ВЗАИМОСВЯЗЬ СОДЕРЖАНИЯ НЕЙРОТРОФИНОВ И КИШЕЧНОГО МИКРОБИОМА ПРИ РАЗЛИЧНЫХ МЕТАБОЛИЧЕСКИХ ТИПАХ ОЖИРЕНИЯ
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Ключевые слова

кишечный микробиом
микробиота кишечника
альфа-разнообразие
нейротрофины
фактор роста нервов
NGF
нейротропный фактор мозга
нейротрофический фактор мозга
BDNF
ожирение
метаболически здоровое ожирение
метаболически нездоровое ожирение

Аннотация

Ожирение ассоциировано с дисбалансом кишечного микробиома и риском поражения нервной системы, при этом риск развития осложнений определяется метаболическим типом ожирения. Целью работы стало изучение взаимосвязи кишечного микробиома и содержания нейротрофинов (BDNF и NGF) при различных метаболических типах ожирения. Обследовано 130 здоровых доноров без ожирения и 104 пациента с ожирением, которые были разделены по метаболическому типу ожирения на подгруппы с метаболически здоровым (МЗО, n=40) и метаболически нездоровым типом (МНЗО, n=55). У пациентов проводилось измерение сывороточной концентрации нейротрофинов и определение таксономического состава микробиома кишечника методом секвенирования вариабельного участка гена 16S рРНК. Таксоны, положительно коррелировавшие с концентрацией BDNF, в основном были представлены бутират и/или ГАМК-продуцирующими микроорганизмам, способным деградировать муцин. Среди здоровых доноров, наиболее распространенным подобным таксоном, было семейство S24-7. При МЗО спектр таких таксонов включал Bacteroides spp., Rikenellaceae, Oscillospira spp., [Barnesiellaceae], Bovatus и Anaerostipes spp., а при МНЗО – Bifidobacterium spp. и Coprococcus spp. Также был выявлен спектр таксонов, негативно коррелировавших с уровнем BDNF, большая часть которых при ожирении принадлежала к грамположительной флоре. Спектр таксонов, коррелировавших с уровнем BDNF, был уникален для каждой группы пациентов, что предполагает значительную роль межвидового взаимодействия микроорганизмов. Содержание NGF при ожирении было ассоциировано с рядом таксонов, тогда как у здоровых лиц подобная связь практически отсутствовала. Позитивные ассоциации с уровнем NGF были отмечены для Odoribacter spp. при МЗО и Slackia spp. при МНЗО. Негативную взаимосвязь с концентрацией NGF при МЗО проявляли Hparainfluenzae, Erysipelotrichaceae, Megamonas spp. и Clostridiaceae, а при МНЗО – ML615J-287 и Clostridiales. Таким образом, ожирение связано с появлением взаимосвязи «кишечный микробиом – NGF», что не характерно для здоровых доноров, и, по-видимому, является следствием усиления кишечной проницаемости.

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Литература

Lee CJ, Sears CL, Maruthur N (2020) Gut microbiome and its role in obesity and insulin resistance. Ann N Y Acad Sci 1461:37–52. https://doi.org/10.1111/nyas.14107

Singer-Englar T, Barlow G, Mathur R (2019) Obesity, diabetes, and the gut microbiome: an updated review. Expert Rev Gastroenterol Hepatol 13:3–15. https://doi.org/10.1080/17474124.2019.1543023

Котрова АД, Шишкин АН, Воропаева ЛС, Лавренова НС, Слепых ЛА, Лукашенко МВ, Ермоленко ЕИ (2021) Гендерная оценка микробиома кишечника у больных с ожирением. Клиническая гастроэнтерология 194:91–99. [Kotrova AD, Shishkin AN, Voropaeva LS, Lavrenova NS, Blind LA, Lukashenko MV, Ermolenko EI (2021) Gender assessment of the intestinal microbiome in obese patients. Clinical Gastroenterology 194:91-99. (In Russ)]. https://doi.org/10.31146/1682- 8658-ecg-194-10-91-99

Гапонов АМ, Волкова НИ, Ганенко ЛА, Набока ЮЛ, Маркелова МИ, Синягина МН, Харченко АМ, Хуснутдинова ДР, Румянцев СА, Тутельян АВ, Макаров ВВ, Юдин СМ, Шестопалов АВ (2021) Особенности микробиома толстой кишки у пациентов с ожирением при его различных фенотипах (оригинальная статья). Журнал микробиологии, эпидемиологии и иммунобиологии 98:144–155. [Gaponov AM, Volkova NI, Ganenko LA, Naboka YUL, Markelova MI, Sinyagina MN, Kharchenko AM, Khusnutdinova DR, Rumyantsev SA, Tutelyan AV, Makarov BB, Yudin SM, Shestopalov AV (2021) Features of the colon microbiome in obese patients with its various phenotypes (original article). Journal of Microbiology, Epidemiology and Immunobiology 98:144-155. (In Russ)]. https://doi.org/10.36233/0372-9311-66

Rosenbaum M, Knight R, Leibel RL (2015) The gut microbiota in human energy homeostasis and obesity. Trends Endocrinol Metab 26:493–501. https://doi.org/10.1016/j.tem.2015.07.002

Hu J, Lin S, Zheng B, Cheung PCK (2018) Short-chain fatty acids in control of energy metabolism. Crit Rev Food Sci Nutr 58:1243–1249.

