短链脂肪酸在2型糖尿病中的作用研究进展

doi:10.12114/j.issn.1007-9572.2023.0533

摘要/Abstract

摘要： 短链脂肪酸（SCFAs）在肠道微生物群调控宿主代谢中起到了主要介导作用，且与2型糖尿病（T2DM）密切相关，可改善T2DM患者的血糖、体质量和血脂指标。尽管有学者认为SCFAs有望成为T2DM的新型治疗靶点，但目前尚未有相关综述。本文总结了短链脂肪酸的生物学特性，讨论了SCFAs调节食欲、炎症、胰岛β细胞、脂质代谢与肝脏糖原代谢的证据，进一步明确调控SCFAs在T2DM中的作用及其研究进展，探讨了调控SCFAs治疗T2DM的潜力。

关键词: 糖尿病，2型, 短链脂肪酸, 胃肠道微生物组, 代谢, 研究进展

Abstract:

Short-chain fatty acids (SCFAs) play a major mediating role in gut microbiota regulation of host metabolism and are strongly associated with type 2 diabetes mellitus (T2DM), which improves glycemic, body weight, and lipid indices in T2DM patients. Although it has been suggested that SCFAs are expected to be novel therapeutic targets for T2DM, no review has been conducted. Therefore, this paper summarizes the biological properties of SCFAs, discusses the evidence that SCFAs regulate appetite, inflammation, pancreatic β-cells, lipid metabolism and hepatic glycogen metabolism, further clarifies the progress of research on regulating the role of SCFAs in T2DM and their mechanisms, and explores the potential of regulating SCFAs for the treatment of T2DM.

Key words: Diabetes mellitus, type 2, Short chain fatty acid, Gastrointestinal microbiome, Metabolism, Research progress

中图分类号:

R 587.1

姜荣生,张龙,管其凡,等. 短链脂肪酸在2型糖尿病中的作用研究进展[J]. 中国全科医学, 2024, 27(24): 3031-3037. DOI: 10.12114/j.issn.1007-9572.2023.0533.
JIANG Rongsheng,ZHANG Long,GUAN Qifan, et al. Advances in the Role of Short-chain Fatty Acids in Type 2 Diabetes[J]. Chinese General Practice, 2024, 27(24): 3031-3037. DOI: 10.12114/j.issn.1007-9572.2023.0533.

