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Potential gut–brain mechanisms behind adverse mental health outcomes of bariatric surgery

Nature Reviews Endocrinology volume 17, pages 549–559 (2021)Cite this article

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Abstract

Bariatric surgery induces sustained weight loss and metabolic benefits via notable effects on the gut–brain axis that lead to alterations in the neuroendocrine regulation of appetite and glycaemia. However, in a subset of patients, bariatric surgery is associated with adverse effects on mental health, including increased risk of suicide or self-harm as well as the emergence of depression and substance use disorders. The contributing factors behind these adverse effects are not well understood. Accumulating evidence indicates that there are important links between gut-derived hormones, microbial and bile acid profiles, and disorders of mood and substance use, which warrant further exploration in the context of changes in gut–brain signalling after bariatric surgery. Understanding the basis of these adverse effects is essential in order to optimize the health and well-being of people undergoing treatment for obesity.

Key points

  • After bariatric surgery, a subset of patients experience adverse mental health outcomes such as depression, anxiety, and increased use of alcohol and drugs.

  • Preclinical and clinical studies link appetite-related gut peptides, including ghrelin, glucagon-like peptide 1, peptide YY and cholecystokinin, with depression and anxiety.

  • Central ghrelin signalling seems to be involved in driving increases in the rewarding properties of alcohol following bariatric surgery.

  • Gut bacteria might influence mood and behaviour, and exposure to drugs of abuse, such as alcohol and opioids, induces gut microbial dysbiosis.

  • Emerging literature indicates that bile acids can have central effects on mood and behavioural responses induced by cocaine.

  • Taken together, these findings implicate potential mechanisms by which bariatric surgery could influence mood and behaviour; further research is essential to understand and prevent adverse mental health outcomes after bariatric surgery.

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Fig. 1: Common bariatric surgery procedures.
Fig. 2: Gut–brain mechanisms proposed to contribute to mental health effects after bariatric surgery.

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References

  1. Sjostrom, L. et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N. Engl. J. Med. 351, 2683–2693 (2004).

    Article  PubMed  Google Scholar 

  2. Sjostrom, L. et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N. Engl. J. Med. 357, 741–752 (2007).

    Article  PubMed  Google Scholar 

  3. Evers, S. S., Sandoval, D. A. & Seeley, R. J. The physiology and molecular underpinnings of the effects of bariatric surgery on obesity and diabetes. Annu. Rev. Physiol. 79, 313–334 (2017).

    Article  CAS  PubMed  Google Scholar 

  4. Miras, A. D. & le Roux, C. W. Mechanisms underlying weight loss after bariatric surgery. Nat. Rev. Gastroenterol. Hepatol. 10, 575–584 (2013).

    Article  PubMed  Google Scholar 

  5. Castaneda, D., Popov, V. B., Wander, P. & Thompson, C. C. Risk of suicide and self-harm is increased after bariatric surgery — a systematic review and meta-analysis. Obes. Surg. 29, 322–333 (2019).

    Article  PubMed  Google Scholar 

  6. Backman, O., Stockeld, D., Rasmussen, F., Naslund, E. & Marsk, R. Alcohol and substance abuse, depression and suicide attempts after Roux-en-Y gastric bypass surgery. Br. J. Surg. 103, 1336–1342 (2016).

    Article  CAS  PubMed  Google Scholar 

  7. Huang, T. T. et al. Current understanding of gut microbiota in mood disorders: an update of human studies. Front. Genet. 10, 98 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ramos, A. et al. Fifth IFSO Global Registry Report. https://www.ifso.com/pdf/5th-ifso-global-registry-report-september-2019.pdf (2019).

  9. Okano-Matsumoto, S., McRoberts, J. A., Tache, Y. & Adelson, D. W. Electrophysiological evidence for distinct vagal pathways mediating CCK-evoked motor effects in the proximal versus distal stomach. J. Physiol. 589, 371–393 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Meek, C. L., Lewis, H. B., Reimann, F., Gribble, F. M. & Park, A. J. The effect of bariatric surgery on gastrointestinal and pancreatic peptide hormones. Peptides 77, 28–37 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. Morinigo, R. et al. Glucagon-like peptide-1, peptide YY, hunger, and satiety after gastric bypass surgery in morbidly obese subjects. J. Clin. Endocrinol. Metab. 91, 1735–1740 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. McCarty, T. R., Jirapinyo, P. & Thompson, C. C. Effect of sleeve gastrectomy on ghrelin, GLP-1, PYY, and GIP gut hormones: a systematic review and meta-analysis. Ann. Surg. 272, 72–80 (2020).

