Gut Microbes and Health: A Focus on the Mechanisms Linking Microbes, Obesity, and Related Disorders

Obesity

Volumn 26, Issue 5, 2018, Pages 792-800

  Rastelli, Marialetizia ^a,b   Knauf, Claude ^a,b,c,d   Cani, Patrice D ^a,b  

^a UNIVERSITÉ CATHOLIQUE DE LOUVAIN   (Belgium)

^b INSERM   (France)

^c UNIVERSITÉ PAUL SABATIER   (France)

^d UMR 1220 TCEM (INRA ENITAB)   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ENDOCANNABINOID; GLUCAGON LIKE PEPTIDE 1; PEPTIDE YY;

ARCUATE NUCLEUS; BODY WEIGHT GAIN; FAT MASS; GLIA CELL; GLUCONEOGENESIS; GLUCOSE METABOLISM; HUMAN; HYPERGLYCEMIA; IMMUNOREGULATION; INSULIN SENSITIVITY; INTESTINE FLORA; INTESTINE INNERVATION; METABOLIC DISORDER; NEUROTRANSMISSION; NONHUMAN; PROTEIN EXPRESSION; REVIEW; SPECIES RICHNESS; GENETICS; METABOLISM; OBESITY; PHYSIOLOGY;

GASTROINTESTINAL MICROBIOME; HUMANS; METABOLIC DISEASES; OBESITY;

EID: 85045743836     PISSN: 19307381     EISSN: 1930739X     Source Type: Journal    
DOI: 10.1002/oby.22175     Document Type: Review

References (116)

