肠道微生态与间歇性低氧的研究进展_Chinese Journal of Respiratory and Critical Care Medicine

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李帅 ¹ , 卢佳琦 ¹ ,  王强 ²

1. ;
2. ;

Corresponding author：

王强, Email: qiangwang97@aliyun.com

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DOI：

10.7507/1671-6205.202209048

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Citation： 李帅, 卢佳琦, 王强. 肠道微生态与间歇性低氧的研究进展. Chinese Journal of Respiratory and Critical Care Medicine, 2023, 22(12): 894-898. doi: 10.7507/1671-6205.202209048 Copy

1.	Poroyko VA, Carreras A, Khalyfa A, et al. Chronic sleep disruption alters gut microbiota, induces systemic and adipose tissue inflammation and insulin resistance in mice. Sci Rep, 2016, 6: 35405.
2.	Koren O, Spor A, Felin J, et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis. P Natl Acad Sci, 2011, 108 Suppl 1(Suppl 1): 4592-4598.
3.	闫燕羽, 刘维英, 刘茹悦, 等. 肠道微生态与呼吸系统疾病的研究进展. 中国呼吸与危重监护杂志, 2022, 21(01): 66-70.
4.	石满杰, 胡瑞宇, 李冰, 等. 肠道菌群失衡在常见呼吸系统疾病中的研究进展. 中国呼吸与危重监护杂志, 2022, 21(03): 215-220.
5.	Anupriya Tripathi, Alexey V Melnik, Jin Xue, et al. Intermittent Hypoxia and Hypercapnia, a Hallmark of Obstructive Sleep Apnea, Alters the Gut Microbiome and Metabolome. mSystems, 2018, 3(3): e00020-00018.
6.	Robles-Vera I, Toral M, Romero M, et al. Antihypertensive effects of probiotics. Curr Hypertens Rep, 2017, 19(4): 26.
7.	Holmes E, Li J V, Marchesi J R, et al. Gut microbiota composition and activity in relation to host metabolic phenotype and disease risk. Cell Metab, 2012, 16(5): 559-564.
8.	Nicholson J K, Holmes E, Kinross J, et al. Host-Gut Microbiota Metabolic Interactions. Science, 2012, 336(6086): 1262-1267.
9.	张奕, 智发朝, 张万岱. 人体不同节段小肠腔菌群和膜菌群的研究. 胃肠病学, 2006(11): 648-652.
10.	Albenberg L, Esipova T V, Judge C P, et al. Correlation between intraluminal oxygen gradient and radial partitioning of intestinal microbiota. Gastroenterology, 2014, 147(5): 1055-1063. e1058.
11.	Espey M G. Role of oxygen gradients in shaping redox relationships between the human intestine and its microbiota. Free Radic Biol Med, 2013, 55: 130-140.
12.	Amyot J, Semache M, Ferdaoussi M, et al. Lipopolysaccharides impair insulin gene expression in isolated islets of Langerhans via Toll-Like Receptor-4 and NF-kappaB signalling. PLoS One, 2012, 7(4): e36200.
13.	Intayoung P, Limtrakul P, S Y. Antiinflammatory activities of crebanine by inhibition of nf-κb and ap-1 activation through suppressing mapks and akt signaling in lps-induced raw264.7 macrophages. Biol Pharm Bull 2016, 39(1): 54-61.
14.	Kim K A, Jeong J J, Yoo S Y, et al. Gut microbiota lipopolysaccharide accelerates inflamm-aging in mice. BMC Microbiol, 2016, 16(1): 9.
15.	邢肖伟, 陶金华, 江曙, 等. 肠道菌群影响黏膜屏障结构与功能的研究进展. 中国微生态学杂志, 2018(6): 725-730.
16.	Taylor C T, Colgan S P. Hypoxia and gastrointestinal disease. J Mol Med (Berl), 2007, 85(12): 1295-1300.
17.	Xu DZ, Lu Q, Kubicka R, et al. The effect of hypoxia/reoxygenation on the cellular function of intestinal epithelial cells. J Trauma, 1999, 46(2): 280-285.
18.	Moreno-Indias I, Cardona F, Tinahones F J, et al. Impact of the gut microbiota on the development of obesity and type 2 diabetes mellitus. Front Microbiol, 2014, 5: 190.
19.	Le Chatelier E, Nielsen T, Qin J, et al. Richness of human gut microbiome correlates with metabolic markers. Nature, 2013, 500(7464): 541-546.
20.	Bonsignore M R, Esquinas C, Barcelo A, et al. Metabolic syndrome, insulin resistance and sleepiness in real-life obstructive sleep apnoea. Eur Respir J, 2012, 39(5): 1136-1143.
