Serotonin signaling to regulate energy metabolism: a gut microbiota perspective

Abstract

Serotonin is one of the most potent gastrointestinal, peripheral, and neuronal signaling molecules and plays a key role in regulating energy metabolism. Accumulating evidence has shown the complex interplay between gut microbiota and host energy metabolism. In this review, we summarize recent findings on the role of gut microbiota in serotonin metabolism and discuss the complicated mechanisms by which serotonin, working in conjunction with the gut microbiota, affects total body energy metabolism in the host. Gut microbiota affects serotonin synthesis, storage, release, transport, and catabolism. In addition, serotonin plays an indispensable role in regulating host energy homeostasis through organ crosstalk and microbe–host communication, particularly with a wide array of serotonergic effects mediated by diverse serotonin receptors with unique tissue specificity. This fresh perspective will help broaden the understanding of serotonergic signaling in modulating energy metabolism, thus shedding light on the design of innovative serotonin-targeting strategies to treat metabolic diseases.

Keywords

serotonin / gut microbiota / metabolism / gut–brain axis

References

[1] Côté F , Thévenot E , Fligny C et al. Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function. Proc Natl Acad Sci USA 2003; 100: 13525- 30.

[2] Shajib MS , Baranov A , Khan WI . Diverse effects of gut-derived serotonin in intestinal inflammation. ACS Chem Neurosci 2017; 8: 920- 31.

[3] Rapport MM , Green AA , Page IH . Serum vasoconstrictor (serotonin): IV. Isolation and characterization. J Biol Chem 1948; 176: 1243- 51.

[4] Erspamer V , Asero B . Identification of enteramine, the specific hormone of the enterochromaffin cell system, as 5-hydroxytryptamine. Nature 1952; 169: 800- 1.

[5] Rapport MM , Green AA , Page IH . Crystalline serotonin. Science 1948; 108: 329- 30.

[6] Yadav VK , Ryu JH , Suda N et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 2008; 135: 825- 37.

[7] Jindal S , Leyton C , Cohen F et al. Indeterminate serotonin release assays are associated with a high mortality rate. Res Pract Thromb Haemost 2022; 6: e12667.

[8] Azmitia EC . Serotonin and brain: evolution, neuroplasticity, and homeostasis. Int Rev Neurobiol 2007; 77: 31- 56.

[9] Vargas MA , Luo N , Yamaguchi A et al. A role for S6 kinase and serotonin in postmating dietary switch and balance of nutrients in D. melanogaster. Curr Biol 2010; 20: 1006- 11.

[10] French AS , Simcock KL , Rolke D et al. The role of serotonin in feeding and gut contractions in the honeybee. J Insect Physiol 2014; 61: 8- 15.

[11] Srinivasan S , Sadegh L , Elle IC et al. Serotonin regulates C. elegans fat and feeding through independent molecular mechanisms. Cell Metab 2008; 7: 533- 44.

[12] Sze JY , Victor M , Loer C et al. Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutant. Nature 2000; 403: 560- 4.

[13] Thursby E , Juge N . Introduction to the human gut microbiota. Biochem J 2017; 474: 1823- 36.

[14] Van Hul M , Cani PD . The gut microbiota in obesity and weight management: microbes as friends or foe? Nat Rev Endocrinol 2023; 19: 258- 71.

[15] Stasi C , Sadalla S , Milani S . The relationship between the serotonin metabolism, gut-microbiota and the gut-brain axis. Curr Drug Metab 2019; 20: 646- 55.

[16] Spohn SN , Mawe GM . Non-conventional features of peripheral serotonin signalling—the gut and beyond. Nat Rev Gastroenterol Hepatol 2017; 14: 412- 20.

[17] Ridaura V , Belkaid Y . Gut microbiota: the link to your second brain. Cell 2015; 161: 193- 4.

[18] Wachsmuth HR , Weninger SN , Duca FA . Role of the gut-brain axis in energy and glucose metabolism. Exp Mol Med 2022; 54: 377- 92.

[19] Cervenka I , Agudelo LZ , Ruas JL . Kynurenines: tryptophan’s metabolites in exercise, inflammation, and mental health. Science 2017; 357: eaaf9794.

[20] Stone TW , Darlington LG . The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders. Br J Pharmacol 2013; 169: 1211- 27.

[21] Ng J , Papandreou A , Heales SJ et al. Monoamine neurotransmitter disorders—clinical advances and future perspectives. Nat Rev Neurol 2015; 11: 567- 84.

[22] Nakamura K , Sugawara Y , Sawabe K et al. Late developmental stage-specific role of tryptophan hydroxylase 1 in brain serotonin levels. J Neurosci 2006; 26: 530- 4.

[23] Bertaccini G . Tissue 5-hydroxytryptamine and urinary 5-hydroxyindoleacetic acid after partial or total removal of the gastro-intestinal tract in the rat. J Physiol 1960; 153: 239- 49.

[24] Zhang Y , Deng R , Yang X et al. Glucose potentiates β‐cell function by inducing Tphl expression in rat islets. FASEB J 2017; 31: 5342- 55.

[25] Huang Z , Liu T , Chattoraj A et al. Posttranslational regulation of TPH1 is responsible for the nightly surge of 5‐HT output in the rat pineal gland. J Pineal Res 2008; 45: 506- 14.

[26] Lexchin J , Cude-Simpson K , Stancer H . Brain and blood indole metabolites after peripheral administration of ¹⁴C-5-HT in rat. Neurochem Res 1977; 2: 39- 50.

[27] Waider J , Araragi N , Gutknecht L et al. Tryptophan hydroxylase-2 (TPH2) in disorders of cognitive control and emotion regulation: a perspective. Psychoneuroendocrinology 2011; 36: 393- 405.

[28] Li Z , Chalazonitis A , Huang YY et al. Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons. J Neurosci 2011; 31: 8998- 9009.

[29] Weihe E , Eiden LE . Chemical neuroanatomy of the vesicular amine transporters. FASEB J. 2000; 14: 2435- 49.

