Reversal of Functional Brain Activity Related to Gut Microbiome and Hormones After VSG Surgery in Patients With Obesity

Jie Hong, Tingting Bo, Liuqing Xi, Xiaoqiang Xu, Naying He, Yafeng Zhan, Wanyu Li, Peiwen Liang, Yufei Chen, Juan Shi, Danjie Li, Fuhua Yan, Weiqiong Gu, Weiqing Wang, Ruixin Liu, Jiqiu Wang, Zheng Wang, Guang Ning, Jie Hong, Tingting Bo, Liuqing Xi, Xiaoqiang Xu, Naying He, Yafeng Zhan, Wanyu Li, Peiwen Liang, Yufei Chen, Juan Shi, Danjie Li, Fuhua Yan, Weiqiong Gu, Weiqing Wang, Ruixin Liu, Jiqiu Wang, Zheng Wang, Guang Ning

Abstract

Context: Vertical sleeve gastrectomy (VSG) is becoming a prioritized surgical intervention for obese individuals; however, the brain circuits that mediate its effective control of food intake and predict surgical outcome remain largely unclear.

Objective: We investigated VSG-correlated alterations of the gut-brain axis.

Methods: In this observational cohort study, 80 patients with obesity were screened. A total of 36 patients together with 26 normal-weight subjects were enrolled and evaluated using the 21-item Three-Factor Eating Questionnaire (TFEQ), MRI scanning, plasma intestinal hormone analysis, and fecal sample sequencing. Thirty-two patients underwent VSG treatment and 19 subjects completed an average of 4-month follow-up evaluation. Data-driven regional homogeneity (ReHo) coupled with seed-based connectivity analysis were used to quantify VSG-related brain activity. Longitudinal alterations of body weight, eating behavior, brain activity, gastrointestinal hormones, and gut microbiota were detected and subjected to repeated measures correlation analysis.

Results: VSG induced significant functional changes in the right putamen (PUT.R) and left supplementary motor area, both of which correlated with weight loss and TFEQ scores. Moreover, postprandial levels of active glucagon-like peptide-1 (aGLP-1) and Ghrelin were associated with ReHo of PUT.R; meanwhile, relative abundance of Clostridia increased by VSG was associated with improvements in aGLP-1 secretion, PUT.R activity, and weight loss. Importantly, VSG normalized excessive functional connectivities with PUT.R, among which baseline connectivity between PUT.R and right orbitofrontal cortex was related to postoperative weight loss.

Conclusion: VSG causes correlated alterations of gut-brain axis, including Clostridia, postprandial aGLP-1, PUT.R activity, and eating habits. Preoperative connectivity of PUT.R may represent a potential predictive marker of surgical outcome in patients with obesity.

Trial registration: ClinicalTrials.gov NCT01084967 NCT02653430.

Keywords: Clostridia; eating habits; fMRI; ghrelin; metagenomic sequencing; postprandial aGLP-1; vertical sleeve gastrectomy.

© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Figure 1.
Figure 1.
Study protocol and associations between regional brain activity, weight loss, and eating behaviors. (A) Diagram of the experimental design. (B) Brain regions showing significant functional changes (indexed by regional homogeneity, ReHo) in patients with obesity before and after VSG surgery (FDR corrected). (C) Comparisons of ReHo in PUT.R and SMA.L across 3 groups (PreOB, n = 33; PostOB, n = 16; NW, n = 25; *P < 0.05; ***P < 0.001). Data are presented as mean ± standard error of the mean. (D) Scatter plots of ReHo in PUT.R/SMA.L against BMI before and after VSG surgery (PreOB, n = 16; PostOB, n = 16). (E) Scatter plots of ReHo in PUT.R/SMA.L against TFEQ subscores before and after VSG surgery (PreOB, n = 16; PostOB, n = 16). Abbreviations: BMI, body mass index; fMRI, functional magnetic resonance imaging; NW, normal-weight subjects; OGTT, oral glucose tolerance test; PostOB, postoperative obese group; PreOB, preoperative obese group; PUT.R, right putamen; SMA.L, left supplementary motor area; TFEQ, Three-Factor Eating Questionnaire; VSG, vertical sleeve gastrectomy.
Figure 2.
Figure 2.
Brain-wide functional connectivity with right putamen is restored after VSG. (A) Seed-based analysis of the right putamen revealed brain-wide alterations of functional connectivity (FDR corrected). Color bar indicates t values. (B) Radar plot shown the comparisons of altered functional connectivity with the right putamen shown in (A) among obese groups and NW (PreOB, n = 33; PostOB, n = 16; NW, n = 25). Involved brain regions are grouped according to 4 putative neural circuits (color-coded) that may regulate eating habits. Asterisks denote significance levels between NW and PreOB (*P < 0.05; **P < 0.01; ***P < 0.001). (C) Correlation heatmap of changes in the right putamen-centered connectivity with BMI and TFEQ subscores (PreOB, n = 16; PostOB, n = 16). Red and blue colors indicate positive and negative correlation coefficients. Symbols denote significance levels of the correlations (+q < 0.05; *q < 0.01). The reported q-values here were FDR corrected for multiple comparisons. (D) Preoperative functional connectivity between PUT.R and OFC.R was significantly correlated with changes in BMI scores in patients with obesity (n = 16). Shaded areas indicate 95% CI. Abbreviations: FG.L, left fusiform gyrus; Frontal.L, white matter area in left frontal lobe; MFG.L, left middle frontal gyrus; MFG.R, right middle frontal gyrus; MOG.L, left middle occipital gyrus; MTG.R, right middle temporal gyrus; OFC.R, right orbitofrontal cortex; PCU, Precuneus; PostCG.L, left postcentral gyrus; PostCG.R, right postcentral gyrus; THA.L, left thalamus; THA.R, right thalamus.
Figure 3.
Figure 3.
Associations between intestinal hormones and regional brain activity. (A) Hormone plots of the oral glucose tolerance test (OGTT) in patients with obesity before (n = 19 for aGLP-1, Ghrelin, and Leptin; n = 18 for PYY) and after (n = 10 for 4 hormones) surgery and in normal-weight subjects (n = 10 for aGLP-1, Ghrelin, and Leptin; n = 9 for PYY). (B) Repeated measures correlations between brain activity and changes of intestinal hormones. Left panel (n = 16) and middle panel (n = 18) are scatter plots of AUC of aGLP-1 and Ghrelin, respectively, in the OGTT test against functional activity of the right putamen (ReHo). Right panel (n = 18) shows a scatter plot of AUC of Ghrelin in the OGTT test against functional connectivity of the PUT.R-MFG.L. (C) Correlation heatmap of changes in aGLP-1 and Ghrelin in the OGTT test with BMI and TFEQ subscores (n = 16 or 18). Red and blue colors indicate positive and negative correlations. Symbols denote significant levels of the correlations (+q 

Figure 4.

Associations between alterations in gut…

Figure 4.

Associations between alterations in gut microbiota, intestinal hormones, and brain activity. (A) Increased…

Figure 4.
Associations between alterations in gut microbiota, intestinal hormones, and brain activity. (A) Increased species of gut microbe in patients with obesity after VSG surgery (PreOB, n = 12; PostOB, n = 12; q 

Figure 5.

Functional pathway analysis of compositional…

Figure 5.

Functional pathway analysis of compositional changes in gut microbiota. (A) Overall microbial functional…

Figure 5.
Functional pathway analysis of compositional changes in gut microbiota. (A) Overall microbial functional enrichment analysis of the gut microbiota before and after surgery based on KEGG pathways (PreOB, n = 12; PostOB, n = 12). KEGG with reporter score > 1.65 or
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References
    1. Ng M, Fleming T, Robinson M, et al. . Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384(9945):766-781. - PMC - PubMed
    1. Arterburn DE, Telem DA, Kushner RF, Courcoulas AP. Benefits and risks of bariatric surgery in adults: a review. JAMA. 2020;324(9):879-887. - PubMed
    1. Casimiro I, Sam S, Brady MJ. Endocrine implications of bariatric surgery: a review on the intersection between incretins, bone, and sex hormones. Physiol Rep. 2019;7(10):e14111. - PMC - PubMed
    1. Miras AD, le Roux CW. Mechanisms underlying weight loss after bariatric surgery. Nat Rev Gastroenterol Hepatol. 2013;10(10):575-584. - PubMed
    1. Madsbad S, Holst JJ. GLP-1 as a mediator in the remission of type 2 diabetes after gastric bypass and sleeve gastrectomy surgery. Diabetes. 2014;63(10):3172-3174. - PubMed
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Figure 4.
Figure 4.
Associations between alterations in gut microbiota, intestinal hormones, and brain activity. (A) Increased species of gut microbe in patients with obesity after VSG surgery (PreOB, n = 12; PostOB, n = 12; q 

Figure 5.