Blaak EE, Canfora EE, Theis S, Frost G, Groen AK, Mithieux G, Nauta A, Scott K, Stahl B, van Harsselaar J, van Tol R, Vaughan EE, Verbeke K (2020) Short chain fatty acids in human gut and metabolic health. Benef Microbes 11:411–455. https://doi.org/10.3920/BM2020.0057

Heiss CN, Olofsson LE (2019) The role of the gut microbiota in development, function and disorders of the central nervous system and the enteric nervous system. J Neuroendocrinol 31:1–11. https://doi.org/10.1111/jne.12684

Sharon G, Sampson TR, Geschwind DH, Mazmanian SK (2016) The Central Nervous System and the Gut Microbiome. Cell 167:915–932. https://doi.org/10.1016/j.cell.2016.10.027

Grasset E, Puel A, Charpentier J, Collet X, Christensen JE, Tercé F, Burcelin R (2017) A Specific Gut Microbiota Dysbiosis of Type 2 Diabetic Mice Induces GLP-1 Resistance through an Enteric NO-Dependent and Gut-Brain Axis Mechanism. Cell Metab 25:1075–1090.e5. https://doi.org/10.1016/j.cmet.2017.04.013

Guillemot-Legris O, Muccioli GG (2017) Obesity-Induced Neuroinflammation: Beyond the Hypothalamus. Trends Neurosci 40:237–253. https://doi.org/10.1016/j.tins.2017.02.005

Iacobini C, Pugliese G, Blasetti Fantauzzi C, Federici M, Menini S (2019) Metabolically healthy versus metabolically unhealthy obesity. Metabolism 92:51–60. https://doi.org/10.1016/j.metabol.2018.11.009

Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, Deng Y, Blennerhassett P, Macri J, McCoy KD, Verdu EF, Collins SM (2011) The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141:599–609, 609.e1–3. https://doi.org/10.1053/j.gastro.2011.04.052

Schéle E, Grahnemo L, Anesten F, Hallén A, Bäckhed F, Jansson J-O (2013) The gut microbiota reduces leptin sensitivity and the expression of the obesity-suppressing neuropeptides proglucagon (Gcg) and brain-derived neurotrophic factor (Bdnf) in the central nervous system. Endocrinology 154:3643–3651. https://doi.org/10.1210/en.2012-2151

Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, Kubo C, Koga Y (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 558:263–275. https://doi.org/10.1113/jphysiol.2004.063388

Desbonnet L, Clarke G, Traplin A, O’Sullivan O, Crispie F, Moloney RD, Cotter PD, Dinan TG, Cryan JF (2015) Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour. Brain Behav Immun 48:165–173. https://doi.org/10.1016/j.bbi.2015.04.004

Fröhlich EE, Farzi A, Mayerhofer R, Reichmann F, Jačan A, Wagner B, Zinser E, Bordag N, Magnes C, Fröhlich E, Kashofer K, Gorkiewicz G, Holzer P (2016) Cognitive impairment by antibiotic-induced gut dysbiosis: Analysis of gut microbiota-brain communication. Brain Behav Immun 56:140–155. https://doi.org/10.1016/j.bbi.2016.02.020

Cui M, Xiao H, Li Y, Dong J, Luo D, Li H, Feng G, Wang H, Fan S (2017) Total abdominal irradiation exposure impairs cognitive function involving miR-34a-5p/BDNF axis. Biochim Biophys Acta - Mol Basis Dis 1863:2333–2341. https://doi.org/10.1016/j.bbadis.2017.06.021

Stilling RM, Ryan FJ, Hoban AE, Shanahan F, Clarke G, Claesson MJ, Dinan TG, Cryan JF (2015) Microbes & neurodevelopment - Absence of microbiota during early life increases activity-related transcriptional pathways in the amygdala. Brain Behav Immun 50:209–220. https://doi.org/10.1016/j.bbi.2015.07.009

Savignac HM, Corona G, Mills H, Chen L, Spencer JPE, Tzortzis G, Burnet PWJ (2013) Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-d-aspartate receptor subunits and d-serine. Neurochem Int 63:756–764. https://doi.org/10.1016/j.neuint.2013.10.006

