目的 探讨婴儿早期肠型和短链脂肪酸（SCFAs）水平变化及其与神经发育相关指标的关联。方法 通过出生队列研究设计,纳入2020年11月至2021年9月在四川大学华西第二医院/华西妇产儿童医院出生的健康足月婴儿163名,分别于出生后0、7、30 d采集粪便样本,在第12月龄时进行ASQ-3问卷评估;根据样本及问卷完整性,在完成ASQ-3问卷评估的69名婴儿中,第0、7、30 d分别纳入38、57、62份健康足月婴儿的粪便样品用于后续16S rRNA测序、气相色谱分析,分析肠型、SCFAs水平与神经发育指标的相关性。结果 婴儿肠道菌群在出生后30 d内呈现显著的时间依赖性演替,肠型从出生时0 d的双歧杆菌优势型（肠型2）逐渐过渡至7 d时链球菌属主导型（肠型1）、30 d时的梭状芽孢杆菌主导型（肠型3）;SCFAs也随时间增长呈动态增长趋势,各时间点梭状芽孢杆菌型（肠型3）的丁酸水平显著高于其他肠型。相关性分析表明,各时间点的肠型与丁酸水平均具有显著的正相关性;第0d肠型与沟通能区得分以及第7 d的肠型与粗大运动能区得分均具有显著的负相关性;而第0 d和30 d的丙酸水平与ASQ-3问卷的解决问题能区、第7 d乙酸水平与精细运动、解决问题、个人-社会能区得分则均呈显著负相关。结论 本研究揭示了婴儿早期肠道菌群动态演替与短链脂肪酸水平的波动性,以及二者与婴儿神经发育水平的关联。
Abstract
Objective To investigate the dynamic changes in early infant enterotypes, the levels of short-chain fatty acids (SCFAs), and their associations with neurodevelopment. Methods Using a birth cohort study design, 163 healthy full-term infants born at West China Second University Hospital/West China Women's and Children's Hospital of Sichuan University between November 2020 and September 2021 were enrolled. Fecal samples were collected on days 0, 7, and 30 after birth, and neurodevelopment was assessed using the ASQ-3 questionnaire at 12 months of age. Based on sample and questionnaire completeness, 69 infants completed the ASQ-3 assessment. A total of 38, 57, and 62 fecal samples from healthy full-term infants were included for subsequent analysis on days 0, 7, and 30, respectively. By integrating 16S rRNA sequencing, gas chromatography analysis, and ASQ-3 assessment, correlations between enterotypes, SCFAs levels, and neurodevelopmental indicators were analyzed. Results Infant gut microbiota underwent significant time-dependent succession within the first 30 days after birth. The enterotype shifted from a Bifidobacterium-dominant profile (enterotype 2) at day 0 to a Streptococcus-dominant profile (enterotype 1) at day 7, and further to a Clostridium-dominant profile (enterotype 3) at day 30. SCFAs levels also increased dynamically over time, with butyrate levels in the Clostridium-dominant enterotype (enterotype 3) being significantly higher than in other enterotypes at each time point. Correlation analyses indicated a significant positive association between enterotype and butyrate levels across all time points. A significant negative correlation was observed between enterotype at day 0 and communication domain scores, as well as between enterotype at day 7 and gross motor domain scores. Furthermore, propionate levels at days 0 and 30 were significantly negatively correlated with problem-solving domain scores on the ASQ-3 questionnaire, while acetate levels at day 7 were significantly negatively correlated with fine motor, problem-solving, and personal-social domain scores. Conclusion This study reveals the dynamic succession of early infant gut microbiota and fluctuations in SCFAs metabolism, as well as their associations with infant neurodevelopmental outcomes.
关键词
婴儿 /
肠型 /
短链脂肪酸 /
神经发育 /
ASQ-3问卷
Key words
infant /
enterotype /
short-chain fatty acids /
neurodevelopment /
ASQ-3 questionnaire
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参考文献
[1] Yadav S, Jha R.Strategies to modulate the intestinal microbiota and their effects on nutrient utilization, performance, and health of poultry[J]. J Anim Sci Biotechnol, 2019, 10: 1–11.
[2] Ramadan YN, Alqifari SF, Alshehri K, et al. Microbiome gut-brain-axis: impact on brain development and mental health[J]. Mol Neurobiol, 2025, 62: 1–21.
[3] Lai S, Yan Y, Pu Y, et al. Enterotypes of the human gut mycobiome[J]. Microbiome, 2023, 1: 179.