Functional pathway analysis of compositional…

Figure 5.

Functional pathway analysis of compositional changes in gut microbiota. (A) Overall microbial functional…

Figure 5.
Functional pathway analysis of compositional changes in gut microbiota. (A) Overall microbial functional enrichment analysis of the gut microbiota before and after surgery based on KEGG pathways (PreOB, n = 12; PostOB, n = 12). KEGG with reporter score > 1.65 or
Similar articles
Cited by
References
    1. Ng M, Fleming T, Robinson M, et al. . Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384(9945):766-781. - PMC - PubMed
    1. Arterburn DE, Telem DA, Kushner RF, Courcoulas AP. Benefits and risks of bariatric surgery in adults: a review. JAMA. 2020;324(9):879-887. - PubMed
    1. Casimiro I, Sam S, Brady MJ. Endocrine implications of bariatric surgery: a review on the intersection between incretins, bone, and sex hormones. Physiol Rep. 2019;7(10):e14111. - PMC - PubMed
    1. Miras AD, le Roux CW. Mechanisms underlying weight loss after bariatric surgery. Nat Rev Gastroenterol Hepatol. 2013;10(10):575-584. - PubMed
    1. Madsbad S, Holst JJ. GLP-1 as a mediator in the remission of type 2 diabetes after gastric bypass and sleeve gastrectomy surgery. Diabetes. 2014;63(10):3172-3174. - PubMed
Show all 61 references
Publication types
MeSH terms
Associated data
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 5.
Figure 5.
Functional pathway analysis of compositional changes in gut microbiota. (A) Overall microbial functional enrichment analysis of the gut microbiota before and after surgery based on KEGG pathways (PreOB, n = 12; PostOB, n = 12). KEGG with reporter score > 1.65 or