O’Sullivan E, Barrett E, Grenham S, Fitzgerald P, Stanton C, Ross RP, Quigley EMM, Cryan JF, Dinan TG (2011) BDNF expression in the hippocampus of maternally separated rats: Does Bifidobacterium breve 6330 alter BDNF levels? Benef Microbes 2:199–207. https://doi.org/10.3920/BM2011.0015

Sun J, Wang F, Hu X, Yang C, Xu H, Yao Y, Liu J (2018) Clostridium butyricum Attenuates Chronic Unpredictable Mild Stress-Induced Depressive-Like Behavior in Mice via the Gut-Brain Axis. J Agric Food Chem 66:8415–8421. https://doi.org/10.1021/acs.jafc.8b02462

Borrelli L, Aceto S, Agnisola C, De Paolo S, Dipineto L, Stilling RM, Dinan TG, Cryan JF, Menna LF, Fioretti A (2016) Probiotic modulation of the microbiota-gut-brain axis and behaviour in zebrafish. Sci Rep 6:1–9. https://doi.org/10.1038/srep30046

Cuomo M, Borrelli L, Monica R Della, Coretti L, De Riso G, Di Durazzo LDL, Fioretti A, Lembo F, Dinan TG, Cryan JF, Cocozza S, Chiariotti L (2021) DNA methylation profiles of Tph1a and BDNF in gut and brain of L. Rhamnosus-treated Zebrafish. Biomolecules 11:1–13. https://doi.org/10.3390/biom11020142

Hwang YH, Park S, Paik JW, Chae SW, Kim DH, Jeong DG, Ha E, Kim M, Hong G, Park SH, Jung SJ, Lee SM, Na KH, Kim J, Chung YC (2019) Efficacy and safety of lactobacillus plantarum C29-fermented soybean (DW2009) in individuals with mild cognitive impairment: A 12-week, multi-center, randomized, double-blind, placebo-controlled clinical trial. Nutrients 11. https://doi.org/10.3390/nu11020305

Li C, Cai YY, Yan ZX (2018) Brain-derived neurotrophic factor preserves intestinal mucosal barrier function and alters gut microbiota in mice. Kaohsiung J Med Sci 34:134–141. https://doi.org/10.1016/j.kjms.2017.11.002

Steinkamp M, Schulte N, Spaniol U, Pflüger C, Hartmann C, Kirsch J, von Boyen GB (2012) Brain derived neurotrophic factor inhibits apoptosis in enteric glia during gut inflammation. Med Sci Monit Int Med J Exp Clin Res 18:BR117–122. https://doi.org/10.12659/msm.882612

Ma D, Forsythe P, Bienenstock J (2004) Live Lactobacillus rhamnosus [corrected] is essential for the inhibitory effect on tumor necrosis factor alpha-induced interleukin-8 expression. Infect Immun 72:5308–5314. https://doi.org/10.1128/IAI.72.9.5308-5314.2004

Ju IG, Hong SM, Yun S-W, Huh E, Kim D-H, Kim SY, Oh MS (2021) CCL01, a novel formulation composed of Cuscuta seeds and Lactobacillus paracasei NK112, enhances memory function via nerve growth factor-mediated neurogenesis. Food Funct 12:10690–10699. https://doi.org/10.1039/d1fo01403j

Rahimlou M, Hosseini SA, Majdinasab N, Haghighizadeh MH, Husain D (2022) Effects of long-term administration of Multi-Strain Probiotic on circulating levels of BDNF, NGF, IL-6 and mental health in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial. Nutr Neurosci 25:411–422. https://doi.org/10.1080/1028415X.2020.1758887

Aygun H, Akin AT, Kızılaslan N, Sumbul O, Karabulut D (2022) Electrophysiological, histopathological and biochemical evaluation of the protective effect of probiotic supplementation against PTZ-induced seizures in rats. Eur J Neurol. https://doi.org/10.1111/ene.15359

Abenavoli L, Scarpellini E, Colica C, Boccuto L, Salehi B, Sharifi-rad J, Aiello V, Romano B, Lorenzo A De, Izzo AA (2019) Gut Microbiota and Obesity: A Role for Probiotics. Nutrients 11:2690. https://doi.org/https://doi.org/10.3390/nu11112690

Expert panel on detection evaluation and treatment of high blood cholesterol in adults (2001) Executive summary of the third report (NCEP) -adult treatment panel III. J Am Med Assoc 285:2486–2497.