    Article  PubMed  Google Scholar 

  13. Xu, H.-C. et al. Systematic review and meta-analysis of the change in ghrelin levels after roux-en-Y gastric bypass. Obes. Surg. 29, 1343–1351 (2019).

    Article  PubMed  Google Scholar 

  14. Chambers, A. P. et al. The effects of vertical sleeve gastrectomy in rodents are ghrelin independent. Gastroenterology 144, 50–52.e5 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Hunt, K. F. et al. Differences in regional brain responses to food ingestion after roux-en-Y gastric bypass and the role of gut peptides: a neuroimaging study. Diabetes Care 39, 1787–1795 (2016).

    Article  CAS  PubMed  Google Scholar 

  16. le Roux, C. W. et al. Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass. Ann. Surg. 246, 780–785 (2007). This study evaluates the time course and contribution of gut-derived satiety hormones on appetite regulation after RYGB.

    Article  PubMed  Google Scholar 

  17. Yoshino, M. et al. Effects of diet versus gastric bypass on metabolic function in diabetes. N. Engl. J. Med. 383, 721–732 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dirksen, C. et al. Mechanisms of improved glycaemic control after Roux-en-Y gastric bypass. Diabetologia 55, 1890–1901 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Schwiertz, A. et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity 18, 190–195 (2010).

    Article  PubMed  Google Scholar 

  22. Le Chatelier, E. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546 (2013).

    Article  PubMed  CAS  Google Scholar 

  23. Canfora, E. E., Meex, R. C. R., Venema, K. & Blaak, E. E. Gut microbial metabolites in obesity, NAFLD and T2DM. Nat. Rev. Endocrinol. 15, 261–273 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. Tremaroli, V. 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. 22, 228–238 (2015). This paper shows long-term alterations in gut microbial composition and function after bariatric surgery and their potential to modulate host metabolism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Liou, A. P. et al. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci. Transl. Med. 5, 178ra141 (2013).

    Article  CAS  Google Scholar 

  26. Russell, D. W. The enzymes, regulation, and genetics of bile acid synthesis. Annu. Rev. Biochem. 72, 137–174 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Staudinger, J. L. et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc. Natl Acad. Sci. USA 98, 3369–3374 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Makishima, M. et al. Vitamin D receptor as an intestinal bile acid sensor. Science 296, 1313–1316 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Steinert, R. E. et al. Bile acids and gut peptide secretion after bariatric surgery: a 1-year prospective randomized pilot trial. Obesity 21, E660–E668 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Jorgensen, N. B. et al. Improvements in glucose metabolism early after gastric bypass surgery are not explained by increases in total bile acids and fibroblast growth factor 19 concentrations. J. Clin. Endocrinol. Metab. 100, E396–E406 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. Chen, Y., Lu, J., Nemati, R., Plank, L. D. & Murphy, R. Acute changes of bile acids and FGF19 after sleeve gastrectomy and roux-en-Y gastric bypass. Obes. Surg. 29, 3605–3621 (2019).

    Article  PubMed  Google Scholar 

  32. Albaugh, V. L. et al. Early increases in bile acids post roux-en-Y gastric bypass are driven by insulin-sensitizing, secondary bile acids. J. Clin. Endocrinol. Metab. 100, E1225–E1233 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Nemati, R. et al. Increased bile acids and FGF19 after sleeve gastrectomy and roux-en-Y gastric bypass correlate with improvement in type 2 diabetes in a randomized trial. Obes. Surg. 28, 2672–2686 (2018).

    Article  PubMed  Google Scholar 

  34. Albaugh, V. L. et al. Role of bile acids and GLP-1 in mediating the metabolic improvements of bariatric surgery. Gastroenterology 156, 1041–1051.e4 (2019).