21.	Ko C Y, Fan J M, Hu A K, et al. Disruption of sleep architecture in Prevotella enterotype of patients with obstructive sleep apnea‐hypopnea syndrome. Brain Behav, 2019, 9(5): e01287.
22.	Ko C-Y, Liu Q-Q, Su H-Z, et al. Gut microbiota in obstructive sleep apnea–hypopnea syndrome: disease-related dysbiosis and metabolic comorbidities. Clin Sci, 2019, 133(7): 905-917.
23.	Taylor C T, Colgan S P. Regulation of immunity and inflammation by hypoxia in immunological niches. Nat Rev Immunol, 2017, 17(12): 774-785.
24.	Moreno-Indias I, Torres M, Montserrat J M, et al. Intermittent hypoxia alters gut microbiota diversity in a mouse model of sleep apnoea. Eur Respir J, 2015, 45(4): 1055-1065.
25.	Payne A N, Chassard C, Lacroix C. Gut microbial adaptation to dietary consumption of fructose, artificial sweeteners and sugar alcohols: implications for host-microbe interactions contributing to obesity. Obes Rev, 2012, 13(9): 799-809.
26.	Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature, 2011, 473(7346): 174-180.
27.	Cho I, Yamanishi S, Cox L, et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature, 2012, 488(7413): 621-626.
28.	Ohland C L, Macnaughton W K. Probiotic bacteria and intestinal epithelial barrier function. Am J Physiol Gastrointest Liver Physiol, 2010, 298(6): G807-819.
29.	Takada M, Nishida K, Kataoka‐Kato A, et al. Probiotic Lactobacillus casei strain Shirota relieves stress‐associated symptoms by modulating the gut–brain interaction in human and animal models. Neurogastroent Motil, 2016, 28(7): 1027-1036.
30.	Irwin C, McCartney D, Desbrow B, et al. Effects of probiotics and paraprobiotics on subjective and objective sleep metrics: a systematic review and meta-analysis. Eur J Clin Nutr, 2020, 74(11): 1536-1549.
31.	Otte J-M. Functional modulation of enterocytes by gram-positive and gram-negative microorganisms. Am J Physiol Gastrointest Liver Physiol, 2004, 286(4): G613-626.
32.	Cao L, Yang X, Sun F, et al. Lactobacillus strain with high adhesion stimulates intestinal mucin expression in broiler. J Poult Sci, 2012, 49(4): 273-281.
33.	Swanson P A, 2nd, Kumar A, Samarin S, et al. Enteric commensal bacteria potentiate epithelial restitution via reactive oxygen species-mediated inactivation of focal adhesion kinase phosphatases. Proc Natl Acad Sci USA, 2011, 108(21): 8803-8808.
34.	Yan F, Cao H, Cover T L, et al. Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth. Gastroenterology, 2007, 132(2): 562-575.
35.	He Y, Liu Z, Huang Y, et al. Role of the p38MAPK signaling pathway in hippocampal neuron autophagy in rats with chronic intermittent hypoxia. J Neurophysiol, 2021, 126(4): 1112-1121.
36.	Liu Q, Liu Y, Li F, et al. Probiotic culture supernatant improves metabolic function through FGF21-adiponectin pathway in mice. J Nutr Biochem, 2020, 75: 108256.
37.	Liu X, Jin G, Tang Q, et al. Early life Lactobacillus rhamnosus GG colonisation inhibits intestinal tumour formation. Br J Cancer, 2022, 126(10): 1421-1431.
38.	Han X, Lee A, Huang S, et al. Lactobacillus rhamnosus GG prevents epithelial barrier dysfunction induced by interferon-gamma and fecal supernatants from irritable bowel syndrome patients in human intestinal enteroids and colonoids. Gut Microbes, 2019, 10(1): 59-76.
