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Cited by 122Autism Spectrum Disorder ResearchGastrointestinal motility and disordersGut microbiota and health

Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders

Open access
Israelyan, Narek, Margolis, Kara Gross·2018·Pharmacological Research
DOI 10.1016/j.phrs.2018.03.020PMC PMC6368356
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Abstract

Autism-spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and repetitive patterns of behavior. ASD is, however, often associated with medical comorbidities and gastrointestinal (GI) dysfunction is among the most common. Studies have demonstrated a correlation between GI dysfunction and the degree of social impairment in ASD. The etiology of GI abnormalities in ASD is unclear, though the association between GI dysfunction and ASD-associated behaviors suggest that overlapping developmental defects in the brain and the intestine and/or a defect in communication between the enteric and central nervous systems (ENS and CNS, respectively), known as the gut-brain axis, could be responsible for the observed phenotypes. Brain-gut abnormalities have been increasingly implicated in several disease processes, including ASD. As a critical modulator of ENS and CNS development and function, serotonin may be a nexus for the gut-brain axis in ASD. This paper reviews the role of serotonin in ASD from the perspective of the ENS. A murine model that has been demonstrated to possess brain, behavioral and GI abnormalities mimicking those seen in ASD harbors the most common serotonin transporter (SERT) based mutation (SERT Ala56) found in children with ASD. Discussion of the gut-brain manifestations in the SERT Ala56 mice, and their correction with developmental administration of a 5-HT 4 agonist, are also addressed in conjunction with other future directions for diagnosis and treatment.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that serotonin (5-HT) may serve as a nexus linking the gut-brain-microbiome axis in autism spectrum disorder (ASD), drawing on evidence from the SERT Ala56 mouse model and related murine and human studies. It surveys the role of enteric serotonin in ENS/CNS development, microbiome-5-HT interactions, and candidate therapeutic directions including 5-HT4 agonists and microbial manipulation.

Key findings

  • GI symptoms occur at a four-fold greater rate in ASD than in the general population, with constipation reported most frequently, and the degree of social impairment correlates with likelihood of constipation.
  • Enteric 5-HT accounts for >90% of the body's 5-HT stores; neuronal 5-HT synthesis is regulated by TPH2 and enterochromaffin (EC)-cell 5-HT by TPH1.
  • Approximately 30% of individuals with ASD exhibit elevated whole-blood 5-HT (hyperserotonemia), and higher whole-blood 5-HT levels correlate with constipation in children with ASD.
  • The SERT Ala56 mouse exhibits whole-blood hyperserotonemia, increased CNS 5-HT clearance, 5-HT1A/2A receptor hypersensitivity, ASD-like behaviors, reduced ENS neuron counts, slowed GI motility, and increased EC cells and Tph1 transcripts; developmental prucalopride (5-HT4 agonist) normalized enteric neuronal numbers and provided long-term rescue of colonic motility.
  • Germ-free mice show decreased whole-blood 5-HT; short-chain fatty acids increase Tph1 mRNA and intestinal 5-HT; MIA offspring show dysbiosis (Clostridia, Bacteroidia) corrected by B. fragilis along with GI permeability and behavioral abnormalities.

Methods

  • Narrative review article; no primary data collection or systematic search methodology is described.
  • Synthesizes human clinical/observational findings (e.g., hyperserotonemia, GI comorbidity, a multi-omics study of microbiome-5-HT-GI pain associations) and murine model evidence (SERT Ala56, BTBR, TPH1/TPH2 knockouts, germ-free, MIA).
  • Discusses future directions including ongoing probiotic and fecal microbiota transplant trials (e.g., NCT02903030, NCT02674984, NCT03408886).

Limitations

  • Stated: microbiome studies in ASD have been small, used very different analytical methods, and evaluated dissimilar patient populations; no precise microbial composition has been identified, and a unifying profile is unlikely given ASD heterogeneity.
  • Stated: the precise in vivo mechanisms governing the bidirectional 5-HT-microbiome relationship are undetermined, and whether microbiome changes cause or result from GI dysfunction remains unclear; murine findings require confirmation in humans.
  • Stated: whether 5-HT4 agonism rescues brain/behavioral abnormalities in SERT Ala56 mice is undetermined, and human safety/efficacy studies are required; nonselective 5-HT4 agonists have been linked to cardiovascular adverse events.
  • Evident from the text: several cited findings are unpublished data (e.g., SERT Ala56 microbiome abnormalities) or from single small/open-label human studies (e.g., the fecal transplant study), limiting the strength of conclusions.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.phrs.2018.03.020

Cites

92 of 92 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 94 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    SERT Ala56 mice demonstrate abnormalities in the intestinal microbiome that correlate with slowed GI transit.