参考文献 78

[1]	GBD Causes of Death Collaborators. Global，regional，and national age-sex-specific mortality for 282 causes of death in 195 countries and territories，1980-2017：a systematic analysis for the Global Burden of Disease Study 2017[J]. Lancet，2018，392（10159）：1736-1788. DOI：10.1016/S0140-6736(18)32203-7.
[2]	CANFORA E E，MEEX R C R，VENEMA K，et al. Gut microbial metabolites in obesity，NAFLD and T2DM[J]. Nat Rev Endocrinol，2019，15（5）：261-273. DOI：10.1038/s41574-019-0156-z.
[3]	VITALE M，GIACCO R，LAIOLA M，et al. Acute and chronic improvement in postprandial glucose metabolism by a diet resembling the traditional Mediterranean dietary pattern：can SCFAs play a role?[J]. Clin Nutr，2021，40（2）：428-437. DOI：10.1016/j.clnu.2020.05.025.
[4]	PALACIOS T，VITETTA L，COULSON S，et al. Targeting the intestinal microbiota to prevent type 2 diabetes and enhance the effect of metformin on glycaemia：a randomised controlled pilot study[J]. Nutrients，2020，12（7）：2041. DOI：10.3390/nu12072041.
[5]	YADAV H，LEE J H，LLOYD J，et al. Beneficial metabolic effects of a probiotic via butyrate-induced GLP-1 hormone secretion[J]. J Biol Chem，2013，288（35）：25088-25097. DOI：10.1074/jbc.M113.452516.
[6]	HE J，ZHANG P W，SHEN L Y，et al. Short-chain fatty acids and their association with signalling pathways in inflammation，glucose and lipid metabolism[J]. Int J Mol Sci，2020，21（17）：6356. DOI：10.3390/ijms21176356.
[7]	MACFARLANE G T，MACFARLANE S. Bacteria，colonic fermentation，and gastrointestinal health[J]. J AOAC Int，2012，95（1）：50-60. DOI：10.5740/jaoacint.sge_macfarlane.
[8]	FREELAND K R，WILSON C，WOLEVER T M S. Adaptation of colonic fermentation and glucagon-like peptide-1 secretion with increased wheat fibre intake for 1 year in hyperinsulinaemic human subjects[J]. Br J Nutr，2010，103（1）：82-90. DOI：10.1017/S0007114509991462.
[9]	TERAMAE H，YOSHIKAWA T，INOUE R，et al. The cellular expression of SMCT2 and its comparison with other transporters for monocarboxylates in the mouse digestive tract[J]. Biomed Res，2010，31（4）：239-249. DOI：10.2220/biomedres.31.239.
[10]	BLOEMEN J G，VENEMA K，VAN DE POLL M C，et al. Short chain fatty acids exchange across the gut and liver in humans measured at surgery[J]. Clin Nutr，2009，28（6）：657-661. DOI：10.1016/j.clnu.2009.05.011.
[11]	PARADA VENEGAS D，DE LA FUENTE M K，LANDSKRON G，et al. Short chain fatty acids （SCFAs）-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases[J]. Front Immunol，2019，10：277. DOI：10.3389/fimmu.2019.00277.
[12]	MATHEWSON N D，JENQ R，MATHEW A V，et al. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease[J]. Nat Immunol，2016，17（5）：505-513. DOI：10.1038/ni.3400.
[13]	VADDER F D，KOVATCHEVA-DATCHARY P，GONCALVES D，et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits[J]. Cell，2014，156（1/2）：84-96. DOI：10.1016/j.cell.2013.12.016.
[14]	BROWN A J，GOLDSWORTHY S M，BARNES A A，et al. The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids[J]. J Biol Chem，2003，278（13）：11312-11319. DOI：10.1074/jbc.M211609200.
[15]	POUL E L，LOISON C，STRUYF S，et al. Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation[J]. J Biol Chem，2003，278（28）：25481-25489. DOI：10.1074/jbc.M301403200.
[16]	FLOCK T，HAUSER A S，LUND N，et al. Selectivity determinants of GPCR-G-protein binding[J]. Nature，2017，545（7654）：317-322. DOI：10.1038/nature22070.
[17]	HOUSLAY M D，MILLIGAN G. Tailoring cAMP-signalling responses through isoform multiplicity[J]. Trends Biochem Sci，1997，22（6）：217-224. DOI：10.1016/s0968-0004(97)01050-5.
[18]	MILLIGAN G. G protein-coupled receptors not currently in the spotlight：free fatty acid receptor 2 and GPR35[J]. Br J Pharmacol，2018，175（13）：2543-2553. DOI：10.1111/bph.14042.
[19]	KIMURA I，ICHIMURA A，OHUE-KITANO R，et al. Free fatty acid receptors in health and disease[J]. Physiol Rev，2020，100（1）：171-210. DOI：10.1152/physrev.00041.2018.
[20]	TUNARU S，KERO J，SCHAUB A，et al. PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect[J]. Nat Med，2003，9（3）：352-355. DOI：10.1038/nm824.