Wu X, Chen PS, Dallas S, Wilson B, Block ML, Wang CC, Kinyamu H, Lu N, Gao X, Leng Y, Chuang DM, Zhang W, Lu RB, Hong JS (2008) Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. Int J Neuropsychopharmacol 11:1123–1134. https://doi.org/10.1017/S1461145708009024

Spichak S, Donoso F, Moloney GM, Gunnigle E, Brown JM, Codagnone M, Dinan TG, Cryan JF (2021) Microbially-derived short-chain fatty acids impact astrocyte gene expression in a sex-specific manner. Brain, Behav Immun - Heal 16:100318. https://doi.org/10.1016/j.bbih.2021.100318

Fukuchi M, Kirikoshi Y, Mori A, Eda R, Ihara D, Takasaki I, Tabuchi A, Tsuda M (2014) Excitatory GABA induces BDNF transcription via CRTC1 and phosphorylated CREB-related pathways in immature cortical cells. J Neurochem 131:134–146. https://doi.org/10.1111/jnc.12801

Strandwitz P, Kim KH, Terekhova D, Liu JK, Sharma A, Levering J, McDonald D, Dietrich D, Ramadhar TR, Lekbua A, Mroue N, Liston C, Stewart EJ, Dubin MJ, Zengler K, Knight R, Gilbert JA, Clardy J, Lewis K (2019) GABA Modulating Bacteria of the Human Gut Microbiota. Nat Microbiol 4:396–403. https://doi.org/10.1038/s41564-018-0307-3.GABA

Allam-Ndoul B, Castonguay-Paradis S, Veilleux A (2020) Gut microbiota and intestinal trans-epithelial permeability. Int J Mol Sci 21:1–14. https://doi.org/10.3390/ijms21176402

Enzyme Database - BRENDA. https://www.brenda-enzymes.org/index.php. Accessed 26 Dec 2021

Yogeswara IBA, Maneerat S, Haltrich D (2020) Glutamate decarboxylase from lactic acid bacteria—a key enzyme in Gaba synthesis. Microorganisms 8:1–24. https://doi.org/10.3390/microorganisms8121923

Louis P, Flint HJ (2017) Formation of propionate and butyrate by the human colonic microbiota. Env Microbiol 19:29–41. https://doi.org/10.1111/1462-2920.

Corfield AP, Wagner SA, Clamp JR, Kriaris MS, Hoskins LC (1992) Mucin degradation in the human colon: production of sialidase, sialate O-acetylesterase, N-acetylneuraminate lyase, arylesterase, and glycosulfatase activities by strains of fecal bacteria. Infect Immun 60:3971–3978. https://doi.org/10.1128/iai.60.10.3971-3978.1992

Wright DP, Rosendale DI, Roberton AM (2000) Prevotella enzymes involved in mucin oligosaccharide degradation and evidence for a small operon of genes expressed during growth on mucin. FEMS Microbiol Lett 190:73–79. https://doi.org/10.1016/S0378-1097(00)00324-4

Chmilewsky F, About I, Chung SH (2017) C5L2 Receptor Represses Brain-Derived Neurotrophic Factor Secretion in Lipoteichoic Acid-Stimulated Pulp Fibroblasts. J Dent Res 96:92–99. https://doi.org/10.1177/0022034516673832

West AE, Pruunsild P, Timmusk T (2014) Neurotrophic Factors: Transcription and Translation.

Murata K, Sawaji Y, Alimasi W, Suzuki H, Endo K, Tanaka H, Yorifuji M, Kosaka T, Shishido T, Yamamoto K (2016) PGE1 Attenuates IL-1β-induced NGF Expression in Human Intervertebral Disc Cells. Spine (Phila Pa 1976) 41:E710–E716. https://doi.org/10.1097/BRS.0000000000001379

Weigt SS, Palchevskiy V, Belperio JA (2017) Inflammasomes and IL-1 biology in the pathogenesis of allograft dysfunction. J Clin Invest 127:2022–2029. https://doi.org/10.1172/JCI93537

Nagura N, Uchida K, Kenmoku T, Inoue G, Nakawaki M, Miyagi M, Takaso M (2019) IL-1β mediates NGF and COX-2 expression through transforming growth factor-activating kinase 1 in subacromial bursa cells derived from rotator cuff tear patients. J Orthop Sci 24:925–929. https://doi.org/10.1016/j.jos.2019.02.006

Cox AJ, West NP, Cripps AW (2015) Obesity, inflammation, and the gut microbiota. Lancet Diabetes Endocrinol 3:207–215. https://doi.org/10.1016/S2213-8587(14)70134-2

Rial SA, Karelis AD, Bergeron KF, Mounier C (2016) Gut microbiota and metabolic health: The potential beneficial effects of a medium chain triglyceride diet in obese individuals. Nutrients 8:1–19. https://doi.org/10.3390/nu8050281