    “SERT Ala56 mice demonstrate abnormalities in the intestinal microbiome that correlate with slowed GI transit (unpublished data).”
    Quote in the paperNot a substantial claim
  • Premisecitation

    During CNS development, 5-HT plays critical roles in the regulation of neuronal differentiation and migration, axonal outgrowth, myelination and synapse formation.

    “During CNS development, 5-HT plays critical roles in the regulation of neuronal differentiation and migration, as well as axonal outgrowth, myelination and synapse formation [24, 25].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24] Gaspar P, Cases O, Maroteaux L, The developmental role of serotonin: news from mouse molecular genetics, Nat Rev Neurosci 4(12) (2003) 1002– 12. 14618156 source

      Not checked in the free run.

    • cites [25] Homberg JR, Kolk SM, Schubert D, Editorial perspective of the Research Topic “Deciphering serotonin’s role in neurodevelopment”, Front Cell Neurosci 7 (2013) 212. 24302896 PMC3831146 source

      Not checked in the free run.

  • Interpretationreasoning

    5-HT and/or its modulators (e.g., SERT) could play an important role in both the brain and intestinal anomalies in ASD.

    “Because 5-HT impacts the development of both the central and enteric nervous systems, 5-HT and/or its modulators (e.g., SERT) could play an important role in the both the brain and intestinal anomalies in ASD.”
    Quote in the paperSubstantial claim
  • Premisecitation

    SERT is primarily responsible for intracellular transport of 5-HT.

    “The serotonin reuptake transporter (SERT; Slc6a4) is primarily responsible for this intracellular transport (Figure 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Mawe GM, Hoffman JM, Serotonin signalling in the gut--functions, dysfunctions and therapeutic targets, Nat Rev Gastroenterol Hepatol 10(8) (2013) 473– 86. 23797870 PMC4048923 source

      Not checked in the free run.

  • Premisecitation

    Murine models with SERT abnormalities during development, such as SERT knockout mice and mice receiving SSRIs during pregnancy and breastfeeding, exhibit ENS hyperplasia and long-lasting deficits in ENS-mediated functions, including in vivo and in vitro GI motility.

    “Murine models possessing abnormalities in SERT during development, such as SERT knockout mice, as well as mice that receive selective serotonin reuptake inhibitors during pregnancy and breastfeeding, exhibit ENS hyperplasia as well as long-lasting deficits in ENS-mediated functions, including in vivo and in vitro gastrointestinal motility [33].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Margolis KG, Li Z, Stevanovic K, Saurman V, Israelyan N, Anderson GM, Snyder I, Veenstra-VanderWeele J, Blakely RD, Gershon MD, Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function, J Clin Invest 126(6) (2016) 2221– 35. 27111230 PMC4887174 source

      Not checked in the free run.

  • May combine two claims. 20
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Premisecitation

    Synthesis of neuronal 5-HT in both the CNS and ENS is regulated by TPH2, while EC-cell derived 5-HT is produced by TPH1.

    “Synthesis of neuronal 5-HT, both in the CNS and ENS, is regulated by TPH2, while EC-cell derived 5-HT is produced by TPH1 [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Gershon MD, 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract, Curr Opin Endocrinol Diabetes Obes 20(1) (2013) 14– 21. 23222853 PMC3708472 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During ENS development, serotonergic neurons are among the first inhabitants of the ENS, where they impact neurogenesis and guide the development and survival of late-born neurons, including those expressing dopamine, GABA and CGRP.

    “During ENS development, serotonergic neurons are among the first inhabitants of the ENS, where they impact neurogenesis and guide the development and survival of late-born neurons, including those expressing dopamine, gamma-Aminobutyric acid (GABA) and calcitonin gene-related peptide (CGRP) [28].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Li ZS, Pham TD, Tamir H, Chen JJ, Gershon MD, Enteric dopaminergic neurons: definition, developmental lineage, and effects of extrinsic denervation, J Neurosci 24(6) (2004) 1330– 9. 14960604 PMC6730344

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Genetic deletion of TPH2 leads to a reduction of neuron density in both neuronal plexuses of the ENS, as well as slowed intestinal transit both in vivo and in vitro.