39.	Hu C, Wang P, Yang Y, et al. Chronic Intermittent Hypoxia Participates in the Pathogenesis of Atherosclerosis and Perturbs the Formation of Intestinal Microbiota. Front Cell Infect Microbiol, 2021, 11: 560201.
40.	Hiippala K, Kainulainen V, Kalliomaki M, et al. Mucosal Prevalence and Interactions with the Epithelium Indicate Commensalism of Sutterella spp. Front Microbiol, 2016, 7: 1706.
41.	Gevers D, Kugathasan S, Denson L A, et al. The treatment-naive microbiome in new-onset Crohn's disease. Cell Host Microbe, 2014, 15(3): 382-392.
42.	Ye J, Lv L, Wu W, et al. Butyrate Protects Mice Against Methionine-Choline-Deficient Diet-Induced Non-alcoholic Steatohepatitis by Improving Gut Barrier Function, Attenuating Inflammation and Reducing Endotoxin Levels. Front Microbiol, 2018, 9: 1967.
43.	Zhang Y, Luo H, Niu Y, et al. Chronic intermittent hypoxia induces gut microbial dysbiosis and infers metabolic dysfunction in mice. Sleep Med, 2022, 91: 84-92.
44.	Badran M, Khalyfa A, Ericsson A, et al. Fecal microbiota transplantation from mice exposed to chronic intermittent hypoxia elicits sleep disturbances in naïve mice. Exp Neurol, 2020, 334: 113439.
45.	Lucking E F, O'Connor K M, Strain C R, et al. Chronic intermittent hypoxia disrupts cardiorespiratory homeostasis and gut microbiota composition in adult male guinea-pigs. EBioMedicine, 2018, 38: 191-205.
46.	Ramos-Romero S, Santocildes G, Pinol-Pinol D, et al. Implication of gut microbiota in the physiology of rats intermittently exposed to cold and hypobaric hypoxia. PLoS One, 2020, 15(11): e0240686.
47.	Valentini F, Evangelisti M, Arpinelli M, et al. Gut microbiota composition in children with obstructive sleep apnoea syndrome: a pilot study. Sleep Med, 2020, 76: 140-147.
48.	Kheirandish-Gozal L, Peris E, Wang Y, et al. Lipopolysaccharide-binding protein plasma levels in children: effects of obstructive sleep apnea and obesity. J Clin Endocrinol Metab, 2014, 99(2): 656-663.
49.	Xue J, Allaband C, Zhou D, et al. Influence of Intermittent Hypoxia/Hypercapnia on Atherosclerosis, Gut Microbiome, and Metabolome. Front Physiol, 2021, 12: 663950.
50.	Luo B, Li Y, Zhu M, et al. Intermittent Hypoxia and Atherosclerosis: From Molecular Mechanisms to the Therapeutic Treatment. Oxid Med Cell Longev, 2022, 2022: 1438470.
51.	Sai Manasa Jandhyala, Rupjyoti Talukdar, Chivkula Subramanyam, et al. Role of the normal gut microbiota. World J Gastroentero, 2015, 21(29): 8787-8803.
52.	Grosicki G J, Riemann B L, Flatt A A, et al. Self-reported sleep quality is associated with gut microbiome composition in young, healthy individuals: a pilot study. Sleep Med, 2020, 73: 76-81.
53.	Smith R P, Easson C, Lyle S M, et al. Gut microbiome diversity is associated with sleep physiology in humans. Plos One, 2019, 14(10): e0222394.
54.	Shobatake R, Ota H, Takahashi N, et al. Anorexigenic Effects of Intermittent Hypoxia on the Gut-Brain Axis in Sleep Apnea Syndrome. Int J Mol Sci, 2021, 23(1): 364.
55.	Wallace C J K, Milev R. The effects of probiotics on depressive symptoms in humans: a systematic review. Ann Gen Psychiatr, 2017, 16: 18.
56.	Bravo J A, Forsythe P, Chew M V, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. P Natl Acad Sci USA, 2011, 108(38): 16050-16055.
57.	McVey Neufeld K A, O'Mahony S M, Hoban A E, et al. Neurobehavioural effects of Lactobacillus rhamnosus GG alone and in combination with prebiotics polydextrose and galactooligosaccharide in male rats exposed to early-life stress. Nutr Neurosci, 2019, 22(6): 425-434.

