEI A, MONTALVA L, GOODBAUM A, et al . Neurodevelopmental impairment in necrotising enterocolitis survivors: systematic review and meta-analysis[J ] . Arch Dis Child Fetal Neonatal Ed, 2020, 105(4): 432-439. DOI: 10.1136/archdischild-2019-317830.

SUN J, PAN X Y, CHRISTIANSEN L I, et al . Necrotizing enterocolitis is associated with acute brain responses in preterm pigs[J ] . J Neuroinflam, 2018, 15(1): 180. DOI: 10.1186/s12974-018-1201-x.

BACK S A. White matter injury in the preterm infant: pathology and mechanisms[J]. Acta Neuropathol, 2017, 134(3): 331-349. DOI: 10.1007/s00401-017-1718-6.

YAMAWAKI Y, YOSHIOKA N, NOZAKI K, et al . Sodium butyrate abolishes lipopolysaccharide-induced depression-like behaviors and hippocampal microglial activation in mice[J ] . Brain Res, 2018, 1680: 13-38. DOI: 10.1016/j.brainres.2017.12.004.

HUUSKONEN J, SUURONEN T, NUUTINEN T, et al . Regulation of microglial inflammatory response by sodium butyrate and short-chain fatty acids[J ] . Br J Pharmacol, 2004, 141(5): 874-880. DOI: 10.1038/sj.bjp.0705682.

LIU H, ZHANG J J, LI X, et al . Post-occlusion administration of sodium butyrate attenuates cognitive impairment in a rat model of chronic cerebral hypoperfusion[J ] . Pharmacol Biochem Behav, 2015, 135: 53-59. DOI: 10.1016/j.pbb.2015.05.012.

SUN J, WANG F Y, LI H X, et al . Neuroprotective effect of sodium butyrate against cerebral ischemia/reperfusion injury in mice[J ] . Biomed Res Int, 2015, 2015: 395895. DOI: 10.1155/2015/395895.

ANDERSSON U, YANG H, HARRIS H. Extracellular HMGB1 as atherapeutic target in inflammatory diseases[J]. Expert Opin Ther Targets, 2018, 22(3): 263-277. DOI: 10.1080/14728222.2018.1439924.

ZAMORA R, GRISHIN A, WONG C, et al . High-mobility group box 1 protein is an inflammatory mediator in necrotizing enterocolitis: protective effect of the macrophage deactivator semapimod[J ] . Am J Physiol Gastrointest Liver Physiol, 2005, 289(4): G643-G652. DOI: 10.1152/ajpgi.00067.2005.

LIANG X, WANG R S, WANG F, et al . Sodium butyrate protects against severe burn-induced remote acute lung injury in rats[J ] . PLoS One, 2013, 8(7): e68786. DOI: 10.1371/journal.pone.0068786.

YANG F, WANG L K, LI X, et al . Sodium butyrate protects against toxin-induced acute liver failure in rats[J ] . Hepatobiliary Pancreat Dis Int, 2014, 13(3): 309-315. DOI: 10.1016/s1499-3872(14)60044-8.

ZHANG T, XIA M, ZHAN Q, et al . Sodium butyrate reduces organ injuries in mice with severe acute pancreatitis through inhibiting HMGB1 expression[J ] . Dig Dis Sci, 2015, 60(7): 1991-1999. DOI: 10.1007/s10620-015-3586-z.

LI N, LIU X X, HONG M, et al . Sodium butyrate allevia tes LPS-induced acute lung injury in mice via inhibiting HMGB1 release[J ] . Int Immunopharmacol, 2018, 56: 242-248. DOI: 10.1016/j.intimp.2018.01.017..

SHI L M, LIN Q L, YANG T, et al . Oral administration of Lentinus edodes β-glucans ameliorates DSS-induced ulcerative colitis in mice via MAPK-Elk-1 and MAPK-PPARγ pathways[J ] . Food Funct, 2016, 7(11): 4614-4627. DOI: 10.1039/C6FO01043A. [LinkOut ] .

LI C L, AI G X, WANG Y F, et al . Oxyberberine, a novel gut microbiota-mediated metabolite of berberine, possesses superior anti-colitis effect: impact on intestinal epithelial barrier, gut microbiota profile and TLR4-MyD88-NF-κB pathway[J ] . Pharmacol Res, 2020, 152: 104603. DOI: 10.1016/j.phrs.2019.104603.

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