1. GBD 2015 Obesity Collaborators. Health effects of overweight and obesity in 195 countries over 25 years. New Engl J Med 2017;377:13-27.
2. Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 2016;164:337-340.
3. Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010;464:59-65.
4. Cani PD. Gut microbiota - at the intersection of everything? Nat Rev Gastroenterol Hepatol 2017;14:321-322.
5. Le Chatelier E, Nielsen T, Qin J, et al. Richness of human gut microbiome correlates with metabolic markers. Nature 2013;500:541-546.
6. Dore J, Blottiere H. The influence of diet on the gut microbiota and its consequences for health. Curr Opin Biotechnol 2015;32C:195-199.
7. Dao MC, Everard A, Aron-Wisnewsky J, et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut 2016;65:426-436.
8. Tilg H, Cani PD, Mayer EA. Gut microbiome and liver diseases. Gut 2016;65:2035-2044.
9. Bachmann R, Leonard D, Delzenne N, Kartheuser A, Cani PD. Novel insight into the role of microbiota in colorectal surgery. Gut 2017;66:738-749.
10. Gibson GR, Hutkins R, Sanders ME, et al. Expert consensus document: the International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol 2017;14:491-502.
11. Cani PD, Dewever C, Delzenne NM. Inulin-type fructans modulate gastrointestinal peptides involved in appetite regulation (glucagon-like peptide-1 and ghrelin) in rats. Br J Nutr 2004;92:521-526.
12. Cani PD, Knauf C, Iglesias MA, Drucker DJ, Delzenne NM, Burcelin R. Improvement of glucose tolerance and hepatic insulin sensitivity by oligofructose requires a functional glucagon-like peptide 1 receptor. Diabetes 2006;55:1484-1490.
13. Cani PD, Possemiers S, Van de WT, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 2009;58:1091-1103.
14. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006;444:1027-1031.
15. Turnbaugh PJ, Backhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 2008;3:213-223.
16. Everard A, Geurts L, Caesar R, et al. Intestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status. Nat Commun 2014;5:5648. doi:10.1038/ncomms6648
17. Ridaura VK, Faith JJ, Rey FE, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 2013;341:1241214. doi:10.1126/science.1241214
18. Cani PD, Bibiloni R, Knauf C, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008;57:1470-1481.
19. Carvalho BM, Guadagnini D, Tsukumo DM, et al. Modulation of gut microbiota by antibiotics improves insulin signaling in high-fat fed mice. Diabetologia 2012;55:2823-2834.
20. Muccioli GG, Naslain D, Backhed F, et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol 2010;6:392. doi:10.1038/msb.2010.46
21. Li J, Jia H, Cai X, et al. An integrated catalog of reference genes in the human gut microbiome. Nat Biotechnol 2014;32:834-841.
22. Qin N, Yang F, Li A, et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014;513:59-64.
23. Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 2015;528:262-266.
24. Costea PI, Zeller G, Sunagawa S, et al. Towards standards for human fecal sample processing in metagenomic studies. Nat Biotechnol 2017;35:1069-1076.
25. Sinha R, Abu-Ali G, Vogtmann E, et al. Assessment of variation in microbial community amplicon sequencing by the Microbiome Quality Control (MBQC) project consortium. Nat Biotechnol 2017;35:1077-1086.
26. Cani PD, Knauf C. How gut microbes talk to organs: the role of endocrine and nervous routes. Mol Metab 2016;5:743-752.
27. Cuomo R, D'Alessandro A, Andreozzi P, Vozzella L, Sarnelli G. Gastrointestinal regulation of food intake: do gut motility, enteric nerves and entero-hormones play together? Minerva Endocrinol 2011;36:281-293.
28. Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci 2011;12:453-466.
29. Fournel A, Drougard A, Duparc T, et al. Apelin targets gut contraction to control glucose metabolism via the brain. Gut 2017;66:258-269.
30. Weber C. Neurogastroenterology: improving glucose tolerance via the gut-brain axis. Nat Rev Gastroenterol Hepatol 2016;13:4. doi:10.1038/nrgastro.2015.204
31. Hyland NP, Cryan JF. Microbe-host interactions: influence of the gut microbiota on the enteric nervous system. Dev Biol 2016;417:182-187.
32. Monteiro-Sepulveda M, Touch S, Mendes-Sa C, et al. Jejunal T cell inflammation in human obesity correlates with decreased enterocyte insulin signaling. Cell Metab 2015;22:113-124.