1. Poroyko VA, Carreras A, Khalyfa A, et al. Chronic sleep disruption alters gut microbiota, induces systemic and adipose tissue inflammation and insulin resistance in mice. Sci Rep, 2016, 6: 35405.
2. Koren O, Spor A, Felin J, et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis. P Natl Acad Sci, 2011, 108 Suppl 1(Suppl 1): 4592-4598.
3. 闫燕羽, 刘维英, 刘茹悦, 等. 肠道微生态与呼吸系统疾病的研究进展. 中国呼吸与危重监护杂志, 2022, 21(01): 66-70.
4. 石满杰, 胡瑞宇, 李冰, 等. 肠道菌群失衡在常见呼吸系统疾病中的研究进展. 中国呼吸与危重监护杂志, 2022, 21(03): 215-220.
5. Anupriya Tripathi, Alexey V Melnik, Jin Xue, et al. Intermittent Hypoxia and Hypercapnia, a Hallmark of Obstructive Sleep Apnea, Alters the Gut Microbiome and Metabolome. mSystems, 2018, 3(3): e00020-00018.
6. Robles-Vera I, Toral M, Romero M, et al. Antihypertensive effects of probiotics. Curr Hypertens Rep, 2017, 19(4): 26.
7. Holmes E, Li J V, Marchesi J R, et al. Gut microbiota composition and activity in relation to host metabolic phenotype and disease risk. Cell Metab, 2012, 16(5): 559-564.
8. Nicholson J K, Holmes E, Kinross J, et al. Host-Gut Microbiota Metabolic Interactions. Science, 2012, 336(6086): 1262-1267.
9. 张奕, 智发朝, 张万岱. 人体不同节段小肠腔菌群和膜菌群的研究. 胃肠病学, 2006(11): 648-652.
10. Albenberg L, Esipova T V, Judge C P, et al. Correlation between intraluminal oxygen gradient and radial partitioning of intestinal microbiota. Gastroenterology, 2014, 147(5): 1055-1063. e1058.
11. Espey M G. Role of oxygen gradients in shaping redox relationships between the human intestine and its microbiota. Free Radic Biol Med, 2013, 55: 130-140.
12. Amyot J, Semache M, Ferdaoussi M, et al. Lipopolysaccharides impair insulin gene expression in isolated islets of Langerhans via Toll-Like Receptor-4 and NF-kappaB signalling. PLoS One, 2012, 7(4): e36200.
13. Intayoung P, Limtrakul P, S Y. Antiinflammatory activities of crebanine by inhibition of nf-κb and ap-1 activation through suppressing mapks and akt signaling in lps-induced raw264.7 macrophages. Biol Pharm Bull 2016, 39(1): 54-61.
14. Kim K A, Jeong J J, Yoo S Y, et al. Gut microbiota lipopolysaccharide accelerates inflamm-aging in mice. BMC Microbiol, 2016, 16(1): 9.
15. 邢肖伟, 陶金华, 江曙, 等. 肠道菌群影响黏膜屏障结构与功能的研究进展. 中国微生态学杂志, 2018(6): 725-730.
16. Taylor C T, Colgan S P. Hypoxia and gastrointestinal disease. J Mol Med (Berl), 2007, 85(12): 1295-1300.
17. Xu DZ, Lu Q, Kubicka R, et al. The effect of hypoxia/reoxygenation on the cellular function of intestinal epithelial cells. J Trauma, 1999, 46(2): 280-285.
18. Moreno-Indias I, Cardona F, Tinahones F J, et al. Impact of the gut microbiota on the development of obesity and type 2 diabetes mellitus. Front Microbiol, 2014, 5: 190.
19. Le Chatelier E, Nielsen T, Qin J, et al. Richness of human gut microbiome correlates with metabolic markers. Nature, 2013, 500(7464): 541-546.
20. Bonsignore M R, Esquinas C, Barcelo A, et al. Metabolic syndrome, insulin resistance and sleepiness in real-life obstructive sleep apnoea. Eur Respir J, 2012, 39(5): 1136-1143.
21. Ko C Y, Fan J M, Hu A K, et al. Disruption of sleep architecture in Prevotella enterotype of patients with obstructive sleep apnea‐hypopnea syndrome. Brain Behav, 2019, 9(5): e01287.
22. Ko C-Y, Liu Q-Q, Su H-Z, et al. Gut microbiota in obstructive sleep apnea–hypopnea syndrome: disease-related dysbiosis and metabolic comorbidities. Clin Sci, 2019, 133(7): 905-917.
