目的 探究低聚果糖(FOS)和低聚半乳糖(GOS)饮食对母体免疫激活(MIA)的孤独症谱系障碍(ASD)大鼠模型的行为及胃肠道功能紊乱的干预作用,为基于肠道功能改善的ASD干预治疗提供新途径。方法 24只Wistar孕鼠随机分为MIA模型组和对照(NS)组。在孕龄15d时,MIA组孕鼠腹腔注射10mg/kg Poly(I∶C),NS组注射相同体积的0.9%无菌生理盐水,3h后活体心脏取血,ELISA法检测IL-6、IFN-γ和TNF-α水平。雄性子代随机分为4组:模型组-普通饲料(MIA-Con)、模型组-益生元饲料(MIA-Fos+Gos)、对照组-普通饲料(NS-Con)、对照组-益生元饲料(NS-Fos+Gos)。MIA-Fos+Gos组和NS-Fos+Gos组从3周断乳开始进行FOS+GOS定制饲料喂养,连续5周。干预结束后进行旷场实验、三箱社交实验、埋珠实验、理毛实验等行为学测试以及粪便含水量和小肠推进率等胃肠道功能评估。结果 与NS组相比,MIA组母鼠血清IL-6、IFN-γ和TNF-α水平显著升高(t=2.390、2.525、2.305,P<0.05),呈免疫激活状态。与NS-Con组相比,MIA-Con组大鼠旷场实验总运动距离、中心区跨越网格线数显著降低,社交能力指数和社交偏好指数下降,埋珠个数增多、理毛时间延长(P<0.05);粪便含水量增加,小肠推进率升高(P<0.05)。给予FOS+GOS饮食干预后,与MIA-Con组相比,MIA-Fos+Gos组大鼠旷场实验总运动距离增加,社交能力指数和社交偏好指数有所提高,埋珠个数减少、理毛时间缩短(P<0.05);粪便含水量和小肠推进率下降(P<0.05)。结论 FOS+GOS饮食可改善MIA所致的ASD子代大鼠的社交缺陷、焦虑刻板行为和胃肠道功能紊乱。
Abstract
Objective To investigate the intervention effects of fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) diets on the behaviors and gastrointestinal dysfunction of rat model of autism spectrum disorder (ASD) induced by maternal immune activation (MIA), in order to provide a new approach for ASD intervention therapy based on intestinal function improvement. Methods Twenty-four Wistar pregnant rats were randomly divided into a MIA model group and a control (NS) group. On gestational day 15 (GD15), pregnant rats in the MIA group were intraperitoneally injected with 10mg/kg of Poly(I∶C), while those in the control group were injected with the same volume of 0.9% sterile saline. Three hours later, blood was collected from the live heart, and the levels of interleukin-6 (IL-6), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) were measured by ELISA. Male offspring were randomly divided into four groups: model group-regular diet (MIA-Con), model group-prebiotic diet (MIA-Fos+Gos), control group-regular diet (NS-Con), and control group-prebiotic diet (NS-Fos+Gos). Rats in the MIA-Fos+Gos and NS-Fos+Gos groups were fed with customized FOS+GOS diets starting from weaning at 3 weeks of age for 5 consecutive weeks. After the intervention, behavioral tests including the open field test, three-chamber social interaction test, marble burying test, and grooming test, as well as gastrointestinal function assessments such as fecal water content and small intestinal transit rate, were conducted. Results Compared with the NS group, the levels of IL-6, IFN-γ, and TNF-α in the serum of pregnant rats in the MIA group significantly increased (t=2.390, 2.525, 2.305, P<0.05), indicating an immune-activated state. Compared with the NS-Con group, rats in the MIA-Con group exhibited significantly decreased total movement distance and number of crossed grid lines in the center zone during the open field test, reduced social ability index and social preference index, increased number of buried marbles, and prolonged grooming time(P<0.05). Additionally, the fecal water content and small intestinal transit rate increased in the MIA-Con group (P<0.05). After the intervention of FOS+GOS diet, compared with the MIA-Con group, rats in the MIA-Fos+Gos group showed that the total movement distance in the open field test of increased, the social ability index and social preference index improved, the number of buried marbles decreased, and the grooming time shortened (P<0.05). Furthermore, the fecal water content and small intestinal propulsion rate decreased in the MIA-Fos+Gos group (P<0.05). Conclusion The FOS+GOS diet could attenuate social deficits, anxiety and stereotypical behaviors, and gastrointestinal dysfunction of male offspring which induced by MIA.
关键词
低聚果糖和低聚半乳糖 /
母体免疫激活 /
孤独症样行为 /
胃肠道功能
Key words
fructo-oligosaccharides and galacto-oligosaccharides /
maternal immune activation /
autism-like behaviors /
gastrointestinal function
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参考文献
[1] Zhou H, Xu X, Yan W, et al. Prevalence of autism spectrum disorder in China: A nationwide multi-center population-based study among children aged 6 to 12 years[J].Neurosci Bull, 2020, 36(9): 961-971.
[2] Gyawali S, Patra BN. Autism spectrum disorder: Trends in research exploring etiopathogenesis[J].Psychiatr Clin Neurosci, 2019, 73(8): 466-475.