[21]	OFFERMANNS S. Hydroxy-carboxylic acid receptor actions in metabolism[J]. Trends Endocrinol Metab，2017，28（3）：227-236. DOI：10.1016/j.tem.2016.11.007.
[22]	KAYE D M，SHIHATA W A，JAMA H A，et al. Deficiency of prebiotic fiber and insufficient signaling through gut metabolite-sensing receptors leads to cardiovascular disease[J]. Circulation，2020，141（17）：1393-1403. DOI：10.1161/CIRCULATIONAHA.119.043081.
[23]	WANG N，GUO D Y，TIAN X，et al. Niacin receptor GPR109A inhibits insulin secretion and is down-regulated in type 2 diabetic islet beta-cells[J]. General & Comparative Endocrinology，2016，237：98-108. DOI：10.1016/j.ygcen.2016.08.011.
[24]	SUN M M，WU W，LIU Z J，et al. Microbiota metabolite short chain fatty acids，GPCR，and inflammatory bowel diseases[J]. J Gastroenterol，2017，52（1）：1-8. DOI：10.1007/s00535-016-1242-9.
[25]	SEALY L，CHALKLEY R. The effect of sodium butyrate on histone modification[J]. Cell，1978，14（1）：115-121. DOI：10.1016/0092-8674(78)90306-9.
[26]	JOHNSTONE R W. Histone-deacetylase inhibitors：novel drugs for the treatment of cancer[J]. Nat Rev Drug Discov，2002，1（4）：287-299. DOI：10.1038/nrd772.
[27]	WALDECKER M，KAUTENBURGER T，DAUMANN H，et al. Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon[J]. J Nutr Biochem，2008，19（9）：587-593. DOI：10.1016/j.jnutbio.2007.08.002.
[28]	SOLIMAN M L，ROSENBERGER T A. Acetate supplementation increases brain histone acetylation and inhibits histone deacetylase activity and expression[J]. Mol Cell Biochem，2011，352（1/2）：173-180. DOI：10.1007/s11010-011-0751-3.
[29]	MURPHY K G，BLOOM S R. Gut hormones and the regulation of energy homeostasis[J]. Nature，2006，444（7121）：854-859. DOI：10.1038/nature05484.
[30]	FREELAND K R，WOLEVER T M S. Acute effects of intravenous and rectal acetate on glucagon-like peptide-1，peptide YY，ghrelin，adiponectin and tumour necrosis factor-alpha[J]. Br J Nutr，2010，103（3）：460-466. DOI：10.1017/S0007114509991863.
[31]	KAJI I，KARAKI S，KUWAHARA A. Short-chain fatty acid receptor and its contribution to glucagon-like peptide-1 release[J]. Digestion，2014，89（1）：31-36. DOI：10.1159/000356211.
[32]	BROOKS L，VIARDOT A，TSAKMAKI A，et al. Fermentable carbohydrate stimulates FFAR2-dependent colonic PYY cell expansiontoincrease satiety[J]. Mol Metab，2017，6（1）：48-60. DOI：10.1016/j.molmet.2016.10.011.
[33]	TOLHURST G，HEFFRON H，LAM Y S，et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2[J]. Diabetes，2012，61（2）：364-371. DOI：10.2337/db11-1019.
[34]	KRIEGER J P，ARNOLD M，PETTERSEN K G，et al. Knockdown of GLP-1 receptors in vagal afferents affects normal food intake and glycemia[J]. Diabetes，2016，65（1）：34-43. DOI：10.2337/db15-0973.
[35]	ABBOTT C R，MONTEIRO M，SMALL C J，et al. The inhibitory effects of peripheral administration of peptide YY（3-36） and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal-brainstem-hypothalamic pathway[J]. Brain Res，2005，1044（1）：127-131. DOI：10.1016/j.brainres.2005.03.011.
[36]	DELZENNE N，BLUNDELL J，BROUNS F，et al. Gastrointestinal targets of appetite regulation in humans[J]. Obes Rev，2010，11（3）：234-50.
[37]	DALAMAGA M，CHOU S H，SHIELDS K，et al. Leptin at the intersection of neuroendocrinology and metabolism：current evidence and therapeutic perspectives [J]. Cell metabolism，2013，18（1）：29-42.
[38]	KIMURA I，OZAWA K，INOUE D，et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43 [J]. Nature Communications，2013，4：1829.
[39]	RAHAT-ROZENBLOOM S，FERNANDES J，CHENG J，et al. Acute increases in serum colonic short-chain fatty acids elicited by inulin do not increase GLP-1 or PYY responses but may reduce ghrelin in lean and overweight humans[J]. Eur J Clin Nutr，2017，71（8）：953-958. DOI：10.1038/ejcn.2016.249.
[40]	FUKUMORI R，SUGINO T，HASEGAWA Y，et al. Plasma ghrelin concentration is decreased by short chain fatty acids in wethers[J]. Domest Anim Endocrinol，2011，41（1）：50-55. DOI：10.1016/j.domaniend.2011.04.001.