23. Taylor C T, Colgan S P. Regulation of immunity and inflammation by hypoxia in immunological niches. Nat Rev Immunol, 2017, 17(12): 774-785.
24. Moreno-Indias I, Torres M, Montserrat J M, et al. Intermittent hypoxia alters gut microbiota diversity in a mouse model of sleep apnoea. Eur Respir J, 2015, 45(4): 1055-1065.
25. Payne A N, Chassard C, Lacroix C. Gut microbial adaptation to dietary consumption of fructose, artificial sweeteners and sugar alcohols: implications for host-microbe interactions contributing to obesity. Obes Rev, 2012, 13(9): 799-809.
26. Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature, 2011, 473(7346): 174-180.
27. Cho I, Yamanishi S, Cox L, et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature, 2012, 488(7413): 621-626.
28. Ohland C L, Macnaughton W K. Probiotic bacteria and intestinal epithelial barrier function. Am J Physiol Gastrointest Liver Physiol, 2010, 298(6): G807-819.
29. Takada M, Nishida K, Kataoka‐Kato A, et al. Probiotic Lactobacillus casei strain Shirota relieves stress‐associated symptoms by modulating the gut–brain interaction in human and animal models. Neurogastroent Motil, 2016, 28(7): 1027-1036.
30. Irwin C, McCartney D, Desbrow B, et al. Effects of probiotics and paraprobiotics on subjective and objective sleep metrics: a systematic review and meta-analysis. Eur J Clin Nutr, 2020, 74(11): 1536-1549.
31. Otte J-M. Functional modulation of enterocytes by gram-positive and gram-negative microorganisms. Am J Physiol Gastrointest Liver Physiol, 2004, 286(4): G613-626.
32. Cao L, Yang X, Sun F, et al. Lactobacillus strain with high adhesion stimulates intestinal mucin expression in broiler. J Poult Sci, 2012, 49(4): 273-281.
33. Swanson P A, 2nd, Kumar A, Samarin S, et al. Enteric commensal bacteria potentiate epithelial restitution via reactive oxygen species-mediated inactivation of focal adhesion kinase phosphatases. Proc Natl Acad Sci USA, 2011, 108(21): 8803-8808.
34. Yan F, Cao H, Cover T L, et al. Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth. Gastroenterology, 2007, 132(2): 562-575.
35. He Y, Liu Z, Huang Y, et al. Role of the p38MAPK signaling pathway in hippocampal neuron autophagy in rats with chronic intermittent hypoxia. J Neurophysiol, 2021, 126(4): 1112-1121.
36. Liu Q, Liu Y, Li F, et al. Probiotic culture supernatant improves metabolic function through FGF21-adiponectin pathway in mice. J Nutr Biochem, 2020, 75: 108256.
37. Liu X, Jin G, Tang Q, et al. Early life Lactobacillus rhamnosus GG colonisation inhibits intestinal tumour formation. Br J Cancer, 2022, 126(10): 1421-1431.
38. Han X, Lee A, Huang S, et al. Lactobacillus rhamnosus GG prevents epithelial barrier dysfunction induced by interferon-gamma and fecal supernatants from irritable bowel syndrome patients in human intestinal enteroids and colonoids. Gut Microbes, 2019, 10(1): 59-76.
39. Hu C, Wang P, Yang Y, et al. Chronic Intermittent Hypoxia Participates in the Pathogenesis of Atherosclerosis and Perturbs the Formation of Intestinal Microbiota. Front Cell Infect Microbiol, 2021, 11: 560201.
40. Hiippala K, Kainulainen V, Kalliomaki M, et al. Mucosal Prevalence and Interactions with the Epithelium Indicate Commensalism of Sutterella spp. Front Microbiol, 2016, 7: 1706.