    “Further, genetic deletion of TPH2 leads to a reduction of neuron density in both neuronal plexuses of the ENS, as well as slowed intestinal transit both in vivo and in vitro [27].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Li Z, Chalazonitis A, Huang YY, Mann JJ, Margolis KG, Yang QM, Kim DO, Cote F, Mallet J, Gershon MD, Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons, J Neurosci 31(24) (2011) 8998– 9009. 21677183 PMC4442094

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In TPH1KO mice, peristaltic reflexes do not occur with mucosal stimulation and instead require stretching of the gut wall; when produced, contractions demonstrate deficiencies in propagation.

    “Motility abnormalities in TPH1KO mice, however, have more recently been observed; generation of peristaltic reflexes do not occur in TPH1KO mice with mucosal stimulation and instead require stretching of the gut wall. Further, even when they are produced, these contractions demonstrate deficiencies in propagation [29].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Heredia DJ, Gershon MD, Koh SD, Corrigan RD, Okamoto T, Smith TK, Important role of mucosal serotonin in colonic propulsion and peristaltic reflexes: in vitro analyses in mice lacking tryptophan hydroxylase 1, J Physiol 591(23) (2013) 5939– 57. 24127620 PMC3872763

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Whole-blood 5-HT is primarily a measure of 5-HT stored in platelets and is likely derived almost entirely from the intestine.

    “Whole-blood 5-HT, which is primarily a measure of 5-HT stored in platelets, is likely to be derived almost entirely from the intestine [37]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Rao M, Gershon MD, The bowel and beyond: the enteric nervous system in neurological disorders, Nat Rev Gastroenterol Hepatol 13(9) (2016) 517– 28. 27435372 PMC5005185 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ASD is often associated with medical comorbidities, and gastrointestinal dysfunction is among the most common.

    “ASD is often associated with multiple medical comorbidities and gastrointestinal (GI) problems are among the most common [4–6].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] Doshi-Velez F, Ge Y, Kohane I, Comorbidity clusters in autism spectrum disorders: an electronic health record time-series analysis, Pediatrics 133(1) (2014) e54– 63. 24323995 PMC3876178 source

      Not checked in the free run.

    • cites [5] Aldinger KA, Lane CJ, Veenstra-VanderWeele J, Levitt P, Patterns of Risk for Multiple Co-Occurring Medical Conditions Replicate Across Distinct Cohorts of Children with Autism Spectrum Disorder, Autism Res 8(6) (2015) 771– 81. 26011086 PMC4736680 source

      Not checked in the free run.

    • cites [6] Kohane IS, McMurry A, Weber G, MacFadden D, Rappaport L, Kunkel L, Bickel J, Wattanasin N, Spence S, Murphy S, Churchill S, The co-morbidity burden of children and young adults with autism spectrum disorders, PLoS One 7(4) (2012) e33224. 22511918 PMC3325235 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Overlapping developmental defects in the brain and intestine and/or a defect in communication between the ENS and CNS could be responsible for the observed phenotypes in ASD.

    “The association between GI dysfunction and ASD-associated behaviors suggest that overlapping developmental defects in the brain and the intestine and/or a defect in communication between the enteric and central nervous systems (ENS and CNS, respectively), known as the gut-brain axis, could be responsible for the observed phenotypes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Enteric 5-HT accounts for >90% of the body's 5-HT stores and is contained in two primary reservoirs: intestinal epithelium EC cells and neurons of the ENS.

    “Enteric 5-HT, which accounts for >90% of the body’s 5-HT stores, is contained in two primary reservoirs: in the intestinal epithelium, where it is produced by enterochromaffin (EC) cells, and in neurons of the ENS [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Gershon MD, 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract, Curr Opin Endocrinol Diabetes Obes 20(1) (2013) 14– 21. 23222853 PMC3708472 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased or decreased levels of SERT can lead to decreased or increased levels, respectively, of 5-HT available for neurotransmission in the brain and intestine.

    “Increased or decreased levels of SERT can thus lead to decreased or increased levels, respectively, of the 5-HT available for neurotransmission in the brain and the intestine [32].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Mawe GM, Hoffman JM, Serotonin signalling in the gut--functions, dysfunctions and therapeutic targets, Nat Rev Gastroenterol Hepatol 10(8) (2013) 473– 86. 23797870 PMC4048923 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SERT Ala56 mice exhibit increased 5-HT clearance in the CNS and hypersensitivity of CNS 5-HT1A and 5-HT2A receptors.