33. Stenkamp-Strahm CM, Nyavor YE, Kappmeyer AJ, Horton S, Gericke M, Balemba OB. Prolonged high fat diet ingestion, obesity, and type 2 diabetes symptoms correlate with phenotypic plasticity in myenteric neurons and nerve damage in the mouse duodenum. Cell Tissue Res 2015;361:411-426.
34. Reichardt F, Baudry C, Gruber L, et al. Properties of myenteric neurones and mucosal functions in the distal colon of diet-induced obese mice. J Physiol 2013;591:5125-5139.
35. Stenkamp-Strahm C, Patterson S, Boren J, Gericke M, Balemba O. High-fat diet and age-dependent effects on enteric glial cell populations of mouse small intestine. Auton Neurosci 2013;177:199-210.
36. Jo HJ, Kim N, Nam RH, et al. Fat deposition in the tunica muscularis and decrease of interstitial cells of Cajal and nNOS-positive neuronal cells in the aged rat colon. Am J Physiol Gastrointest Liver Physiol 2014;306:G659-G669.
37. Neunlist M, Rolli-Derkinderen M, Latorre R, et al. Enteric glial cells: recent developments and future directions. Gastroenterology 2014;147:1230-1237.
38. Kabouridis PS, Lasrado R, McCallum S, et al. The gut microbiota keeps enteric glial cells on the move; prospective roles of the gut epithelium and immune system. Gut Microbes 2015;6:398-403.
39. Everard A, Cani PD. Gut microbiota and GLP-1. Rev Endocr Metab Disord 2014;15:189-196.
40. Greiner TU, Backhed F. Microbial regulation of GLP-1 and L-cell biology. Mol Metab 2016;5:753-758.
41. Cani PD, Plovier H, Van Hul M, et al. Endocannabinoids - at the crossroads between the gut microbiota and host metabolism. Nat Rev Endocrinol 2016;12:133-143.
42. Kellow NJ, Coughlan MT, Reid CM. Metabolic benefits of dietary prebiotics in human subjects: a systematic review of randomised controlled trials. Br J Nutr 2014;111:1147-1161.
43. Zakeri R, Batterham RL. Potential mechanisms underlying the effect of bariatric surgery on eating behaviour. Curr Opin Endocrinol Diabetes Obes 2017;25:3-11.
44. Svane MS, Jorgensen NB, Bojsen-Moller KN, et al. Peptide YY and glucagon-like peptide-1 contribute to decreased food intake after Roux-en-Y gastric bypass surgery. Int J Obes (Lond) 2016;40:1699-1706.
45. Amato A, Cinci L, Rotondo A, Serio R, et al. Peripheral motor action of glucagon-like peptide-1 through enteric neuronal receptors. Neurogastroenterol Motil 2010;22:664-e203. doi:10.1111/j.1365-2982.2010.01476.x
46. Washington MC, Raboin SJ, Thompson W, Larsen CJ, Sayegh AI. Exenatide reduces food intake and activates the enteric nervous system of the gastrointestinal tract and the dorsal vagal complex of the hindbrain in the rat by a GLP-1 receptor. Brain Res 2010;1344:124-133.
47. Grasset E, Puel A, Charpentier J, et al. 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 2017;26:278. doi:10.1016/j.cmet.2017.06.003
48. Brooks L, Viardot A, Tsakmaki A, et al. Fermentable carbohydrate stimulates FFAR2-dependent colonic PYY cell expansion to increase satiety. Mol Metab 2017;6:48-60.
49. Jackerott M, Larsson LI. Immunocytochemical localization of the NPY/PYY Y1 receptor in enteric neurons, endothelial cells, and endocrine-like cells of the rat intestinal tract. J Histochem Cytochem 1997;45:1643-1650.
50. Mao YK, Wang YF, Ward G, Cipris S, Daniel EE, McDonald TJ. Peptide YY receptor in submucosal and myenteric plexus synaptosomes of canine small intestine. Am J Physiol 1996;271:G36-G41.
51. Everard A, Belzer C, Geurts L, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A 2013;110:9066-9071.
52. Geurts L, Everard A, Van Hul M, et al. Adipose tissue NAPE-PLD controls fat mass development by altering the browning process and gut microbiota. Nat Commun 2015;6:6495. doi:10.1038/ncomms7495
53. Cohen LJ, Esterhazy D, Kim SH, et al. Commensal bacteria make GPCR ligands that mimic human signalling molecules. Nature 2017;549:48-53.
54. Wong JM, de SR, Kendall CW, Emam A, Jenkins DJ. Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol 2006;40:235-243.
55. Cummings JH, Pomare EW, Branch WJ, Naylor CP, Macfarlane GT. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 1987;28:1221-1227.
56. Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol 2015;11:577-591.
57. Roediger WE. Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut 1980;21:793-798.
58. Louis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol 2017;19:29-41.
59. Fukumoto S, Tatewaki M, Yamada T, et al. Short-chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats. Am J Physiol Regul Integr Comp Physiol 2003;284:R1269-R1276.