References

    1. Ng M, Fleming T, Robinson M, et al. . Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384(9945):766-781.
    1. Arterburn DE, Telem DA, Kushner RF, Courcoulas AP. Benefits and risks of bariatric surgery in adults: a review. JAMA. 2020;324(9):879-887.
    1. Casimiro I, Sam S, Brady MJ. Endocrine implications of bariatric surgery: a review on the intersection between incretins, bone, and sex hormones. Physiol Rep. 2019;7(10):e14111.
    1. Miras AD, le Roux CW. Mechanisms underlying weight loss after bariatric surgery. Nat Rev Gastroenterol Hepatol. 2013;10(10):575-584.
    1. Madsbad S, Holst JJ. GLP-1 as a mediator in the remission of type 2 diabetes after gastric bypass and sleeve gastrectomy surgery. Diabetes. 2014;63(10):3172-3174.
    1. Al-Najim W, Docherty NG, le Roux CW. Food intake and eating behavior after bariatric surgery. Physiol Rev. 2018;98(3):1113-1141.
    1. Gautron L, Elmquist JK, Williams KW. Neural control of energy balance: translating circuits to therapies. Cell. 2015;161(1):133-145.
    1. Ten Kulve JS, Veltman DJ, Gerdes VEA, et al. . Elevated postoperative endogenous GLP-1 levels mediate effects of roux-en-Y gastric bypass on neural responsivity to food cues. Diabetes Care. 2017;40(11):1522-1529.
    1. Frank S, Heinze JM, Fritsche A, et al. . Neuronal food reward activity in patients with type 2 diabetes with improved glycemic control after bariatric surgery. Diabetes Care. 2016;39(8):1311-1317.
    1. Stefater MA, Wilson-Pérez HE, Chambers AP, Sandoval DA, Seeley RJ. All bariatric surgeries are not created equal: insights from mechanistic comparisons. Endocr Rev. 2012;33(4): 595-622.
    1. Dang JT, Karmali S. Is RYGB more effective than sleeve gastrectomy? Nat Rev Endocrinol. 2019;15(3):134-135.
    1. Pearce AL, Mackey E, Cherry JBC, et al. . Effect of adolescent bariatric surgery on the brain and cognition: a pilot study. Obesity (Silver Spring). 2017;25(11):1852-1860.
    1. Li G, Ji G, Hu Y, et al. . Bariatric surgery in obese patients reduced resting connectivity of brain regions involved with self-referential processing. Hum Brain Mapp. 2018;39(12): 4755-4765.
    1. Biswal B, Yetkin FZ, Haughton VM, Hyde JS. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med. 1995;34(4):537-541.
    1. He Y, Ma G, Zhai F, et al. . Dietary patterns and glucose tolerance abnormalities in Chinese adults. Diabetes Care. 2009;32(11):1972-1976.
    1. Larraufie P, Roberts GP, McGavigan AK, et al. . Important role of the GLP-1 axis for glucose homeostasis after bariatric surgery. Cell Rep. 2019;26(6):1399-1408.e6.
    1. Cummings DE, Weigle DS, Frayo RS, et al. . Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med. 2002;346(21):1623-1630.
    1. De Silva A, Salem V, Long CJ, et al. . The gut hormones PYY 3-36 and GLP-1 7-36 amide reduce food intake and modulate brain activity in appetite centers in humans. Cell Metab. 2011;14(5):700-706.
    1. Malik S, McGlone F, Bedrossian D, Dagher A. Ghrelin modulates brain activity in areas that control appetitive behavior. Cell Metab. 2008;7(5):400-409.
    1. Ochner CN, Kwok Y, Conceição E, et al. . Selective reduction in neural responses to high calorie foods following gastric bypass surgery. Ann Surg. 2011;253(3):502-507.
    1. Kong LC, Tap J, Aron-Wisnewsky J, et al. . Gut microbiota after gastric bypass in human obesity: increased richness and associations of bacterial genera with adipose tissue genes. Am J Clin Nutr. 2013;98(1):16-24.
    1. Sinclair P, Brennan DJ, le Roux CW. Gut adaptation after metabolic surgery and its influences on the brain, liver and cancer. Nat Rev Gastroenterol Hepatol. 2018;15(10):606-624.
    1. Liu R, Hong J, Xu X, et al. . Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention. Nat Med. 2017;23(7):859-868.
    1. Tremaroli V, Karlsson F, Werling M, et al. . Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation. Cell Metab. 2015;22(2):228-238.
    1. Stunkard AJ, Messick S. The three-factor eating questionnaire to measure dietary restraint, disinhibition and hunger. J Psychosom Res. 1985;29(1):71-83.
    1. Cappelleri JC, Bushmakin AG, Gerber RA, et al. . Psychometric analysis of the Three-Factor Eating Questionnaire-R21: results from a large diverse sample of obese and non-obese participants. Int J Obes (Lond). 2009;33(6):611-620.
    1. Chao-Gan Y, Yu-Feng Z. DPARSF: a MATLAB toolbox for “Pipeline” data analysis of resting-state fMRI. Front Syst Neurosci. 2010;4:13.
    1. Cui Y, Jiao Y, Chen YC, et al. . Altered spontaneous brain activity in type 2 diabetes: a resting-state functional MRI study. Diabetes. 2014;63(2):749-760.
    1. Ehrlich S, Borchardt V, Walter M, Seidel M. F63. Abnormal spontaneous regional brain activity in acutely underweight patients with anorexia nervosa. Biol Psychiatry. 2019;85(10):S237.
    1. Zang Y, Jiang T, Lu Y, He Y, Tian L. Regional homogeneity approach to fMRI data analysis. Neuroimage. 2004;22(1):394-400.
    1. Truong DT, Franzosa EA, Tickle TL, et al. . MetaPhlAn2 for enhanced metagenomic taxonomic profiling. Nat Methods. 2015;12(10):902-903.