    “including increased 5-HT clearance in the CNS, hypersensitivity of CNS 5-HT1A and 5-HT2A receptors”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Veenstra-VanderWeele J, Muller CL, Iwamoto H, Sauer JE, Owens WA, Shah CR, Cohen J, Mannangatti P, Jessen T, Thompson BJ, Ye R, Kerr TM, Carneiro AM, Crawley JN, Sanders-Bush E, McMahon DG, Ramamoorthy S, Daws LC, Sutcliffe JS, Blakely RD, Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior, Proc Natl Acad Sci U S A 109(14) (2012) 5469– 74. 22431635 PMC3325657 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Immune system impairment has been noted in both mothers of ASD patients and in ASD patients themselves.

    “Additionally, immune system impairment has been noted in both mothers of ASD patients and in ASD patients themselves [71].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Goines P, Van de Water J, The immune system’s role in the biology of autism, Curr Opin Neurol 23(2) (2010) 111– 7. 20160651 PMC2898160

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of the highly selective 5-HT4 agonist prucalopride during critical periods of neurodevelopment, including gestation and breastfeeding, normalized enteric neuronal numbers in SERT Ala56 mice and provided long-term rescue of colonic motility.

    “It was recently demonstrated that administration of the highly selective 5-HT4 agonist, prucalopride during critical periods of neurodevelopment, including gestation and breastfeeding, normalized enteric neuronal numbers in the SERT Ala56 mice and also provided long-term rescue of colonic motility [33].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Margolis KG, Li Z, Stevanovic K, Saurman V, Israelyan N, Anderson GM, Snyder I, Veenstra-VanderWeele J, Blakely RD, Gershon MD, Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function, J Clin Invest 126(6) (2016) 2221– 35. 27111230 PMC4887174

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Five rare Slc6a4 variants overexpressed in individuals with ASD are gain-of-function mutations that confer hyperactivity to SERT.

    “They identified five variants that were overexpressed in the individuals with ASD; each variant was a gain-of-function mutation that conferred a hyperactivity to SERT [36, 52].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [36] Muller CL, Anacker AMJ, Veenstra-VanderWeele J, The serotonin system in autism spectrum disorder: From biomarker to animal models, Neuroscience 321 (2016) 24– 41. 26577932 PMC4824539 source

      Not checked in the free run.

    • cites [52] Prasad HC, Steiner JA, Sutcliffe JS, Blakely RD, Enhanced activity of human serotonin transporter variants associated with autism, Philos Trans R Soc Lond B Biol Sci 364(1514) (2009) 163– 73. 18957375 PMC2674096

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SERT Ala56 mice exhibit an increase in EC cells and Tph1 transcripts in the intestinal mucosa.

    “Further, these mice also exhibit differences in the intestinal mucosa, including an increase in EC cells as well as Tph1 transcripts”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Margolis KG, Li Z, Stevanovic K, Saurman V, Israelyan N, Anderson GM, Snyder I, Veenstra-VanderWeele J, Blakely RD, Gershon MD, Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function, J Clin Invest 126(6) (2016) 2221– 35. 27111230 PMC4887174

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Newer, more selective 5-HT4 agonists have an improved safety profile.

    “although the newer, more selective 5-HT4 agonists have an improved safety profile”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Tack J, Camilleri M, Chang L, Chey WD, Galligan JJ, Lacy BE, Muller-Lissner S, Quigley EM, Schuurkes J, De Maeyer JH, Stanghellini V, Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders, Aliment Pharmacol Ther 35(7) (2012) 745– 67. 22356640 PMC3491670

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Existing treatments for ASD are used primarily for specific symptoms (e.g., irritability and agitation) and do not address the underlying neurobehavioral etiologies.

    “existing treatments are used primarily for specific symptoms (e.g., irritability and agitation) [83], without the ability to address the underlying neurobehavioral etiologies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] McPheeters ML, Warren Z, Sathe N, Bruzek JL, Krishnaswami S, Jerome RN, Veenstra-Vanderweele J, A systematic review of medical treatments for children with autism spectrum disorders, Pediatrics 127(5) (2011) e1312– 21. 21464191 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    There is currently no distinct microbiome profile characteristic of ASD or a specific profile associated with its neurobehavioral manifestations.

    “There is currently no distinct microbiome profile characteristic of ASD or a specific profile that is associated with its neurobehavioral manifestations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    SERT is found in epithelial cells of the intestine, pulmonary endothelial cells, and in organs and cells that do not synthesize 5-HT, including platelets and T and B lymphocytes.

    “SERT is also found in the epithelial cells of the intestine [86], pulmonary endothelial cells [87], and in organs and cells that do not synthesize 5-HT, including platelets and T and B lymphocytes [32].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [86] Spohn SN, Mawe GM, Non-conventional features of peripheral serotonin signalling - the gut and beyond, Nat Rev Gastroenterol Hepatol 14(7) (2017) 412– 420. 28487547 PMC5672796

      Not checked in the free run.