60. Soret R, Chevalier J, De Coppet P, et al. Short-chain fatty acids regulate the enteric neurons and control gastrointestinal motility in rats. Gastroenterology 2010;138:1772-1782.
61. Bhattarai Y, Schmidt BA, Linden DR, et al. Human-derived gut microbiota modulates colonic secretion in mice by regulating 5-HT3 receptor expression via acetate production. Am J Physiol Gastrointest Liver Physiol 2017;313:G80-G87.
62. Nohr MK, Egerod KL, Christiansen SH, et al. Expression of the short chain fatty acid receptor GPR41/FFAR3 in autonomic and somatic sensory ganglia. Neuroscience 2015;290:126-137.
63. De Vadder F, Kovatcheva-Datchary P, Goncalves D, et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 2014;156:84-96.
64. Frost G, Sleeth ML, Sahuri-Arisoylu M, et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat Commun 2014;5:3611. doi:10.1038/ncomms4611
65. Perry RJ, Peng L, Barry NA, et al. Acetate mediates a microbiome-brain-beta-cell axis to promote metabolic syndrome. Nature 2016;534:213-217.
66. Bindels LB, Leclercq I. Colonic acetate in obesity: location matters! Clin Sci (Lond) 2016;130:2083-2086.
67. Mertens KL, Kalsbeek A, Soeters MR, Eggink HM. Bile acid signaling pathways from the enterohepatic circulation to the central nervous system. Front Neurosci 2017;11:617. doi:10.3389/fnins.2017.00617
68. Higashi T, Watanabe S, Tomaru K, et al. Unconjugated bile acids in rat brain: analytical method based on LC/ESI-MS/MS with chemical derivatization and estimation of their origin by comparison to serum levels. Steroids 2017;125:107-113.
69. Kliewer SA, Mangelsdorf DJ. Bile acids as hormones: the FXR-FGF15/19 pathway. Dig Dis 2015;33:327-331.
70. Marcelin G, Jo YH, Li X, et al. Central action of FGF19 reduces hypothalamic AGRP/NPY neuron activity and improves glucose metabolism. Mol Metab 2014;3:19-28.
71. Abbott CR, Monteiro M, Small CJ, 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. Brain Res 2005;1044:127-131.
72. Orskov C, Poulsen SS, Moller M, Holst JJ. Glucagon-like peptide I receptors in the subfornical organ and the area postrema are accessible to circulating glucagon-like peptide I. Diabetes 1996;45:832-835.
73. Wahlstrom A, Sayin SI, Marschall HU, Backhed F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab 2016;24:41-50.
74. Sampson TR, Mazmanian SK. Control of brain development, function, and behavior by the microbiome. Cell Host Microbe 2015;17:565-576.
75. Mittal R, Debs LH, Patel AP, et al. Neurotransmitters: the critical modulators regulating gut-brain axis. J Cell Physiol 2017;232:2359-2372.
76. Reigstad CS, Salmonson CE, Rainey JF, 3rd, et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB 2015;29:1395-1403.
77. O'Mahony SM, Clarke G, Borre YE, Dinan TG, Cryan JF. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res 2015;277:32-48.
78. Wikoff WR, Anfora AT, Liu J, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci U S A 2009;106:3698-3703.
79. Clarke G, Grenham S, Scully P, et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 2013;18:666-673.
80. Crumeyrolle-Arias M, Jaglin M, Bruneau A, et al. Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology 2014;42:207-217.
81. Diaz Heijtz R, Wang S, Anuar F, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A 2011;108:3047-3052.
82. Asano Y, Hiramoto T, Nishino R, et al. Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice. Am J Physiol Gastrointest Liver Physiol 2012;303:G1288-G1295.
83. Hyland NP, Cryan JF. A gut feeling about GABA: Focus on GABA(B) receptors. Front Pharmacol 2010;1:124. doi:10.3389/fphar.2010.00124
84. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A 2011;108:16050-16055.
85. Barrett E, Ross RP, O'Toole PW, Fitzgerald GF, Stanton C. Gamma-aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol 2012;113:411-417.
86. Mazzoli R, Pessione E. The neuro-endocrinological role of microbial glutamate and GABA signaling. Front Microbiol 2016;7:1934. doi:10.3389/fmicb.2016.01934
87. Ji XB, Hollocher TC. Reduction of nitrite to nitric oxide by enteric bacteria. Biochem Biophys Res Commun 1988;157:106-108.
88. Gusarov I, Starodubtseva M, Wang ZQ, et al. Bacterial nitric-oxide synthases operate without a dedicated redox partner. J Biol Chem 2008;283:13140-13147.
89. Tennoune N, Chan P, Breton J, et al. Bacterial ClpB heat-shock protein, an antigen-mimetic of the anorexigenic peptide alpha-MSH, at the origin of eating disorders. Transl Psychiatry 2014;4:e458. doi:10.1038/tp.2014.98