[30] Lawal HO , Krantz DE . SLC18: vesicular neurotransmitter transporters for monoamines and acetylcholine. Mol Aspects Med 2013; 34: 360- 72.

[31] Wang F , Knutson K , Alcaino C et al. Mechanosensitive ion channel Piezo2 is important for enterochromaffin cell response to mechanical forces. J Physiol 2017; 595: 79- 91.

[32] Alcaino C , Knutson KR , Treichel AJ et al. A population of gut epithelial enterochromaffin cells is mechanosensitive and requires Piezo2 to convert force into serotonin release. Proc Natl Acad Sci USA 2018; 115: E7632- 41.

[33] Del Rosario JS , Yudin Y , Su S et al. Gi‐coupled receptor activation potentiates Piezo2 currents via Gβγ. EMBO Rep 2020; 21: e49124.

[34] Bautista DM , Jordt SE , Nikai T et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 2006; 124: 1269- 82.

[35] Nozawa K , Kawabata-Shoda E , Doihara H et al. TRPA1 regulates gastrointestinal motility through serotonin release from enterochromaffin cells. Proc Natl Acad Sci USA 2009; 106: 3408- 13.

[36] Bellono NW , Bayrer JR , Leitch DB et al. Enterochromaffin cells are gut chemosensors that couple to sensory neural pathways. Cell 2017; 170: 185- 98.e6.

[37] Knutson KR , Whiteman ST , Alcaino C et al. Intestinal enteroendocrine cells rely on ryanodine and IP₃ calcium store receptors for mechanotransduction. J Physiol 2023; 601: 287- 305.

[38] Gao J , Xiong T , Grabauskas G et al. Mucosal serotonin reuptake transporter (SERT) expression in irritable bowel syndrome is modulated by gut microbiota via mast cell-prostaglandin E2. Gastroenterology 2022; 162: 1962- 74.e6.

[39] Xie Y , Wang C , Zhao D et al. Dietary proteins regulate serotonin biosynthesis and catabolism by specific gut microbes. J Agric Food Chem 2020; 68: 5880- 90.

[40] Brenner B , Harney JT , Ahmed BA et al. Plasma serotonin levels and the platelet serotonin transporter. J Neurochem 2007; 102: 206- 15.

[41] Sandler M , Reveley M , Glover V . Human platelet monoamine oxidase activity in health and disease: a review. J Clin Pathol 1981; 34: 292- 302.

[42] Shih J , Chen K , Ridd M . Monoamine oxidase: from genes to behavior. Annu Rev Neurosci 1999; 22: 197- 217.

[43] Magro A , Osswald W , Reis D , Vanhoutte P , editors. Central and Peripheral Mechanisms of Cardiovascular Regulation. New York, NY: Springer 1986.

[44] Choi W , Moon JH , Kim H . Serotonergic regulation of energy metabolism in peripheral tissues. J Endocrinol 2020; 245: R1- 10.

[45] Kaludercic N , Mialet-Perez J , Paolocci N et al. Monoamine oxidases as sources of oxidants in the heart. J Mol Cell Cardiol 2014; 73: 34- 42.

[46] Fukui M , Tanaka M , Toda H et al. High plasma 5-hydroxyindole-3-acetic acid concentrations in subjects with metabolic syndrome. Diabetes Care 2012; 35: 163- 7.

[47] De Giovanni M , Tam H , Valet C et al. GPR35 promotes neutrophil recruitment in response to serotonin metabolite 5-HIAA. Cell 2022; 185: 815- 30.e19.

[48] Yamazaki F , Kuroiwa T , Takikawa O et al. Human indolylamine 2, 3-dioxygenase. Its tissue distribution, and characterization of the placental enzyme. Biochem J 1985; 230: 635- 8.

[49] Chamberlain RS , Herman BH . A novel biochemical model linking dysfunctions in brain melatonin, proopiomelanocortin peptides, and serotonin in autism. Biol Psychiatry 1990; 28: 773- 93.

[50] Conde K , Fang S , Xu Y . Unraveling the serotonin saga: from discovery to weight regulation and beyond - a comprehensive scientific review. Cell Biosci 2023; 13: 143.

[51] Wang H , Gu Y , Khalid R et al. Herbal medicines for insomnia through regulating 5-hydroxytryptamine receptors: a systematic review. Chin J Nat Med 2023; 21: 483- 98.

[52] Sałaciak K , Pytka K . Biased agonism in drug discovery: is there a future for biased 5-HT1A receptor agonists in the treatment of neuropsychiatric diseases? Pharmacol Ther 2021; 227: 107872.

[53] Beecher K , Wang J , Chehrehasa F et al. Dissecting the contribution of 5-HT1A auto- and heteroreceptors in sucrose overconsumption in mice. Biomed Pharmacother 2022; 148: 112699.

[54] Li, L , Wyler SC , León-Mercado LA et al. Delineating a serotonin 1B receptor circuit for appetite suppression in mice. J Exp Med 2022; 219: e20212307.

[55] Hannon J , Hoyer D . Molecular biology of 5-HT receptors. Behav Brain Res 2008; 195: 198- 213.

[56] Nonogaki K . The regulatory role of the central and peripheral serotonin network on feeding signals in metabolic diseases. Int J Mol Sci 2022; 23: 1600.

[57] Przegalinski E , Witek K , Wydra K et al. 5-HT_2C receptor stimulation in obesity treatment: orthosteric agonists vs. allosteric modulators. Nutrients 2023; 15: 1449.

[58] Nonogaki K , Strack AM , Dallman MF et al. Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT_2C receptor gene. Nat Med 1998; 4: 1152- 6.

[59] Hoyer D , Hannon JP , Martin GR . Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 2002; 71: 533- 54.

[60] Thompson AJ , Lummis SC . 5-HT₃ receptors. Curr Pharm Des 2006; 12: 3615- 30.

[61] Gianni G , Pasqualetti M . Wiring and volume transmission: an overview of the dual modality for serotonin neurotransmission. ACS Chem Neurosci 2023; 14: 4093- 104.