41. Gevers D, Kugathasan S, Denson L A, et al. The treatment-naive microbiome in new-onset Crohn's disease. Cell Host Microbe, 2014, 15(3): 382-392.
42. Ye J, Lv L, Wu W, et al. Butyrate Protects Mice Against Methionine-Choline-Deficient Diet-Induced Non-alcoholic Steatohepatitis by Improving Gut Barrier Function, Attenuating Inflammation and Reducing Endotoxin Levels. Front Microbiol, 2018, 9: 1967.
43. Zhang Y, Luo H, Niu Y, et al. Chronic intermittent hypoxia induces gut microbial dysbiosis and infers metabolic dysfunction in mice. Sleep Med, 2022, 91: 84-92.
44. Badran M, Khalyfa A, Ericsson A, et al. Fecal microbiota transplantation from mice exposed to chronic intermittent hypoxia elicits sleep disturbances in naïve mice. Exp Neurol, 2020, 334: 113439.
45. Lucking E F, O'Connor K M, Strain C R, et al. Chronic intermittent hypoxia disrupts cardiorespiratory homeostasis and gut microbiota composition in adult male guinea-pigs. EBioMedicine, 2018, 38: 191-205.
46. Ramos-Romero S, Santocildes G, Pinol-Pinol D, et al. Implication of gut microbiota in the physiology of rats intermittently exposed to cold and hypobaric hypoxia. PLoS One, 2020, 15(11): e0240686.
47. Valentini F, Evangelisti M, Arpinelli M, et al. Gut microbiota composition in children with obstructive sleep apnoea syndrome: a pilot study. Sleep Med, 2020, 76: 140-147.
48. Kheirandish-Gozal L, Peris E, Wang Y, et al. Lipopolysaccharide-binding protein plasma levels in children: effects of obstructive sleep apnea and obesity. J Clin Endocrinol Metab, 2014, 99(2): 656-663.
49. Xue J, Allaband C, Zhou D, et al. Influence of Intermittent Hypoxia/Hypercapnia on Atherosclerosis, Gut Microbiome, and Metabolome. Front Physiol, 2021, 12: 663950.
50. Luo B, Li Y, Zhu M, et al. Intermittent Hypoxia and Atherosclerosis: From Molecular Mechanisms to the Therapeutic Treatment. Oxid Med Cell Longev, 2022, 2022: 1438470.
51. Sai Manasa Jandhyala, Rupjyoti Talukdar, Chivkula Subramanyam, et al. Role of the normal gut microbiota. World J Gastroentero, 2015, 21(29): 8787-8803.
52. Grosicki G J, Riemann B L, Flatt A A, et al. Self-reported sleep quality is associated with gut microbiome composition in young, healthy individuals: a pilot study. Sleep Med, 2020, 73: 76-81.
53. Smith R P, Easson C, Lyle S M, et al. Gut microbiome diversity is associated with sleep physiology in humans. Plos One, 2019, 14(10): e0222394.
54. Shobatake R, Ota H, Takahashi N, et al. Anorexigenic Effects of Intermittent Hypoxia on the Gut-Brain Axis in Sleep Apnea Syndrome. Int J Mol Sci, 2021, 23(1): 364.
55. Wallace C J K, Milev R. The effects of probiotics on depressive symptoms in humans: a systematic review. Ann Gen Psychiatr, 2017, 16: 18.
56. Bravo J A, Forsythe P, Chew M V, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. P Natl Acad Sci USA, 2011, 108(38): 16050-16055.
57. McVey Neufeld K A, O'Mahony S M, Hoban A E, et al. Neurobehavioural effects of Lactobacillus rhamnosus GG alone and in combination with prebiotics polydextrose and galactooligosaccharide in male rats exposed to early-life stress. Nutr Neurosci, 2019, 22(6): 425-434.

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肠道微生态与间歇性低氧的研究进展

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