    Article  CAS  PubMed  Google Scholar 

  35. Kalarchian, M. A. et al. Mental disorders and weight change in a prospective study of bariatric surgery patients: 7 years of follow-up. Surg. Obes. Relat. Dis. 15, 739–748 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Mitchell, J. E. et al. Course of depressive symptoms and treatment in the longitudinal assessment of bariatric surgery (LABS-2) study. Obesity 22, 1799–1806 (2014).

    Article  PubMed  Google Scholar 

  37. Mitchell, J. E. et al. Possible risk factors for increased suicide following bariatric surgery. Obesity 21, 665–672 (2013).

    Article  PubMed  Google Scholar 

  38. Stammers, L. et al. Identifying stress-related eating in behavioural research: a review. Hormones Behav. 124, 104752 (2020).

    Article  Google Scholar 

  39. Lagerros, Y. T., Brandt, L., Hedberg, J., Sundbom, M. & Bodén, R. Suicide, self-harm, and depression after gastric bypass surgery: a nationwide cohort study. Ann. Surg. 265, 235–243 (2017).

    Article  PubMed  Google Scholar 

  40. Hamad, G. G. et al. The effect of gastric bypass on the pharmacokinetics of serotonin reuptake inhibitors. Am. J. Psychiatry 169, 256–263 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Neovius, M. et al. Risk of suicide and non-fatal self-harm after bariatric surgery: results from two matched cohort studies. Lancet Diabetes Endocrinol. 6, 197–207 (2018). This article shows an increased risk of suicide and self-harm after bariatric surgery in two separate cohorts, among patients with and without known psychiatric disorders.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Morgan, D. J. R., Ho, K. M. & Platell, C. Incidence and determinants of mental health service use after bariatric surgery. JAMA Psychiatry 77, 60–67 (2020).

    Article  PubMed  Google Scholar 

  43. Knop, J. & Fischer, A. Duodenal ulcer, suicide, psychopathology and alcoholism. Acta Psychiatr. Scand. 63, 346–355 (1981).

    Article  CAS  PubMed  Google Scholar 

  44. Klarer, M. et al. Gut vagal afferents differentially modulate innate anxiety and learned fear. J. Neurosci. 34, 7067–7076 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lutter, M. et al. The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat. Neurosci. 11, 752–753 (2008). Through several experimental approaches, this paper shows a role of ghrelin in defending against anxiety-like and depression-like behaviour.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Alvarez-Crespo, M. et al. The amygdala as a neurobiological target for ghrelin in rats: neuroanatomical, electrophysiological and behavioral evidence. PLoS ONE 7, e46321 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Spencer, S. J. et al. Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress. Biol. Psychiatry 72, 457–465 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Asakawa, A. et al. A role of ghrelin in neuroendocrine and behavioral responses to stress in mice. Neuroendocrinology 74, 143–147 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Currie, P. J. et al. Ghrelin is an orexigenic peptide and elicits anxiety-like behaviors following administration into discrete regions of the hypothalamus. Behav. Brain Res. 226, 96–105 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. Hansson, C. et al. Central administration of ghrelin alters emotional responses in rats: behavioural, electrophysiological and molecular evidence. Neuroscience 180, 201–211 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Carlini, V. P. et al. Acute ghrelin administration reverses depressive-like behavior induced by bilateral olfactory bulbectomy in mice. Peptides 35, 160–165 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Huang, H. J. et al. Ghrelin alleviates anxiety- and depression-like behaviors induced by chronic unpredictable mild stress in rodents. Behav. Brain Res. 326, 33–43 (2017).

    Article  CAS  PubMed  Google Scholar 

  53. Schmid, D. A. et al. Ghrelin stimulates appetite, imagination of food, GH, ACTH, and cortisol, but does not affect leptin in normal controls. Neuropsychopharmacology 30, 1187–1192 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Kluge, M. et al. Effects of ghrelin on psychopathology, sleep and secretion of cortisol and growth hormone in patients with major depression. J. Psychiatr. Res. 45, 421–426 (2011).