[62] Jiang SH , Wang YH , Hu LP et al. The physiology, pathology and potential therapeutic application of serotonylation. J Cell Sci 2021; 134: jcs257337.

[63] Paulmann N , Grohmann M , Voigt JP et al. Intracellular serotonin modulates insulin secretion from pancreatic β-cells by protein serotonylation. PLoS Biol 2009; 7: e1000229.

[64] Walther DJ , Peter JU , Winter S et al. Serotonylation of small GTPases is a signal transduction pathway that triggers platelet α-granule release. Cell 2003; 115: 851- 62.

[65] Al-Zoairy R , Pedrini MT , Khan MI et al. Serotonin improves glucose metabolism by serotonylation of the small GTPase Rab4 in L6 skeletal muscle cells. Diabetol. Metab. Syndr 2017; 9: 1.

[66] Fu L , Zhang L . Serotonylation: a novel histone H3 marker. Signal Transduct Target Ther 2019; 4: 15.

[67] Farrelly LA , Thompson RE , Zhao S et al. Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature 2019; 567: 535- 9.

[68] Zhao J , Chen W , Pan Y et al. Structural insights into the recognition of histone H3Q5 serotonylation by WDR5. Sci Adv 2021; 7: eabf4291.

[69] Wei L , Warburton RR , Preston IR et al. Serotonylated fibronectin is elevated in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2012; 302: L1273- 9.

[70] Ferrer L , Elsaraf M , Mindt M et al. L-serine biosensor-controlled fermentative production of L-tryptophan derivatives by Corynebacterium glutamicum. Biol 2022; 11: 744.

[71] Michalska K , Kowiel M , Bigelow L et al. 3D domain swapping in the TIM barrel of the α subunit of Streptococcus pneumoniae tryptophan synthase. Acta Crystallogr Section D 2020; 76: 166- 75.

[72] Xiong B , Zhu Y , Tian D et al. Flux redistribution of central carbon metabolism for efficient production of l‐tryptophan in Escherichia coli. Biotechnol Bioeng 2021; 118: 1393- 404.

[73] Wang J , Xu W , Wang R et al. The outer membrane protein Amuc_1100 of Akkermansia muciniphila promotes intestinal 5-HT biosynthesis and extracellular availability through TLR2 signalling. Food Funct 2021; 12: 3597- 610.

[74] Yano JM , Yu K , Donaldson GP et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 2015; 161: 264- 76.

[75] Tian P , Chen Y , Zhu H et al. Bifidobacterium breve CCFM1025 attenuates major depression disorder via regulating gut microbiome and tryptophan metabolism: a randomized clinical trial. Brain Behav Immun 2022; 100: 233- 41.

[76] Engevik MA , Luck B , Visuthranukul C et al. Human-derived Bifidobacterium dentium modulates the mammalian serotonergic system and gut-brain axis. Cell Mol Gastroenterol Hepatol 2021; 11: 221- 48.

[77] Zhai L , Huang C , Ning Z et al. Ruminococcus gnavus plays a pathogenic role in diarrhea-predominant irritable bowel syndrome by increasing serotonin biosynthesis. Cell Host Microbe 2023; 31: 33- 44.e5.

[78] Nzakizwanayo J , Dedi C , Standen G et al. Escherichia coli Nissle 1917 enhances bioavailability of serotonin in gut tissues through modulation of synthesis and clearance. Sci Rep 2015; 5: 17324.

[79] Sugiyama Y , Mori Y , Nara M et al. Gut bacterial aromatic amine production: aromatic amino acid decarboxylase and its effects on peripheral serotonin production. Gut Microbes 2022; 14: 2128605.

[80] Wlodarska M , Luo C , Kolde R et al. Indoleacrylic acid produced by commensal peptostreptococcus species suppresses inflammation. Cell Host Microbe 2017; 22: 25- 37.e6.

[81] Lamas B , Richard ML , Leducq V et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med 2016; 22: 598- 605.

[82] Ye L , Bae M , Cassilly CD et al. Enteroendocrine cells sense bacterial tryptophan catabolites to activate enteric and vagal neuronal pathways. Cell Host Microbe 2021; 29: 179- 96.e9.

[83] Gu Y , Wang C , Qin X et al. Saccharomyces boulardii, a yeast probiotic, inhibits gut motility through upregulating intestinal serotonin transporter and modulating gut microbiota. Pharmacol Res 2022; 181: 106291.

[84] Fung TC , Vuong HE , Luna CDG et al. Intestinal serotonin and fluoxetine exposure modulate bacterial colonization in the gut. Nat Microbiol 2019; 4: 2064- 73.

[85] Raboni S , Bettati S , Mozzarelli A . Tryptophan synthase: a mine for enzymologists. Cell Mol Life Sci 2009; 66: 2391- 403.

[86] Zhao L-P , Wu J , Zhao W-J et al. DSS-induced colitis activates the kynurenine pathway in serum and brain by affecting IDO-1 and gut microbiota. Front Immunol 2023; 13: 1089200.

[87] Williams BB , Van Benschoten AH , Cimermancic P et al. Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe 2014; 16: 495- 503.

[88] Kwon YH , Wang H , Denou E et al. Modulation of gut microbiota composition by serotonin signaling influences intestinal immune response and susceptibility to colitis. Cell Mol Gastroenterol Hepatol 2019; 7: 709- 28.

[89] Knecht LD , O'Connor G , Mittal R et al. Serotonin activates bacterial quorum sensing and enhances the virulence of Pseudomonas aeruginosa in the host. EBioMedicine 2016; 9: 161- 9.

[90] Kumar A , Russell RM , Pifer R et al. The serotonin neurotransmitter modulates virulence of enteric pathogens. Cell Host Microbe 2020; 28: 41- 53.e8.

[91] van Galen KA , Ter Horst KW , Serlie MJ . Serotonin, food intake, and obesity. Obes Rev 2021; 22: e13210.