    • cites [87] Maclean MR, Dempsie Y, The serotonin hypothesis of pulmonary hypertension revisited, Adv Exp Med Biol 661 (2010) 309– 22. 20204739

      Not checked in the free run.

    • cites [32] Mawe GM, Hoffman JM, Serotonin signalling in the gut--functions, dysfunctions and therapeutic targets, Nat Rev Gastroenterol Hepatol 10(8) (2013) 473– 86. 23797870 PMC4048923 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treating dysbiosis in MIA mice with Bacteroides fragilis corrected both GI permeability defects and ASD-related behavioral abnormalities.

    “treating the dysbiosis in these mice with Bacteroides fragilis corrected both the GI permeability defects and ASD-related behavioral abnormalities [75].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Codelli JA, Chow J, Reisman SE, Petrosino JF, Patterson PH, Mazmanian SK, Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders, Cell 155(7) (2013) 1451– 63. 24315484 PMC3897394 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Over 70% of individuals with ASD are taking medication(s).

    “Although over 70% of these individuals are taking medication(s) [82]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Esbensen AJ, Greenberg JS, Seltzer MM, Aman MG, A longitudinal investigation of psychotropic and non-psychotropic medication use among adolescents and adults with autism spectrum disorders, J Autism Dev Disord 39(9) (2009) 1339– 49. 19434487 PMC2829244

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The single study evaluating GI and behavioral outcomes after fecal transplant in ASD was small and open-label.

    “the study was small and open-label.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Kang DW, Adams JB, Gregory AC, Borody T, Chittick L, Fasano A, Khoruts A, Geis E, Maldonado J, McDonough-Means S, Pollard EL, Roux S, Sadowsky MJ, Lipson KS, Sullivan MB, Caporaso JG, Krajmalnik-Brown R, Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study, Microbiome 5(1) (2017) 10. 28122648 PMC5264285 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Microbiome studies thus far demonstrate a bidirectional relationship between 5-HT and the enteric microbiota.

    “Although microbiome studies thus far demonstrate a bidirectional relationship between 5-HT and the enteric microbiota”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Distinct microbial differences have been noted in individuals with ASD, but studies have been small, utilized very different methods of analysis and evaluated dissimilar patient populations.

    “Although distinct microbial differences have been noted individuals with ASD, studies have been small, utilized very different methods of analysis and have evaluated dissimilar patient populations [80].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Navarro F, Liu Y, Rhoads JM, Can probiotics benefit children with autism spectrum disorders?, World J Gastroenterol 22(46) (2016) 10093– 10102. 28028357 PMC5155168 source

      Not checked in the free run.

23 of 23

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Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Reference 49 does not match the described serotonin study

    Minor

    The text identifies reference 49 as a study of whole-blood serotonin associated with Slc6a4. The listed reference is instead a genome-wide autism linkage screen reporting chromosomes 2q, 7q, and 16p.

  • Reference 56 does not match the mouse finding

    Minor

    The text cites reference 56 for an ENS-development finding in SERT Ala56 mice, but the listed reference concerns gastrointestinal problems and perinatal risk factors in human sibling pairs.

2 of 2

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Related

Authors
Israelyan, N., & Margolis, K. G.
Affiliations
  • Columbia University (US)
  • Morgan Stanley Children's Hospital (US)
Corresponding author
Margolis, Kara Gross
ORCID
Venue
Pharmacological Research
Publisher
Elsevier BV
Published
2018-06
Volume
132
Pages
1-6
ISSN
1043-6618 (ISSN-L)
DOI
10.1016/j.phrs.2018.03.020
PMC
PMC6368356
OpenAlex
W2794541117
Cited by
122
References
92
Citations by year
2026: 11 · 2025: 11 · 2024: 18 · 2023: 13 · 2022: 23 · 2021: 18 · 2020: 7 · 2019: 14 · 2018: 7
FWCI
1.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Pharmacological Research (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIH KO8 (DK093786)
  • Department of Defense (PR160365)
  • Center for Discovery (KGM)
  • NIA (T35AG044303)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
autism spectrum disorder, serotonin, gut-brain axis, gastrointestinal dysfunction, enteric nervous system, serotonin transporter, 5-HT4 receptor agonist, social behavior, neurodevelopmental disorders
MeSH terms
Autism Spectrum Disorder, Gastrointestinal Microbiome, Animals, Brain, Humans, Serotonin, Serotonin Plasma Membrane Transport Proteins

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