    Article  PubMed  Google Scholar 

  55. Lundholm, K. et al. Effects by daily long term provision of ghrelin to unselected weight-losing cancer patients: a randomized double-blind study. Cancer 116, 2044–2052 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Cain, B. M. et al. Distribution and colocalization of cholecystokinin with the prohormone convertase enzymes PC1, PC2, and PC5 in rat brain. J. Comp. Neurol. 467, 307–325 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Rezayat, M., Roohbakhsh, A., Zarrindast, M. R., Massoudi, R. & Djahanguiri, B. Cholecystokinin and GABA interaction in the dorsal hippocampus of rats in the elevated plus-maze test of anxiety. Physiol. Behav. 84, 775–782 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Hernando, F., Fuentes, J. A., Roques, B. P. & Ruiz-Gayo, M. The CCKB receptor antagonist, L-365,260, elicits antidepressant-type effects in the forced-swim test in mice. Eur. J. Pharmacol. 261, 257–263 (1994).

    Article  CAS  PubMed  Google Scholar 

  59. Chen, Q. et al. Bi-directional effect of cholecystokinin receptor-2 overexpression on stress-triggered fear memory and anxiety in the mouse. PLoS ONE 5, e15999 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Becker, C. et al. Repeated social defeat-induced depression-like behavioral and biological alterations in rats: involvement of cholecystokinin. Mol. Psychiatry 13, 1079–1092 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Bradwejn, J., Koszycki, D. & Meterissian, G. Cholecystokinin-tetrapeptide induces panic attacks in patients with panic disorder. Can. J. Psychiatry 35, 83–85 (1990).

    Article  CAS  PubMed  Google Scholar 

  62. van Megen, H. J., Westenberg, H. G., den Boer, J. A., Haigh, J. R. & Traub, M. Pentagastrin induced panic attacks: enhanced sensitivity in panic disorder patients. Psychopharmacology 114, 449–455 (1994).

    Article  PubMed  Google Scholar 

  63. Bradwejn, J. et al. The panicogenic effects of cholecystokinin-tetrapeptide are antagonized by L-365,260, a central cholecystokinin receptor antagonist, in patients with panic disorder. Arch. Gen. Psychiatry 51, 486–493 (1994).

    Article  CAS  PubMed  Google Scholar 

  64. Adams, J. B. et al. A double-blind, placebo-controlled study of a CCK-B receptor antagonist, CI-988, in patients with generalized anxiety disorder. J. Clin. Psychopharmacol. 15, 428–434 (1995).

    Article  CAS  PubMed  Google Scholar 

  65. Kramer, M. S. et al. A placebo-controlled trial of L-365,260, a CCKB antagonist, in panic disorder. Biol. Psychiatry 37, 462–466 (1995).

    Article  CAS  PubMed  Google Scholar 

  66. de Montigny, C. Cholecystokinin tetrapeptide induces panic-like attacks in healthy volunteers. Preliminary findings. Arch. Gen. Psychiatry 46, 511–517 (1989).

    Article  PubMed  Google Scholar 

  67. Secher, A. et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J. Clin. Invest. 124, 4473–4488 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Alvarez, E. et al. The expression of GLP-1 receptor mRNA and protein allows the effect of GLP-1 on glucose metabolism in the human hypothalamus and brainstem. J. Neurochem. 92, 798–806 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Rinaman, L. Interoceptive stress activates glucagon-like peptide-1 neurons that project to the hypothalamus. Am. J. Physiol. 277, R582–R590 (1999).

    CAS  PubMed  Google Scholar 

  70. Kinzig, K. P. et al. CNS glucagon-like peptide-1 receptors mediate endocrine and anxiety responses to interoceptive and psychogenic stressors. J. Neurosci. 23, 6163–6170 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Isacson, R. et al. The glucagon-like peptide 1 receptor agonist exendin-4 improves reference memory performance and decreases immobility in the forced swim test. Eur. J. Pharmacol. 650, 249–255 (2011).

    Article  CAS  PubMed  Google Scholar 

  72. Anderberg, R. H. et al. GLP-1 is both anxiogenic and antidepressant; divergent effects of acute and chronic GLP-1 on emotionality. Psychoneuroendocrinology 65, 54–66 (2016).

    Article  CAS  PubMed  Google Scholar 

  73. Strawn, J. R., D’Alessio, D. A., Keck, P. E. Jr. & Seeley, R. J. Failure of glucagon-like peptide-1 to induce panic attacks or anxiety in patients with panic disorder. J. Psychiatr. Res. 42, 787–789 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. van Bloemendaal, L. et al. GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes 63, 4186–4196 (2014).