[92] He Y , Brouwers B , Liu H et al. Human loss-of-function variants in the serotonin 2C receptor associated with obesity and maladaptive behavior. Nat Med 2022; 28: 2537- 46.

[93] Koopman KE , Booij J , Fliers E et al. Diet-induced changes in the lean brain: hypercaloric high-fat-high-sugar snacking decreases serotonin transporters in the human hypothalamic region. Mol Metab 2013; 2: 417- 22.

[94] Heisler LK , Kanarek RB , Gerstein A . Fluoxetine decreases fat and protein intakes but not carbohydrate intake in male rats. Pharmacol Biochem Behav 1997; 58: 767- 73.

[95] Heisler LK , Kanarek RB , Homoleski B . Reduction of fat and protein intakes but not carbohydrate intake following acute and chronic fluoxetine in female rats. Pharmacol Biochem Behav 1999; 63: 377- 85.

[96] Burke LK , Heisler L . 5‐hydroxytryptamine medications for the treatment of obesity. J Neuroendocrinol 2015; 27: 389- 98.

[97] Bohula EA , Wiviott SD , McGuire DK et al. Cardiovascular safety of lorcaserin in overweight or obese patients. N Engl J Med 2018; 379: 1107- 17.

[98] Voigt JP , Fink H . Serotonin controlling feeding and satiety. Behav Brain Res 2015; 277: 14- 31.

[99] Dahlstrom A , Fuxe K . Evidencefor the existence of monoaminecontaining neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand 1964; 60: 293- 4.

[100] He Z , Gao Y , Alhadeff AL et al. Cellular and synaptic reorganization of arcuate NPY/AgRP and POMC neurons after exercise. Mol Metab 2018; 18: 107- 19.

[101] Xu Y , Jones JE , Kohno D et al. 5-HT_2C Rs expressed by proopiomelanocortin neurons regulate energy homeostasis. Neuron 2008; 60: 582- 9.

[102] Brierley DI , Holt MK , Singh A et al. Central and peripheral GLP-1 systems independently suppress eating. Nat Metab 2021; 3: 258- 73.

[103] Bubar M , Cunningham K . Distribution of serotonin 5-HT_2C receptors in the ventral tegmental area. Neuroscience 2007; 146: 286- 97.

[104] Xu P , He Y , Cao X et al. Activation of serotonin 2C receptors in dopamine neurons inhibits binge-like eating in mice. Biol Psychiatry 2017; 81: 737- 47.

[105] Valencia-Torres L , Olarte-Sánchez CM , Lyons DJ et al. Activation of ventral tegmental area 5-HT_2C receptors reduces incentive motivation. Neuropsychopharmacology 2017; 42: 1511- 21.

[106] Xia G , Han Y , Meng F et al. Reciprocal control of obesity and anxiety-depressive disorder via a GABA and serotonin neural circuit. Mol Psychiatry 2021; 26: 2837- 53.

[107] Morrison SF , Madden CJ , Tupone D . Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metab 2014; 19: 741- 56.

[108] McGlashon JM , Gorecki MC , Kozlowski AE et al. Central serotonergic neurons activate and recruit thermogenic brown and beige fat and regulate glucose and lipid homeostasis. Cell Metab 2015; 21: 692- 705.

[109] Choi Y-H , Fujikawa T , Lee J et al. Revisiting the ventral medial nucleus of the hypothalamus: the roles of SF-1 neurons in energy homeostasis. Front Neurosci 2013; 7: 71.

[110] Leon RM , Borner T , Reiner DJ et al. Hypophagia induced by hindbrain serotonin is mediated through central GLP-1 signaling and involves 5-HT_2C and 5-HT₃ receptor activation. Neuropsychopharmacology 2019; 44: 1742- 51.

[111] Wagner S , Brierley DI , Leeson-Payne A et al. Obesity medication lorcaserin activates brainstem GLP-1 neurons to reduce food intake and augments GLP-1 receptor agonist induced appetite suppression. Mol Metab 2023; 68: 101665.

[112] Holt MK , Llewellyn-Smith IJ , Reimann F et al. Serotonergic modulation of the activity of GLP-1 producing neurons in the nucleus of the solitary tract in mouse. Mol Metab 2017; 6: 909- 21.

[113] Kooijman S , Wang Y , Parlevliet ET et al. Central GLP-1 receptor signalling accelerates plasma clearance of triacylglycerol and glucose by activating brown adipose tissue in mice. Diabetologia 2015; 58: 2637- 46.

[114] Lockie SH , Heppner KM , Chaudhary N et al. Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling. Diabetes 2012; 61: 2753- 62.

[115] Jenkins TA , Nguyen JC , Polglaze KE et al. Influence of tryptophan and serotonin on mood and cognition with a possible role of the gut-brain axis. Nutr 2016; 8: 56.

[116] Hu J , Johnson TA , Zhang H et al. The microbiota-gut-brain axis: gut microbiota modulates conspecific aggression in diversely selected laying hens. Microorganisms 2022; 10: 1081.

[117] Liu Z , Dai X , Zhang H et al. Gut microbiota mediates intermittentfasting alleviation of diabetes-induced cognitive impairment. Nat Commun 2020; 11: 855.

[118] Agustí A , Campillo I , Balzano T et al. Bacteroides uniformis CECT 7771 modulates the brain reward response to reduce binge eating and anxiety-like behavior in rat. Mol Neurobiol 2021; 58: 4959- 79.

[119] Liaqat H , Parveen A , Kim SY . Neuroprotective natural products’ regulatory effects on depression via gut-brain axis targeting tryptophan. Nutr 2022; 14: 3270.

[120] Roth W , Zadeh K , Vekariya R et al. Tryptophan metabolism and gut-brain homeostasis. Int J Mol Sci 2021; 22: 2973.

[121] Browning KN . Role of central vagal 5-HT₃ receptors in gastrointestinal physiology and pathophysiology. Front Neurosci 2015; 9: 413.