[41]	SOHAIL M U，ALTHANI A，ANWAR H，et al. Role of the gastrointestinal tract microbiome in the pathophysiology of diabetes mellitus[J]. J Diabetes Res，2017，2017：9631435. DOI：10.1155/2017/9631435.
[42]	KUSHWAHA V，RAI P，VARSHNEY S，et al. Sodium butyrate reduces endoplasmic reticulum stress by modulating CHOP and empowers favorable anti-inflammatory adipose tissue immune-metabolism in HFD fed mice model of obesity[J]. Food Chem，2022，4：100079. DOI：10.1016/j.fochms.2022.100079.
[43]	WANG H B，WANG P Y，WANG X，et al. Butyrate enhances intestinal epithelial barrier function via up-regulation of tight junction protein Claudin-1 transcription[J]. Dig Dis Sci，2012，57（12）：3126-3135. DOI：10.1007/s10620-012-2259-4.
[44]	CHANG P V，HAO L M，OFFERMANNS S，et al. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition[J]. Proc Natl Acad Sci U S A，2014，111（6）：2247-2252. DOI：10.1073/pnas.1322269111.
[45]	CORRÊA-OLIVEIRA R，FACHI J L，VIEIRA A，et al. Regulation of immune cell function by short-chain fatty acids[J]. Clin Transl Immunology，2016，5（4）：e73. DOI：10.1038/cti.2016.17.
[46]	GEUKING M B，MCCOY K D，MACPHERSON A J. Metabolites from intestinal microbes shape Treg[J]. Cell Res，2013，23（12）：1339-1340. DOI：10.1038/cr.2013.125.
[47]	DE OLIVEIRA F L，SALGAÇO M K，DE OLIVEIRA M T，et al. Exploring the potential of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 as promising psychobiotics using SHIME[J]. Nutrients，2023，15（6）：1521. DOI：10.3390/nu15061521.
[48]	PARK J S，LEE E J，LEE J C，et al. Anti-inflammatory effects of short chain fatty acids in IFN-gamma-stimulated RAW 264.7 murine macrophage cells：involvement of NF-kappaB and ERK signaling pathways[J]. Int Immunopharmacol，2007，7（1）：70-77. DOI：10.1016/j.intimp.2006.08.015.
[49]	SEGAIN J P，RAINGEARD DE LA BLÉTIÈRE D，BOURREILLE A，et al. Butyrate inhibits inflammatory responses through NF kappa B inhibition：implications for Crohn's disease[J]. Gut，2000，47（3）：397-403. DOI：10.1136/gut.47.3.397.
[50]	CHEN G X，RAN X，LI B，et al. Sodium butyrate inhibits inflammation and maintains epithelium barrier integrity in a TNBS-induced inflammatory bowel disease mice model[J]. EBioMedicine，2018，30：317-325. DOI：10.1016/j.ebiom.2018.03.030.
[51]	ZHANG Y C，LEI Y T，HONARPISHEH M，et al. Butyrate and class Ⅰ histone deacetylase inhibitors promote differentiation of neonatal porcine islet cells into beta cells[J]. Cells，2021，10（11）：3249. DOI：10.3390/cells10113249.
[52]	HU S X，KUWABARA R，DE HAAN B J，et al. Acetate and butyrate improve β-cell metabolism and mitochondrial respiration under oxidative stress[J]. Int J Mol Sci，2020，21（4）：1542. DOI：10.3390/ijms21041542.
[53]	XIMENES H M，HIRATA A E，ROCHA M S，et al. Propionate inhibits glucose-induced insulin secretion in isolated rat pancreatic islets[J]. Cell Biochem Funct，2007，25（2）：173-178. DOI：10.1002/cbf.1297.
[54]	PERRY R J，PENG L，BARRY N A，et al. Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome[J]. Nature，2016，534（7606）：213-217. DOI：10.1038/nature18309.
[55]	PRIYADARSHINI M，VILLA S R，FULLER M，et al. An acetate-specific GPCR，FFAR2，regulates insulin secretion[J]. Mol Endocrinol，2015，29（7）：1055-1066. DOI：10.1210/me.2015-1007.
[56]	PRIYADARSHINI M，LAYDEN B T. FFAR3 modulates insulin secretion and global gene expression in mouse islets[J]. Islets，2015，7（2）：e1045182. DOI：10.1080/19382014.2015.1045182.
[57]	TANG C，AHMED K，GILLE A，et al. Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes[J]. Nat Med，2015，21（2）：173-177. DOI：10.1038/nm.3779.
[58]	BOON J，HOY A J，STARK R，et al. Ceramides contained in LDL are elevated in type 2 diabetes and promote inflammation and skeletal muscle insulin resistance[J]. Diabetes，2013，62（2）：401-410. DOI：10.2337/db12-0686.
[59]	YANG L，LIN H Q，LIN W T，et al. Exercise ameliorates insulin resistance of type 2 diabetes through motivating short-chain fatty acid-mediated skeletal muscle cell autophagy[J]. Biology，2020，9（8）：203. DOI：10.3390/biology9080203.