    Article  PubMed  CAS  Google Scholar 

  75. Bode, B. W. et al. Patient-reported outcomes following treatment with the human GLP-1 analogue liraglutide or glimepiride in monotherapy: results from a randomized controlled trial in patients with type 2 diabetes. Diabetes Obes. Metab. 12, 604–612 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kahal, H., Kilpatrick, E., Rigby, A., Coady, A. & Atkin, S. The effects of treatment with liraglutide on quality of life and depression in young obese women with PCOS and controls. Gynecol. Endocrinol. 35, 142–145 (2019).

    Article  CAS  PubMed  Google Scholar 

  77. Grant, P., Lipscomb, D. & Quin, J. Psychological and quality of life changes in patients using GLP-1 analogues. J. Diabetes Complications 25, 244–246 (2011).

    Article  PubMed  Google Scholar 

  78. Adrian, T. E. et al. Neuropeptide Y distribution in human brain. Nature 306, 584–586 (1983).

    Article  CAS  PubMed  Google Scholar 

  79. Redrobe, J. P., Dumont, Y., Fournier, A. & Quirion, R. The neuropeptide Y (NPY) Y1 receptor subtype mediates NPY-induced antidepressant-like activity in the mouse forced swimming test. Neuropsychopharmacology 26, 615–624 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Karl, T., Burne, T. H. J. & Herzog, H. Effect of Y1 receptor deficiency on motor activity, exploration, and anxiety. Behav. Brain Res. 167, 87–93 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Morales-Medina, J. C. et al. Role of neuropeptide Y Y1 and Y2 receptors on behavioral despair in a rat model of depression with co-morbid anxiety. Neuropharmacology 62, 200–208 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Yamada, C., Mogami, S., Kanno, H. & Hattori, T. Peptide YY causes apathy-like behavior via the dopamine D2 receptor in repeated water-immersed mice. Mol. Neurobiol. 55, 7555–7566 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Painsipp, E. et al. Reduced anxiety-like and depression-related behavior in neuropeptide Y Y4 receptor knockout mice. Genes Brain Behav. 7, 532–542 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Asakawa, A. et al. Mouse pancreatic polypeptide modulates food intake, while not influencing anxiety in mice. Peptides 20, 1445–1448 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Zhou, Z. et al. Genetic variation in human NPY expression affects stress response and emotion. Nature 452, 997–1001 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Domschke, K. et al. Neuropeptide Y (NPY) gene: Impact on emotional processing and treatment response in anxious depression. Eur. Neuropsychopharmacol. 20, 301–309 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Kristenssson, E. et al. Acute psychological stress raises plasma ghrelin in the rat. Regul. Pept. 134, 114–117 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Lambert, E. et al. Ghrelin modulates sympathetic nervous system activity and stress response in lean and overweight men. Hypertension 58, 43–50 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Langer, F. B. et al. Sleeve gastrectomy and gastric banding: effects on plasma ghrelin levels. Obes. Surg. 15, 1024–1029 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Diaz Heijtz, R. et al. Normal gut microbiota modulates brain development and behavior. Proc. Natl Acad. Sci. USA 108, 3047–3052 (2011).

    Article  PubMed  Google Scholar 

  91. Naseribafrouei, A. et al. Correlation between the human fecal microbiota and depression. Neurogastroenterol. Motil. 26, 1155–1162 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. Jiang, H. Y. et al. Altered gut microbiota profile in patients with generalized anxiety disorder. J. Psychiatr. Res. 104, 130–136 (2018).

    Article  PubMed  Google Scholar 

  93. Zheng, P. et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol. Psychiatry 21, 786–796 (2016).

    Article  CAS  PubMed  Google Scholar 

  94. Li, J. et al. Short term intrarectal administration of sodium propionate induces antidepressant-like effects in rats exposed to chronic unpredictable mild stress. Front. Psychiatry 9, 454 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Kelly, J. R. et al. Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J. Psychiatr. Res. 82, 109–118 (2016).

    Article  PubMed  Google Scholar 

  96. Kelly, J. R. et al. Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects. Brain Behav. Immun. 61, 50–59 (2017).

    Article  CAS  PubMed  Google Scholar 

  97. Messaoudi, M. et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br. J. Nutr. 105, 755–764 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Pinto-Sanchez, M. I. et al. Probiotic bifidobacterium longum NCC3001 reduces depression scores and alters brain activity: a pilot study in patients with irritable bowel syndrome. Gastroenterology 153, 448–459.e8 (2017).