[122] Ripken D , van der Wielen N , Wortelboer HM et al. Nutrientinduced glucagon like peptide-1 release is modulated by serotonin. J Nutr Biochem 2016; 32: 142- 50.

[123] Yabut JM , Crane JD , Green AE et al. Emerging roles for serotonin in regulating metabolism: new implications for an ancient molecule. Endocr Rev 2019; 40: 1092- 107.

[124] Cerminara M , Spirito G , Pisciotta L et al. Case report: whole exome sequencing revealed disease-causing variants in two genes in a patient with autism spectrum disorder, intellectual disability, hyperactivity, sleep and gastrointestinal disturbances. Front Genet 2021; 12: 625564.

[125] Reigstad CS , Salmonson CE , Rainey JF et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J 2015; 29: 1395- 403.

[126] Martin AM , Jones LA , Jessup CF et al. Diet differentially regulates enterochromaffin cell serotonin content, density and nutrient sensitivity in the mouse small and large intestine. Neurogastroenterol Motil 2020; 32: e13869.

[127] Hoffman JM , Tyler K , MacEachern SJ et al. Activation of colonic mucosal 5-HT₄ receptors accelerates propulsive motility and inhibits visceral hypersensitivity. Gastroenterology 2012; 142: 844- 54.e4.

[128] Markham A . Telotristat ethyl: first global approval. Drugs 2017; 77: 793- 8.

[129] Wei L , Singh R , Ha SE et al. Serotonin deficiency is associated with delayed gastric emptying. Gastroenterology 2021; 160: 2451- 66.e19.

[130] Braun T , Voland P , Kunz L et al. Enterochromaffin cells of the human gut: sensors for spices and odorants. Gastroenterology 2007; 132: 1890- 901.

[131] Hansen L , Deacon CF , Ørskov C et al. Glucagon-like peptide-1-(7-36) amide is transformed to glucagon-like peptide-1-(9-36) amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 1999; 140: 5356- 63.

[132] Lund ML , Egerod KL , Engelstoft MS et al. Enterochromaffin 5-HT cells-A major target for GLP-1 and gut microbial metabolites. Mol Metab 2018; 11: 70- 83.

[133] Lund ML , Sorrentino G , Egerod KL et al. L-cell differentiation is induced by bile acids through GPBAR1 and paracrine GLP-1 and serotonin signaling. Diabetes 2020; 69: 614- 23.

[134] Mujagic Z , Kasapi M , Jonkers DM et al. Integrated fecal microbiome-metabolome signatures reflect stress and serotonin metabolism in irritable bowel syndrome. Gut Microbes 2022; 14: 2063016.

[135] Ge X , Ding C , Zhao W et al. Antibiotics-induced depletion of mice microbiota induces changes in host serotonin biosynthesis and intestinal motility. J Transl Med 2017; 15: 13.

[136] De Vadder F , Grasset E , Mannerås Holm L et al. Gut microbiota regulates maturation of the adult enteric nervous system via enteric serotonin networks. Proc Natl Acad Sci USA 2018; 115: 6458- 63.

[137] Golubeva AV , Joyce SA , Moloney G et al. Microbiota-related changes in bile acid & tryptophan metabolism are associated with gastrointestinal dysfunction in a mouse model of autism. EBioMedicine 2017; 24: 166- 78.

[138] Sumara G , Sumara O , Kim JK et al. Gut-derived serotonin is a multifunctional determinant to fasting adaptation. Cell Metab 2012; 16: 588- 600.

[139] Xu Y , Berglund ED , Sohn J-W et al. 5-HT_2C Rs expressed by proopiomelanocortin neurons regulate insulin sensitivity in liver. Nat Neurosci 2010; 13: 1457- 9.

[140] Lu S , Ma Z , Gu Y et al. Downregulation of glucose‐6‐phosphatase expression contributes to fluoxetine‐induced hepatic steatosis. J Appl Toxicol 2021; 41: 1232- 40.

[141] Crane JD , Palanivel R , Mottillo EP et al. Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis. Nat Med 2015; 21: 166- 72.

[142] Ko M , Kamimura K , Owaki T et al. Modulation of serotonin in the gut-liver neural axis ameliorates the fatty and fibrotic changes in non-alcoholic fatty liver. Dis Model Mech 2021; 14: dmm048922.

[143] Li HY , Huang SY , Zhou DD et al. Theabrownin inhibits obesity and non-alcoholic fatty liver disease in mice via serotonin-related signaling pathways and gut-liver axis. J Adv Res 2023; 52: 59- 72.

[144] Ming X , Chung ACK , Mao D et al. Pancreatic sirtuin 3 deficiency promotes hepatic steatosis by enhancing 5-hydroxytryptamine synthesis in mice with diet-induced obesity. Diabetes 2021; 70: 119- 31.

[145] Choi W , Namkung J , Hwang I et al. Serotonin signals through a gut-liver axis to regulate hepatic steatosis. Nat Commun 2018; 9: 4824.

[146] Kim M , Hwang I , Pagire HS et al. Design, synthesis, and biological evaluation of new peripheral 5HT_2A antagonists for nonalcoholic fatty liver disease. J Med Chem 2020; 63: 4171- 82.

[147] Nocito A , Dahm F , Jochum W et al. Serotonin mediates oxidative stress and mitochondrial toxicity in a murine model of nonalcoholic steatohepatitis. Gastroenterology 2007; 133: 608- 18.

[148] Ruddell RG , Oakley F , Hussain Z et al. A role for serotonin (5-HT) in hepatic stellate cell function and liver fibrosis. Am J Pathol 2006; 169: 861- 76.

[149] Aron-Wisnewsky J , Vigliotti C , Witjes J et al. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol 2020; 17: 279- 97.

[150] Sandoval DA , D’Alessio DA . Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol Rev 2015; 95: 513- 48.

[151] GYLFE E . Association between 5-hydroxytryptamine release and insulin secretion. J Endocrinol 1978; 78: 239- 48.