90. Breton J, Tennoune N, Lucas N, et al. Gut commensal E. coli proteins activate host satiety pathways following nutrient-induced bacterial growth. Cell Metab 2016;23:324-334.
91. Barbara G, Scaioli E, Barbaro MR, et al. Gut microbiota, metabolome and immune signatures in patients with uncomplicated diverticular disease. Gut 2017;66:1252-1261.
92. Leclercq S, Matamoros S, Cani PD, et al. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci U S A 2014;111:E4485-E4493.
93. Postler TS, Ghosh S. Understanding the holobiont: how microbial metabolites affect human health and shape the immune system. Cell Metab 2017;26:110-130.
94. Pallister T, Jackson MA, Martin TC, et al. Hippurate as a metabolomic marker of gut microbiome diversity: modulation by diet and relationship to metabolic syndrome. Sci Rep 2017;7:13670. doi:10.1038/s41598-017-13722-4
95. Piening BD, Zhou W, Contrepois K, et al. Integrative personal omics profiles during periods of weight fain and loss. Cell Syst 2018;6:157-170.e8.
96. Roager HM, Vogt JK, Kristensen M, et al. Whole grain-rich diet reduces body weight and systemic low-grade inflammation without inducing major changes of the gut microbiome: a randomised cross-over trial [published online November 1, 2017]. Gut 2017. doi:10.1136/gutjnl-2017-314786
97. Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007;56:1761-1772.
98. Kim F, Pham M, Luttrell I, et al. Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res 2007;100:1589-1596.
99. Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, et al. Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 2007;56:1986-1998.
100. Laugerette F, Vors C, Geloen A, et al. Emulsified lipids increase endotoxemia: possible role in early postprandial low-grade inflammation. J Nutr Biochem 2011;22:53-59.
101. Amar J, Burcelin R, Ruidavets JB, et al. Energy intake is associated with endotoxemia in apparently healthy men. Am J Clin Nutr 2008;87:1219-1223.
102. Pussinen PJ, Havulinna AS, Lehto M, Sundvall J, Salomaa V. Endotoxemia is associated with an increased risk of incident diabetes. Diabetes Care 2011;34:392-397.
103. Jayashree B, Bibin YS, Prabhu D, et al. Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes. Mol Cell Biochem 2014;388:203-210.
104. Dewulf EM, Cani PD, Claus SP, et al. Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women. Gut 2013;62:1112-1121.
105. Malaguarnera M, Vacante M, Antic T, et al. Bifidobacterium longum with fructo-oligosaccharides in patients with non alcoholic steatohepatitis. Dig Dis Sci 2012;57:545-553.
106. Magalhaes I, Pingris K, Poitou C, et al. Mucosal-associated invariant T cell alterations in obese and type 2 diabetic patients. J Clin Invest 2015;125:1752-1762
107. Chassaing B, Raja SM, Lewis JD, Srinivasan S, Gewirtz AT. Colonic microbiota encroachment correlates with dysglycemia in humans. Cell Mol Gastroenterol Hepatol 2017;4:205-221.
108. Casselbrant A, Elias E, Fandriks L, Wallenius V. Expression of tight-junction proteins in human proximal small intestinal mucosa before and after Roux-en-Y gastric bypass surgery. Surg Obes Relat Dis 2015;11:45-53.
109. Zhang D, Zhang L, Zheng Y, Yue F, Russell RD, Zeng Y. Circulating zonulin levels in newly diagnosed Chinese type 2 diabetes patients. Diabetes Res Clin Pract 2014;106:312-318.
110. Wells JM, Brummer RJ, Derrien M, et al. Homeostasis of the gut barrier and potential biomarkers. Am J Pysiol Gastrointest Liver Pysiol 2017;312:G171-G193.
111. Bogunovic M, Dave SH, Tilstra JS, et al. Enteroendocrine cells express functional Toll-like receptors. A Am J Pysiol Gastrointest Liver Pysiol 2007;292:G1770-G1783.
112. de La Serre CB, de Lartigue G, Raybould HE. Chronic exposure to low dose bacterial lipopolysaccharide inhibits leptin signaling in vagal afferent neurons. Physiol Behav 2015;139:188-194.
113. Forsythe P, Kunze WA. Voices from within: gut microbes and the CNS. Cell Mol Life Sci 2013;70:55-69.
114. Bercik P, Denou E, Collins J, et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 2011;141:599-609, 609.e1-3.
115. Sen T, Cawthon CR, Ihde BT, et al. Diet-driven microbiota dysbiosis is associated with vagal remodeling and obesity. Physiol Behav 2017;173:305-317.
116. Vaughn AC, Cooper EM, DiLorenzo PM, et al. Energy-dense diet triggers changes in gut microbiota, reorganization of gutbrain vagal communication and increases body fat accumulation. Acta Neurobiol Exp (Wars) 2017;77:18-30.