    Article  PubMed  Google Scholar 

  99. Valles-Colomer, M. et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat. Microbiol. 4, 623–632 (2019).

    Article  CAS  PubMed  Google Scholar 

  100. Yamawaki, Y. et al. Antidepressant-like effect of sodium butyrate (HDAC inhibitor) and its molecular mechanism of action in the rat hippocampus. World J. Biol. Psychiatry 13, 458–467 (2012).

    Article  PubMed  Google Scholar 

  101. Sun, J. et al. Antidepressant-like effects of sodium butyrate and its possible mechanisms of action in mice exposed to chronic unpredictable mild stress. Neurosci. Lett. 618, 159–166 (2016).

    Article  CAS  PubMed  Google Scholar 

  102. Huang, C. et al. Identification of functional farnesoid X receptors in brain neurons. FEBS Lett. 590, 3233–3242 (2016).

    Article  CAS  PubMed  Google Scholar 

  103. Huang, F. et al. Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior. Front. Behav. Neurosci. 9, 70 (2015).

    PubMed  PubMed Central  Google Scholar 

  104. Chen, W. G., Zheng, J. X., Xu, X., Hu, Y. M. & Ma, Y. M. Hippocampal FXR plays a role in the pathogenesis of depression: a preliminary study based on lentiviral gene modulation. Psychiatry Res. 264, 374–379 (2018).

    Article  PubMed  Google Scholar 

  105. Lu, X. et al. Tauroursodeoxycholic acid produces antidepressant-like effects in a chronic unpredictable stress model of depression via attenuation of neuroinflammation, oxido-nitrosative stress, and endoplasmic reticulum stress. Fundam. Clin. Pharmacol. 32, 363–377 (2018).

    Article  CAS  PubMed  Google Scholar 

  106. Şen, O., Ünübol, H., Türkçapar, A. G. & Yerdel, M. A. Risk of alcohol use disorder after sleeve gastrectomy. J. Laparoendosc. Adv. Surg. Tech. A 31, 24–28 (2020).

    Article  PubMed  Google Scholar 

  107. Li, L. & Wu, L. T. Substance use after bariatric surgery: a review. J. Psychiatr. Res. 76, 16–29 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Raebel, M. A. et al. Chronic use of opioid medications before and after bariatric surgery. JAMA 310, 1369–1376 (2013). A retrospective cohort study of 11,719 individuals that shows increased opioid use following bariatric surgery.

    Article  CAS  PubMed  Google Scholar 

  109. Bak, M., Seibold-Simpson, S. M. & Darling, R. The potential for cross-addiction in post-bariatric surgery patients: considerations for primary care nurse practitioners. J. Am. Assoc. Nurse Pract. 28, 675–682 (2016).

    Article  PubMed  Google Scholar 

  110. McFadden, K. M. Cross-addiction: from morbid obesity to substance abuse. Bariatr. Nurs. Surg. Patient Care 5, 145–178 (2010).

    Article  Google Scholar 

  111. King, W. C. et al. Prevalence of alcohol use disorders before and after bariatric surgery. JAMA 307, 2516–2525 (2012). The first large multicentre observational study showing increased alcohol use and incidence of AUD in the second year following bariatric surgery as compared with the year before or 1 year after.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hajnal, A. et al. Alcohol reward is increased after Roux-en-Y gastric bypass in dietary obese rats with differential effects following ghrelin antagonism. PLoS ONE 7, e49121 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Sirohi, S., Richardson, B. D., Lugo, J. M., Rossi, D. J. & Davis, J. F. Impact of Roux-en-Y gastric bypass surgery on appetite, alcohol intake behaviors, and midbrain ghrelin signaling in the rat. Obesity 25, 1228–1236 (2017).

    Article  CAS  PubMed  Google Scholar 

  114. King, W. C. et al. Alcohol and other substance use after bariatric surgery: prospective evidence from a U.S. multicenter cohort study. Surg. Obes. Relat. Dis. 13, 1392–1402 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Orellana, E. R., Jamis, C., Horvath, N. & Hajnal, A. Effect of vertical sleeve gastrectomy on alcohol consumption and preferences in dietary obese rats and mice: a plausible role for altered ghrelin signaling. Brain Res. Bull. 138, 26–36 (2018).