[3] Gardner RM, Brynge M, Sjöqvist H, et al. Maternal immune activation and autism in the offspring-what is the evidence for causation?[J].Biol Psychiatr, 2024,S0006-3223(24)01760-8.
[4] Ferguson BJ, Dovgan K, Takahashi N, et al. The relationship among gastrointestinal symptoms, problem behaviors, and internalizing symptoms in children and adolescents with autism spectrum disorder[J].Front Psychiatry, 2019, 10: 194.
[5] Settanni CR, Bibbò S, Ianiro G, et al. Gastrointestinal involvement of autism spectrum disorder: Focus on gut microbiota[J].Expert Rev Gastroenterol Hepatol, 2021, 15(6): 599-622.
[6] Sorboni SG, Moghaddam HS, Jafarzadeh-Esfehani R, et al. A comprehensive review on the role of the gut microbiome in human neurological disorders[J].Clin Microbiol Rev, 2022, 35(1): e0033820.
[7] Burokas A, Arboleya S, Moloney RD, et al. Targeting the microbiota-gut-brain axis: Prebiotics have anxiolytic and antidepressant-like effects and reverse the impact of chronic stress in mice[J].Biol Psychiatry, 2017, 82(7): 472-487.
[8] Zhang S, Lv S, Li Y, et al. Prebiotics modulate the microbiota-gut-brain axis and ameliorate cognitive impairment in APP/PS1 mice[J].Eur J Nutr, 2023, 62(7): 2991-3007.
[9] 王月.脂多糖对孤独症大鼠行为学发育的影响及病理机制[D].合肥:安徽医科大学, 2022.
Wang Y. Effects of lipopolysaccharide on behavioral development and pathological mechanism of autism rats[D].Hefei:Anhui Medical University, 2022.(in Chinese)
[10] Lee GA, Lin YK, Lai JH, et al. Maternal immune activation causes social behavior deficits and hypomyelination in male rat offspring with an autism-like microbiota profile[J].Brain Sci, 2021, 11(8):1085.
[11] 董红晓.孤独症模型大鼠脑星形胶质细胞谷氨酸转运体表达的研究[D].苏州:苏州大学, 2021.
Dong HX. The expression of astrocyte glutamate transporter in rat model of autism[D].Suzhou: Suzhou University, 2021.(in Chinese)
[12] 刘思濛.酪酸梭菌改善自闭症谱系障碍小鼠肠道屏障功能和行为症状的机制研究[D].郑州: 郑州大学, 2019.
Liu SM. Clostridium butyricum modulates intestinal barrier function and behavioral abnormalities in two mouse models of autism spectrum disorder[D].Zhengzhou:Zhengzhou University, 2019.(in Chinese)
[13] Kwon HK, Choi GB, Huh JR. Maternal inflammation and its ramifications on fetal neurodevelopment[J].Trends Immunol, 2022, 43(3): 230-244.
[14] Haddad FL, Patel SV, Schmid S. Maternal immune activation by poly I∶C as a preclinical model for neurodevelopmental disorders: A focus on autism and schizophrenia[J].Neurosci Biobehav Rev, 2020, 113: 546-567.
[15] Gzieło K, Piotrowska D, Litwa E, et al. Maternal immune activation affects socio-communicative behavior in adult rats[J].Sci Rep, 2023, 13(1): 1918.
[16] 叶莎莎,闫俊艳,肖露,等.孕期脂多糖诱导的孤独症样大鼠肠道5-羟色胺相关代谢通路的变化[J].中国病理生理杂志, 2023, 39(4): 577-587.
Ye SS, Yan JY, Xiao L, et al. Changes of colonic 5-hydroxytryptamine-related metabolic pathways in autism-like rats induced by lipopolysaccharide during pregnancy[J].Chinese Journal of Pathophysiology, 2023, 39(4): 577-587.(in Chinese)
[17] Hung LY, Margolis KG. Autism spectrum disorders and the gastrointestinal tract: Insights into mechanisms and clinical relevance[J].Nat Rev Gastroenterol Hepatol, 2024, 21(3): 142-163.
[18] Prince N, Peralta Marzal LN, Markidi A, et al. Prebiotic diet normalizes aberrant immune and behavioral phenotypes in a mouse model of autism spectrum disorder[J].Acta Pharmacol Sin, 2024, 45(8):1591-1603.
[19] Salminen S, Stahl B, Vinderola G, et al. Infant formula supplemented with biotics: Current knowledge and future perspectives[J].Nutrients, 2020, 12(7):1952.
[20] Li H, Wang P, Huang L, et al. Effects of regulating gut microbiota on the serotonin metabolism in the chronic unpredictable mild stress rat model[J].Neurogastroenterol Motil, 2019, 31(10): e13677.
[21] Chunchai T, Thunapong W, Yasom S, et al. Decreased microglial activation through gut-brain axis by prebiotics, probiotics, or synbiotics effectively restored cognitive function in obese-insulin resistant rats[J].J Neuroinflammation, 2018, 15(1): 11.
基金
贺林院士新医学科研基金(JYHL2022MS17)
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