[4] 李海亮, 毛绍名, 邓颖, 等. 肠道微生物与过敏性疾病关系研究进展[J]. 中国微生态学杂志, 2017, 29: 6.
[5] Sellin JH, De Soignie R.Short-chain fatty acids have polarized effects on sodium transport and intracellular pH in rabbit proximal colon[J]. Gastroenterology, 1998, 114: 737–747.
[6] Silva YP, Bernardi A, Frozza RL.The role of short-chain fatty acids from gut microbiota in gut-brain communication[J]. Front Endocrinol, 2020, 11: 25.
[7] 杨建新. 什刹海社区儿童发育筛查和追踪调查分析[J].中国全科医学, 2011, 14: 247–248.
[8] Sawhney SS, Thänert R, Thänert A, et al. Gut microbiome evolution from infancy to 8 years of age[J]. Nat Med, 2025,31: 2004–2015.
[9] Vatanen T, Franzosa E A, Schwager R, et al. The human gut microbiome in early-onset type 1 diabetes from the TEDDY study[J]. Nature, 2018, 562: 589–594.
[10] Marques TM, Wall R, Ross RP, et al. Programming infant gut microbiota: influence of dietary and environmental factors[J]. Curr Opin Biotechnol, 2010, 21: 149–156.
[11] Bradley PH, Pollard KS.Proteobacteria explain significant functional variability in the human gut microbiome[J]. Microbiome, 2017, 5: 1–23.
[12] Ouyang R, Ding J, Huang Y, et al. Maturation of the gut metabolome during the first year of life in humans[J]. Gut Microbes, 2023, 15: 19.
[13] Koh A, De Vadder F, Kovatcheva-Datchary P, et al. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites[J]. Cell, 2016, 165: 1332–1345.
[14] 周超,唐含林,徐鹏,等.丁酸盐在小鼠结肠炎损伤中的缓解作用及机制研究[J].免疫学杂志,2020,36:28–33.
[15] Wu J, Huang H, Wang L, et al. A tailored series of engineered yeasts for the cell-dependent treatment of inflammatory bowel disease by rational butyrate supplementation[J]. Gut Microbes, 2024, 16: 1–28.
[16] Bukharin OV, Andryuschenko SV, Perunova NB, et al. Mechanism of persistence of indigenous bifidobacteria under the impact of acetate in the human colon biotope[J]. J Microbiol, Epidemiol Immunobiol, 2021, 98: 276–282.
[17] Nshanian M, Gruber JJ, Geller BS, et al. Short-chain fatty acid metabolites propionate and butyrate are unique epigenetic regulatory elements linking diet, metabolism and gene expression[J]. Nat Metab, 2025, 7: 196–211.
[18] Liu Y, Zhong X, Lin S, et al. Limosilactobacillus reuteri and caffeoylquinic acid synergistically promote adipose browning and ameliorate obesity-associated disorders[J]. Microbiome, 2022, 10: 226.
[19] Ikeda T, Nishida A, Yamano M, et al. Short-chain fatty acid receptors and gut microbiota as therapeutic targets in metabolic, immune, and neurological diseases[J]. Pharmacol Ther, 2022, 239: 1–12.
[20] Serrano JL, Lopes D, Reis MJA, et al. Bis-thiobarbiturates as promising xanthine oxidase inhibitors: synthesis and biological evaluation[J]. Biomedicines, 2021, 9: 1443.
[21] Shao W, Pan B, Li Z, et al. Gut microbiota mediates ambient PM2.5 exposure-induced abnormal glucose metabolism via short-chain fatty acids[J]. J Hazard Mater, 2024, 476: 1–20.
[22] Wang Y, Zhu S, He W, et al. The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia[J]. Basic Res Cardiol, 2024, 119: 1045–1062.
[23] Ling IC, Niu DM, Yang CF, et al. Correlation between toxic organic acid fluctuations and neurodevelopment in patients with methylmalonic acidemia[J]. Orphanet J Rare Dis, 2025, 20: 179.
[24] Silva YP, Bernardi A, Frozza RL.The role of short-chain fatty acids from gut microbiota in gut-brain communication[J]. Front Endocrinol, 2020, 11: 25.
[25] Hung LY, Alves ND, Del Colle A, et al. Intestinal epithelial serotonin as a novel target for treating disorders of gut-brain interaction and mood[J]. Gastroenterology, 2025, 168: 754–768.
基金
国家自然科学基金青年基金(No. 82204037); 中国营养学会营养科研基金(No. CNS-Feihe2022-12)
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