    Article  CAS  PubMed  Google Scholar 

  116. Saules, K. K. et al. Bariatric surgery history among substance abuse treatment patients: prevalence and associated features. Surg. Obes. Relat. Dis. 6, 615–621 (2010).

    Article  PubMed  Google Scholar 

  117. Biegler, J. M., Freet, C. S., Horvath, N., Rogers, A. M. & Hajnal, A. Increased intravenous morphine self-administration following Roux-en-Y gastric bypass in dietary obese rats. Brain Res. Bull. 123, 47–52 (2016).

    Article  CAS  PubMed  Google Scholar 

  118. Wiedemann, A. A., Saules, K. K. & Ivezaj, V. Emergence of new onset substance use disorders among post-weight loss surgery patients. Clin. Obes. 3, 194–201 (2013).

    Article  CAS  PubMed  Google Scholar 

  119. Ivezaj, V., Saules, K. K. & Wiedemann, A. A. “I didn’t see this coming”: why are postbariatric patients in substance abuse treatment? Patients’ perceptions of etiology and future recommendations. Obes. Surg. 22, 1308–1314 (2012).

    Article  PubMed  Google Scholar 

  120. Sketriene, D., Ch’ng, S. S. & Brown, R. M. in Anti-Obesity Drug Discovery and Development Vol. 5 (eds Atta-ur-Rahman & Choudhary, M. I.) Ch. 1, 1–57 (Bentham Science Publishers, 2020).

  121. Brown, R. M. et al. Addiction-like synaptic impairments in diet-induced obesity. Biol. Psychiatry 81, 797–806 (2017).

    Article  PubMed  Google Scholar 

  122. Yoder, R., MacNeela, P., Conway, R. & Heary, C. How do individuals develop alcohol use disorder after bariatric surgery? A grounded theory exploration. Obes. Surg. 28, 717–724 (2018).

    Article  PubMed  Google Scholar 

  123. Hardman, C. A. & Christiansen, P. Psychological issues and alcohol misuse following bariatric surgery. Nat. Rev. Endocrinol. 14, 377–378 (2018).

    Article  PubMed  Google Scholar 

  124. Acevedo, M. B. et al. Sleeve gastrectomy surgery: when 2 alcoholic drinks are converted to 4. Surg. Obes. Relat. Dis. 14, 277–283 (2018).

    Article  PubMed  Google Scholar 

  125. Hagedorn, J. C., Encarnacion, B., Brat, G. A. & Morton, J. M. Does gastric bypass alter alcohol metabolism? Surg. Obes. Relat. Dis. 3, 543–548 (2007).

    Article  PubMed  Google Scholar 

  126. Lloret-Linares, C. et al. Effect of a Roux-en-Y gastric bypass on the pharmacokinetics of oral morphine using a population approach. Clin. Pharmacokinet. 53, 919–930 (2014).

    Article  CAS  PubMed  Google Scholar 

  127. Strommen, M., Helland, A., Kulseng, B. & Spigset, O. Bioavailability of methadone after sleeve gastrectomy: a planned case observation. Clin. Ther. 38, 1532–1536 (2016).

    Article  PubMed  Google Scholar 

  128. Whitfield, J. B. et al. Variation in alcohol pharmacokinetics as a risk factor for alcohol dependence. Alcohol. Clin. Exp. Res. 25, 1257–1263 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Polston, J. E. et al. Roux-en-Y gastric bypass increases intravenous ethanol self-administration in dietary obese rats. PLoS ONE 8, e83741 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Davis, J. F. et al. Roux en Y gastric bypass increases ethanol intake in the rat. Obes. Surg. 23, 920–930 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Thiele, T. E., Sparta, D. R., Hayes, D. M. & Fee, J. R. A role for neuropeptide Y in neurobiological responses to ethanol and drugs of abuse. Neuropeptides 38, 235–243 (2004).