[152] Di Gialleonardo V , Signore A , Scheerstra EA et al. ¹¹C-hydroxytryptophan uptake and metabolism in endocrine and exocrine pancreas. J Nucl Med 2012; 53: 1755- 63.

[153] Andrew A , Kramer B , Rawdon B . Gut and pancreatic amine precursor uptake and decarboxylation cells are not neural crest derivatives. Gastroenterology 1983; 84: 429- 31.

[154] Moon JH , Kim YG , Kim K et al. Serotonin regulates adult β-cell mass by stimulating perinatal β-cell proliferation. Diabetes 2020; 69: 205- 14.

[155] Kim K , Oh CM , Ohara-Imaizumi M et al. Functional role of serotonin in insulin secretion in a diet-induced insulin-resistant state. Endocrinology 2015; 156: 444- 52.

[156] Castell A-L , Goubault C , Ethier M et al. β Cell mass expansion during puberty involves serotonin signaling and determines glucose homeostasis in adulthood. JCI Insight 2022; 7: e160854.

[157] Naderi R , Shirpoor A , Samadi M et al. Tropisetron attenuates pancreas apoptosis in the STZ-induced diabetic rats: involvement of SIRT1/NF-κB signaling. Pharmacol Rep 2020; 72: 1657- 65.

[158] Naderi R , Shirpoor A , Samadi M et al. Tropisetron improves pancreas function and increases insulin synthesis and secretion in the STZ-induced diabetic rats: involvement of UCP2/ZnT8 pathway. J Pharm Pharmacol 2020; 72: 1082- 91.

[159] Nagata M , Yokooji T , Nakai T et al. Blockade of multiple monoamines receptors reduce insulin secretion from pancreatic β-cells. Sci Rep 2019; 9: 16438.

[160] Almaça J , Molina J , Menegaz D et al. Human beta cells produce and release serotonin to inhibit glucagon secretion from alpha cells. Cell Rep 2016; 17: 3281- 91.

[161] Makhmutova M , Weitz J , Tamayo A et al. Pancreatic β-cells communicate with vagal sensory neurons. Gastroenterology 2021; 160: 875- 88.e11.

[162] Pietzner M , Budde K , Rühlemann M et al. Exocrine pancreatic function modulates plasma metabolites through changes in gut microbiota composition. J Clin Endocrinol Metab 2021; 106: e2290- 8.

[163] Shamsi F , Wang CH , Tseng YH . The evolving view of thermogenic adipocytes—ontogeny, niche and function. Nat Rev Endocrinol 2021; 17: 726- 44.

[164] Wu J , Boström P , Sparks LM et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012; 150: 366- 76.

[165] Stunes A , Reseland J , Hauso O et al. Adipocytes express a functional system for serotonin synthesis, reuptake and receptor activation. Diabetes Obes Metab 2011; 13: 551- 8.

[166] Oh C-M , Namkung J , Go Y et al. Regulation of systemic energy homeostasis by serotonin in adipose tissues. Nat Commun 2015; 6: 6794.

[167] Rozenblit-Susan S , Chapnik N , Froy O . Serotonin prevents differentiation into brown adipocytes and induces transdifferentiation into white adipocytes. Int J Obes (Lond) 2018; 42: 704- 10.

[168] Braz GRF , da Silva AI , Silva SCA et al. Chronic serotonin reuptake inhibition uncouples brown fat mitochondria and induces beiging/browning process of white fat in overfed rats. Life Sci 2020; 245: 117307.

[169] Chiu YJ , Tu HH , Kung ML et al. Fluoxetine ameliorates high-fat diet-induced metabolic abnormalities partially via reduced adipose triglyceride lipase-mediated adipocyte lipolysis. Biomed Pharmacother 2021; 141: 111848.

[170] Hansson B , Medina A , Fryklund C et al. Serotonin (5-HT) and 5-HT_2A receptor agonists suppress lipolysis in primary rat adipose cells. Biochem Biophys Res Commun 2016; 474: 357- 63.

[171] Shong KE , Oh CM , Namkung J et al. Serotonin regulates de novo lipogenesis in adipose tissues through serotonin receptor 2A. Endocrinol Metab (Seoul) 2020; 35: 470- 9.

[172] Choi WG , Choi W , Oh TJ et al. Inhibiting serotonin signaling through HTR2B in visceral adipose tissue improves obesityrelated insulin resistance. J Clin Invest 2021; 131: e145331.

[173] Kao AC , Spitzer S , Anthony DC et al. Prebiotic attenuation of olanzapine-induced weight gain in rats: analysis of central and peripheral biomarkers and gut microbiota. Transl Psychiatry 2018; 8: 66.

[174] Zhuang P , Zhang Y , Shou Q et al. Eicosapentaenoic and docosahexaenoic acids differentially alter gut microbiome and reverse high‐fat diet-induced insulin resistance.Mol Nutr Food Res 2020; 64: e1900946.

[175] Coelho WS , Costa KC , Sola-Penna M . Serotoninstimulates mouse skeletal muscle 6-phosphofructo-1-kinase through tyrosine-phosphorylation of the enzyme altering its intracellular localization. Mol Genet Metab 2007; 92: 364- 70.

[176] Visco DB , Manhães-de-Castro R , Chaves WF et al. Selective serotonin reuptake inhibitors affect structure, function and metabolism of skeletal muscle: a systematic review. Pharmacol Res 2018; 136: 194- 204.

[177] Guillet-Deniau I , Burnol AF , Girard J . Identification and localization of a skeletal muscle secrotonin 5-HT_2A receptor coupled to the Jak/STAT pathway. J Biol Chem 1997; 272: 14825- 9.

[178] Daily JW , Park S . Sarcopenia is a cause and consequence of metabolic dysregulation in aging humans: effects of gut dysbiosis, glucose dysregulation, diet and lifestyle. Cells 2022; 11: 338.

[179] Van Long N , Chien PN , Tung TX et al. Complementary combination of biomarkers for diagnosis of sarcopenia in C57BL/6J mice. Life Sci 2023; 312: 121213.