    1. Feng Q, Liang S, Jia H, et al. . Gut microbiome development along the colorectal adenoma-carcinoma sequence. Nat Commun. 2015;6:6528.
    1. Vieira-Silva S, Falony G, Darzi Y, et al. . Species-function relationships shape ecological properties of the human gut microbiome. Nat Microbiol. 2016;1(8):16088.
    1. Chen G, Saad ZS, Britton JC, Pine DS, Cox RW. Linear mixed-effects modeling approach to FMRI group analysis. Neuroimage. 2013;73:176-190.
    1. Flannery JS, Riedel MC, Poudel R, et al. . Habenular and striatal activity during performance feedback are differentially linked with state-like and trait-like aspects of tobacco use disorder. Sci Adv. 2019;5(10):eaax2084.
    1. Bates D, Machler M, Bolker BM, Walker SC. Fitting linear mixed-effects models using lme4. J Stat Softw. 2015;67(1):1-48.
    1. Yin HH, Knowlton BJ. The role of the basal ganglia in habit formation. Nat Rev Neurosci. 2006;7(6):464-476.
    1. Jahanshahi M, Obeso I, Rothwell JC, Obeso JA. A fronto-striato-subthalamic-pallidal network for goal-directed and habitual inhibition. Nat Rev Neurosci. 2015;16(12):719-732.
    1. Bakdash JZ, Marusich LR. Repeated measures correlation. Front Psychol. 2017;8:456.
    1. Olivo G, Zhou W, Sundbom M, et al. . Resting-state brain connectivity changes in obese women after Roux-en-Y gastric bypass surgery: a longitudinal study. Sci Rep. 2017;7(1):6616.
    1. Thanarajah SE, Backes H, DiFeliceantonio AG, et al. . Food intake recruits orosensory and post-ingestive dopaminergic circuits to affect eating desire in humans. Cell Metab. 2019;29(3): 695-706.e4.
    1. van Bloemendaal L, Veltman DJ, Ten Kulve JS, et al. . Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans. Diabetes Obes Metab. 2015;17(9):878-886.
    1. Sweet LH, Hassenstab JJ, McCaffery JM, et al. . Brain response to food stimulation in obese, normal weight, and successful weight loss maintainers. Obesity (Silver Spring). 2012;20(11):2220-2225.
    1. Murdaugh DL, Cox JE, Cook EW 3rd, Weller RE. fMRI reactivity to high-calorie food pictures predicts short- and long-term outcome in a weight-loss program. Neuroimage. 2012;59(3):2709-2721.
    1. Scholtz S, Miras AD, Chhina N, et al. . Obese patients after gastric bypass surgery have lower brain-hedonic responses to food than after gastric banding. Gut. 2014;63(6):891-902.
    1. Kringelbach ML. The human orbitofrontal cortex: linking reward to hedonic experience. Nat Rev Neurosci. 2005;6(9):691-702.
    1. Farr OM, Sofopoulos M, Tsoukas MA, et al. . GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial. Diabetologia. 2016;59(5):954-965.
    1. Wilson-Pérez HE, Chambers AP, Ryan KK, et al. . Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon-like Peptide 1 receptor deficiency. Diabetes. 2013;62(7):2380-2385.
    1. Faulconbridge LF, Ruparel K, Loughead J, et al. . Changes in neural responsivity to highly palatable foods following roux-en-Y gastric bypass, sleeve gastrectomy, or weight stability: An fMRI study. Obesity (Silver Spring). 2016;24(5):1054-1060.
    1. Chambers AP, Kirchner H, Wilson-Perez HE, et al. . The effects of vertical sleeve gastrectomy in rodents are ghrelin independent. Gastroenterology. 2013;144(1):50-52.e5.
    1. Perakakis N, Kokkinos A, Peradze N, et al. . Circulating levels of gastrointestinal hormones in response to the most common types of bariatric surgery and predictive value for weight loss over one year: Evidence from two independent trials. Metabolism. 2019;101:153997.
    1. Furet JP, Kong LC, Tap J, et al. . Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes. 2010;59(12):3049-3057.
    1. Liou AP, Paziuk M, Luevano JM Jr, Machineni S, Turnbaugh PJ, Kaplan LM. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med. 2013;5(178):178ra41.
    1. Zhang H, DiBaise JK, Zuccolo A, et al. . Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci U S A. 2009;106(7):2365-2370.
    1. Faria SL, Santos A, Magro DO, et al. . Gut microbiota modifications and weight regain in morbidly obese women after roux-en-Y gastric bypass. Obes Surg. 2020;30(12):4958-4966.
    1. Ley RE, Bäckhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A. 2005;102(31):11070-11075.
    1. Hwang I, Park YJ, Kim YR, et al. . Alteration of gut microbiota by vancomycin and bacitracin improves insulin resistance via glucagon-like peptide 1 in diet-induced obesity. Faseb J. 2015;29(6):2397-2411.
    1. Everard A, Cani PD. Gut microbiota and GLP-1. Rev Endocr Metab Disord. 2014;15(3):189-196.
    1. Yadav H, Lee JH, Lloyd J, Walter P, Rane SG. Beneficial metabolic effects of a probiotic via butyrate-induced GLP-1 hormone secretion. J Biol Chem. 2013;288(35):25088-25097.
    1. Blaut M. Gut microbiota and energy balance: role in obesity. Proc Nutr Soc. 2015;74(3):227-234.
    1. Petersen C, Bell R, Klag KA, et al. . T cell-mediated regulation of the microbiota protects against obesity. Science. 2019;365(6451):eaat9351.

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