    Article  CAS  PubMed  Google Scholar 

  132. Davis, J. F. et al. Gastric bypass surgery attenuates ethanol consumption in ethanol-preferring rats. Biol. Psychiatry 72, 354–360 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Skibicka, K. P., Hansson, C., Alvarez-Crespo, M., Friberg, P. A. & Dickson, S. L. Ghrelin directly targets the ventral tegmental area to increase food motivation. Neuroscience 180, 129–137 (2011).

    Article  CAS  PubMed  Google Scholar 

  134. Jerlhag, E. et al. Requirement of central ghrelin signaling for alcohol reward. Proc. Natl Acad. Sci. USA 106, 11318–11323 (2009). This article shows the involvement of central ghrelin signalling in the rewarding effects of alcohol.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Jerlhag, E., Ivanoff, L., Vater, A. & Engel, J. A. Peripherally circulating ghrelin does not mediate alcohol-induced reward and alcohol intake in rodents. Alcohol. Clin. Exp. Res. 38, 959–968 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Wee, C. C. et al. High-risk alcohol use after weight loss surgery. Surg. Obes. Relat. Dis. 10, 508–513 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Shirazi, R. H., Dickson, S. L. & Skibicka, K. P. Gut peptide GLP-1 and its analogue, exendin-4, decrease alcohol intake and reward. PLoS ONE 8, e61965 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Meckel, K. R. & Kiraly, D. D. A potential role for the gut microbiome in substance use disorders. Psychopharmacology 236, 1513–1530 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Jadhav, K. S. et al. Gut microbiome correlates with altered striatal dopamine receptor expression in a model of compulsive alcohol seeking. Neuropharmacology 141, 249–259 (2018).

    Article  CAS  PubMed  Google Scholar 

  140. Wang, F. et al. Morphine induces changes in the gut microbiome and metabolome in a morphine dependence model. Sci. Rep. 8, 3596 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Reddy, I. A. et al. Bile diversion, a bariatric surgery, and bile acid signaling reduce central cocaine reward. PLoS Biol. 16, e2006682 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Docherty, N. G. & le Roux, C. W. Bariatric surgery for the treatment of chronic kidney disease in obesity and type 2 diabetes mellitus. Nat. Rev. Nephrol. 16, 709–720 (2020).

    PubMed  Google Scholar 

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Acknowledgements

This manuscript received no external funding. R.M.B. acknowledges the support of an ARC DECRA Fellowship (DE190101244). P.S. acknowledges the support of a National Health and Medical Research Council Investigator Grant (1178482). We acknowledge the numerous researchers whose work we were unable to cite due to space limitations.

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Authors and Affiliations

  1. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia

    Robyn M. Brown & Eva Guerrero-Hreins

  2. Department of Biochemistry and Pharmacology, School of Biomedical Sciences, University of Melbourne, Parkville, Victoria, Australia

    Robyn M. Brown & Eva Guerrero-Hreins

  3. Department of Surgery, Central Clinical School, Monash University, Alfred Hospital, Melbourne, Victoria, Australia

    Wendy A. Brown

  4. Diabetes Complications Research Centre, Conway Institute, School of Medicine and Medical Sciences, University College, Dublin, Ireland

    Carel W. le Roux

  5. Department of Medicine (St Vincent’s), University of Melbourne, Melbourne, Victoria, Australia

    Priya Sumithran

  6. Department of Endocrinology, Austin Health, Melbourne, Victoria, Australia

    Priya Sumithran

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P.S., R.M.B. and E.G.H. researched data for the article and wrote the manuscript. All authors substantially contributed to the discussion of content and reviewed and/or edited the manuscript before submission.

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Correspondence to Priya Sumithran.

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Competing interests

C.W.l.R. reports grants from Science Foundation Ireland and grants from Health Research Board during the conduct of the study; other from Novo Nordisk and GI Dynamics, personal fees from Eli Lilly, grants and personal fees from Johnson and Johnson, personal fees from Sanofi Aventis, Astra Zeneca, Janssen, Bristol-Myers Squibb and Boehringer-Ingelheim outside the submitted work. P.S. reports personal fees from Novo Nordisk outside the submitted work. The other authors declare no competing interests.

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Brown, R.M., Guerrero-Hreins, E., Brown, W.A. et al. Potential gut–brain mechanisms behind adverse mental health outcomes of bariatric surgery. Nat Rev Endocrinol 17, 549–559 (2021). https://doi.org/10.1038/s41574-021-00520-2

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