[180] Ticinesi A , Nouvenne A , Cerundolo N et al. Gut microbiota, muscle mass and function in aging: a focus on physical frailty and sarcopenia. Nutrients 2019; 11: 1633.

[181] Wang Y , Zhang Y , Lane NE et al. Population‐based metagenomics analysis reveals altered gut microbiome in sarcopenia: data from the Xiangya Sarcopenia study. J Cachexia, Sarcopenia Muscle 2022; 13: 2340- 51.

[182] Lee MC , Hsu YJ , Chuang HL et al. In vivo ergogenic properties of the Bifidobacterium longum OLP-01 isolated from a weightlifting gold medalist. Nutrients 2019; 11: 2003.

[183] Pourhamzeh M , Moravej FG , Arabi M et al. The roles of serotonin in neuropsychiatric disorders. Cell Mol Neurobiol 2022; 42: 1671- 92.

[184] Guzel T , Mirowska-Guzel D . The role of serotonin neurotransmission in gastrointestinal tract and pharmacotherapy. Molecules 2022; 27: 1680.

[185] Neumann J , Hofmann B , Dhein S et al. Cardiac roles of serotonin (5-HT) and 5-HT-receptors in health and disease. Int J Mol Sci 2023; 24: 4765.

[186] Kwak SH , Park BL , Kim H et al. Association of variations in TPH1 and HTR2B with gestational weight gain and measures of obesity. Obesity (Silver Spring) 2012; 20: 233- 8.

[187] Li P , Tiwari HK , Lin WY et al. Genetic association analysis of 30 genes related to obesity in a European American population. Int J Obes (Lond) 2014; 38: 724- 9.

[188] Chen C , Chen W , Chen C et al. Genetic variations in the serotoninergic system contribute to body-mass index in Chinese adolescents. PLoS One 2013; 8: e58717.

[189] Zhang M , Li Q , Wang KL et al. Lipolysis and gestational diabetes mellitus onset: a case-cohort genome-wide association study in Chinese. J Transl Med 2023; 21: 47.

[190] Kring SI , Werge T , Holst C et al. Polymorphisms of serotonin receptor 2A and 2C genes and COMT in relation to obesity and type 2 diabetes. PLoS One 2009; 4: e6696.

[191] Halder I , Muldoon MF , Ferrell RE et al. Serotonin receptor 2A (HTR2A) gene polymorphisms are associated with blood pressure, central adiposity, and the metabolic syndrome. Metab Syndr Relat Disord 2007; 5: 323- 30.

[192] Kwon Y-J , Hong K-W , Park BJ et al. Serotonin receptor 3B polymorphisms are associated with type 2 diabetes: the Korean genome and epidemiology study. Diabetes Res Clin Pract 2019; 153: 76- 85.

[193] Gu X , Al Dubayee M , Alshahrani A et al. Distinctive metabolomics patterns associated with insulin resistance and type 2 diabetes mellitus. Front Mol Biosci 2020; 7: 609806.

[194] Ljung T , Ahlberg AC , Holm G et al. Treatment of abdominally obese men with a serotonin reuptake inhibitor: a pilot study. J Intern Med 2001; 250: 219- 24.

[195] Zha W , Ho HTB , Hu T et al. Serotonin transporter deficiency drives estrogen-dependent obesity and glucose intolerance. Sci Rep 2017; 7: 1137.

[196] Marcus MD , Wing RR , Ewing L et al. A double-blind, placebocontrolled trial of fluoxetine plus behavior modification in the treatment of obese binge-eaters and non-binge-eaters. Am J Psychiatry 1990; 147: 876- 81.

[197] Darga LL , Carroll-Michals L , Botsford SJ et al. Fluoxetine’s effect on weight loss in obese subjects. Am J Clin Nutr 1991; 54: 321- 5.

[198] Gafoor R , Booth HP , Gulliford MC . Antidepressant utilisation and incidence of weight gain during 10 years’ follow-up: population based cohort study. BMJ 2018; 361: k1951.

[199] Ortuño MJ , Schneeberger M , Ilanges A et al. Melanocortin 4 receptor stimulation prevents antidepressant-associated weight gain in mice caused by long-term fluoxetine exposure. J Clin Investig 2021; 131: e151976.

[200] Wang Y , Zhou J , Ye J et al. Multi-omics reveal microbial determinants impacting the treatment outcome of antidepressants in major depressive disorder. Microbiome 2023; 11: 195.

[201] Guerdjikova AI , McElroy SL , Kotwal R et al. High‐dose escitalopram in the treatment of binge‐eating disorder with obesity: a placebo‐controlled monotherapy trial. Hum Psychopharmacol - Clin Exp 2007; 23: 1- 11.

[202] Sehgal R , Ilha M , Vaittinen M et al. Indole-3-propionic acid, a gut-derived tryptophan metabolite, associates with hepatic fibrosis. Nutrients 2021; 13: 3509.

[203] Zhang B , Jiang M , Zhao J et al. The mechanism underlying the influence of indole-3-propionic acid: a relevance to metabolic disorders. Front Endocrinol (Lausanne) 2022; 13: 841703.

[204] Rozenblit-Susan S , Chapnik N , Froy O . Metabolic effect of fluvoxamine in mouse peripheral tissues. Mol Cell Endocrinol 2016; 424: 12- 22.

[205] Wang P , Alvarez-Perez JC , Felsenfeld DP et al. A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat Med 2015; 21: 383- 8.

[206] Djamshidian A , Bernschneider-Reif S , Poewe W et al. Banisteriopsis caapi, a forgotten potential therapy for parkinson’s disease? Mov Disord Clin Pract 2016; 3: 19- 26.

[207] Zhu Z , Huang R , Liu W et al. Whole Agrocybe cylindracea prevented obesity linking with modification of gut microbiota and associated fecal metabolites in high‐fat diet‐fed mice. Mol Nutr Food Res 2022; 66: e2100897.