[60]	GAO Z G，YIN J，ZHANG J，et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice[J]. Diabetes，2009，58（7）：1509-1517. DOI：10.2337/db08-1637.
[61]	CHRIETT S，ZERZAIHI O，VIDAL H，et al. The histone deacetylase inhibitor sodium butyrate improves insulin signalling in palmitate-induced insulin resistance in L6 rat muscle cells through epigenetically-mediated up-regulation of Irs1[J]. Mol Cell Endocrinol，2017，439：224-232. DOI：10.1016/j.mce.2016.09.006.
[62]	YAMASHITA H，MARUTA H，JOZUKA M，et al. Effects of acetate on lipid metabolism in muscles and adipose tissues of type 2 diabetic Otsuka Long-Evans Tokushima Fatty （OLETF） rats[J]. Biosci Biotechnol Biochem，2009，73（3）：570-576. DOI：10.1271/bbb.80634.
[63]	CHAMBERS E S，VIARDOT A，PSICHAS A，et al. Effects of targeted delivery of propionate to the human colon on appetite regulation，body weight maintenance and adiposity in overweight adults[J]. Gut，2015，64（11）：1744-1754. DOI：10.1136/gutjnl-2014-307913.
[64]	AHMED K，TUNARU S，OFFERMANNS S. GPR109A，GPR109B and GPR81，a family of hydroxy-carboxylic acid receptors[J]. Trends Pharmacol Sci，2009，30（11）：557-562. DOI：10.1016/j.tips.2009.09.001.
[65]	WILLEBRORDS J，PEREIRA I V，MAES M，et al. Strategies，models and biomarkers in experimental non-alcoholic fatty liver disease research[J]. Prog Lipid Res，2015，59：106-125. DOI：10.1016/j.plipres.2015.05.002.
[66]	MATHEUS V A，MONTEIRO L，OLIVEIRA R B，et al. Butyrate reduces high-fat diet-induced metabolic alterations，hepatic steatosis and pancreatic beta cell and intestinal barrier dysfunctions in prediabetic mice[J]. Exp Biol Med，2017，242（12）：1214-1226. DOI：10.1177/1535370217708188.
[67]	KHAN S，JENA G. Sodium butyrate reduces insulin-resistance，fat accumulation and dyslipidemia in type-2 diabetic rat：a comparative study with metformin[J]. Chem Biol Interact，2016，254：124-134. DOI：10.1016/j.cbi.2016.06.007.
[68]	DENG M J，QU F，CHEN L，et al. SCFAs alleviated steatosis and inflammation in mice with NASH induced by MCD[J]. J Endocrinol，2020，245（3）：425-437. DOI：10.1530/JOE-20-0018.
[69]	CARON A，LEE S，ELMQUIST J K，et al. Leptin and brain-adipose crosstalks[J]. Nat Rev Neurosci，2018，19（3）：153-165. DOI：10.1038/nrn.2018.7.
[70]	LI Z，YI C X，KATIRAEI S，et al. Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit[J]. Gut，2018，67（7）：1269-1279. DOI：10.1136/gutjnl-2017-314050.
[71]	ARAÚJO J R，TAZI A，BURLEN-DEFRANOUX O，et al. Fermentation products of commensal bacteria alter enterocyte lipid metabolism[J]. Cell Host Microbe，2020，27（3）：358-375.e7. DOI：10.1016/j.chom.2020.01.028.
[72]	DEN BESTEN G，BLEEKER A，GERDING A，et al. Short-chain fatty acids protect against high-fat diet-induced obesity via a PPARγ-dependent switch from lipogenesis to fat oxidation[J]. Diabetes，2015，64（7）：2398-2408. DOI：10.2337/db14-1213.
[73]	MOLLICA M P，MATTACE RASO G，CAVALIERE G，et al. Butyrate regulates liver mitochondrial function，efficiency，and dynamics in insulin-resistant obese mice[J]. Diabetes，2017，66（5）：1405-1418. DOI：10.2337/db16-0924.
[74]	PATEL B M，GOYAL R K. Liver and insulin resistance：new wine in old bottle!!![J]. Eur J Pharmacol，2019，862：172657. DOI：10.1016/j.ejphar.2019.172657.
[75]	YOSHIDA H，ISHII M，AKAGAWA M. Propionate suppresses hepatic gluconeogenesis via GPR43/AMPK signaling pathway[J]. Arch Biochem Biophys，2019，672：108057. DOI：10.1016/j.abb.2019.07.022.
[76]	SUN M B，LI D，HUA M，et al. Black bean husk and black rice anthocyanin extracts modulated gut microbiota and serum metabolites for improvement in type 2 diabetic rats[J]. Food Funct，2022，13（13）：7377-7391. DOI：10.1039/d2fo01165d.
[77]	ZHANG W Q，ZHAO T T，GUI D K，et al. Sodium butyrate improves liver glycogen metabolism in type 2 diabetes mellitus[J]. J Agric Food Chem，2019，67（27）：7694-7705. DOI：10.1021/acs.jafc.9b02083.
[78]	ZHAO T T，GU J L，ZHANG H X，et al. Sodium butyrate-modulated mitochondrial function in high-insulin induced HepG2 cell dysfunction[J]. Oxid Med Cell Longev，2020，2020：1904609. DOI：10.1155/2020/1904609.