[208] Cataldo LR , Mizgier ML , Sagua RB et al. Prolonged activation of the Htr2b serotonin receptor impairs glucose stimulated insulin secretion and mitochondrial function in MIN6 cells. PLoS One 2017; 12: e0170213.

[209] Bohula EA , Scirica BM , Inzucchi SE et al. Effect of lorcaserin on prevention and remission of type 2 diabetes in overweight and obese patients (CAMELLIA-TIMI 61): a randomised, placebocontrolled trial. Lancet (London, England) 2018; 392: 2269- 79.

[210] Song EJ , Shin NR , Jeon S et al. Lorcaserin and phentermine exert anti-obesity effects with modulation of the gut microbiota. Front Microbiol 2023; 13: 1109651.

[211] Mazzola-Pomietto P , Aulakh CS , Murphy DL . Temperature, food intake, and locomotor activity effects of a 5-HT₃ receptor agonist and two 5-HT₃ receptor antagonists in rats. Psychopharmacology (Berl) 1995; 121: 488- 93.

[212] Cremata VY Jr , Koe BK . Clinical-pharmacological evaluation of p-chlorophenylalanine: a new serotonin-depleting agent. Clin Pharmacol Ther 1966; 7: 768- 76.

[213] Lipton MA , Gordon R , Guroff G et al. p-Chlorophenylalanineinduced chemical manifestations of phenylketonuria in rats. Science 1967; 156: 248- 50.

[214] Weber LJ . p-Chlorophenylalanine depletion of gastrointestinal 5-hydroxytryptamine. Biochem Pharmacol 1970; 19: 2169- 72.

[215] Liu Q , Yang Q , Sun W et al. Discovery and characterization of novel tryptophan hydroxylase inhibitors that selectively inhibit serotonin synthesis in the gastrointestinal tract. J Pharmacol Exp Ther 2008; 325: 47- 55.

[216] Chajadine M , Laurans L , Radecke T et al. Harnessing intestinal tryptophan catabolism to relieve atherosclerosis in mice. Nat Commun 2024; 15: 6390.

[217] Lyseng-Williamson KA . Telotristat ethyl: a review in carcinoid syndrome diarrhoea. Drugs 2018; 78: 941- 50.

[218] Margolis KG , Stevanovic K , Li Z et al. Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine. Gut 2014; 63: 928- 37.

[219] Grilo CM , Masheb RM , Wilson GT . Efficacy of cognitive behavioral therapy and fluoxetine for the treatment of binge eating disorder: a randomized double-blind placebo-controlled comparison. Biol Psychiatry 2005; 57: 301- 9.

[220] Michelson D , Amsterdam JD , Quitkin FM et al. Changes in weight during a 1-year trial of fluoxetine. Am J Psychiatry 1999; 156: 1170- 6.

[221] Fava M , Judge R , Hoog SL et al. Fluoxetine versus sertraline and paroxetine in major depressive disorder: changes in weight with long-term treatment. J Clin Psychiatry 2000; 61: 863- 7.

[222] Kivimäki M , Hamer M , Batty GD et al. Antidepressant medication use, weight gain, and risk of type 2 diabetes: a population-based study. Diabetes Care 2010; 33: 2611- 6.

[223] Blumenthal SR , Castro VM , Clements CC et al. An electronic health records study of long-term weight gain following antidepressant use. JAMA Psychiatry 2014; 71: 889- 96.

[224] Wickstrom L , Pettersson K . Treatment of diabetics with monoamine-oxidase inhibitors. Lancet 1964; 2: 995- 7.

[225] Frohman LA . Stimulation of insulin secretion in rats by pargyline and mebanazine. Diabetes 1971; 20: 266- 70.

[226] Carpéné C , Iffiú-Soltesz Z , Bour S et al. Reduction of fat deposition by combined inhibition of monoamine oxidases and semicarbazide-sensitive amine oxidases in obese Zucker rats. Pharmacol Res 2007; 56: 522- 30.

[227] Carpéné C , Mercader J , Le Gonidec S et al. Body fat reduction without cardiovascular changes in mice after oral treatment with the MAO inhibitor phenelzine. Br J Pharmacol 2018; 175: 2428- 40.

[228] Nagy CT , Koncsos G , Varga ZV et al. Selegiline reduces adiposity induced by high‐fat, high‐sucrose diet in male rats. Br J Pharmacol 2018; 175: 3713- 26.

[229] Mercader J , Sabater AG , Le Gonidec S et al. Oral phenelzine treatment mitigates metabolic disturbances in mice fed a high-fat diet. J Pharmacol Exp Ther 2019; 371: 555- 66.

[230] Gordon CJ , Duncan WC . Autonomic and behavioral thermoregulation in the golden-hamster during subchronic administration of clorgyline. Pharmacol Biochem Behav 1994; 48: 119- 25.

[231] Halford JCG , Harrold JA , Boyland EJ et al. Serotonergic drugs: effects on appetite expression and use for the treatment of obesity. Drugs 2007; 67: 27- 55.

[232] Barnes NM , Ahern GP , Becamel C et al. . International union of basic and clinical pharmacology. Classification of receptors for 5-hydroxytryptamine; pharmacology and function. Pharmacol Rev 2021; 73: 310- 520.

[233] Halford JCG . Lorcaserin—not a new weapon in the battle with appetite. Nat Rev Endocrinol 2010; 6: 663- 4.

[234] Sharretts J , Galescu O , Gomatam S et al. Cancer risk associated with lorcaserin—the FDA’s review of the CAMELLIA-TIMI 61 trial. N Engl J Med 2020; 383: 1000- 2.

[235] Dockray GJ . Enteroendocrine cell signalling via the vagus nerve. Curr Opin Pharmacol 2013; 13: 954- 8.

[236] Zhang W , Qu W , Wang H et al. Antidepressants fluoxetine and amitriptyline induce alterations in intestinal microbiota and gut microbiome function in rats exposed to chronic unpredictable mild stress. Transl Psychiatry 2021; 11: 131.

RIGHTS & PERMISSIONS

The Author(s). Published by Oxford University Press on behalf of Higher Education Press.