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Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function
Open accessAbstract
Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4-mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation.
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“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].”
From Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders (2018) · cites this paper as [33]
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“both of which may be contributory to the demonstrated increase in whole blood 5-HT levels [33].”
From Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders (2018) · cites this paper as [33]
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“As a consequence of abnormal ENS development, SERT Ala56 mice have abnormally slowed in vivo and in vitro motility throughout the entire intestine, including a decrease in the frequency and speed of colonic peristaltic contractions”
From Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders (2018) · cites this paper as [33]
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“SERT is primarily located on serotonergic nerve terminals and axons in the adult brain, and its density is considered to be a representative marker of the integrity of the serotonergic neuron [26].”
Abo-Shaban, T., Sharna, S. S., Hosie, S., Lee, C. Y. Q., Balasuriya, G. K., McKeown, S. J., Franks, A. E., & Hill‐Yardin, E. L. (2022) · Journal of Neural Transmission · doi:10.1007/s00702-022-02561-x · Cited by 26
Is there sexual dimorphism of hyperserotonemia in autism spectrum disorder?
Shuffrey, L. C., Guter, S. J., Delaney, S., Jacob, S., Anderson, G. M., Sutcliffe, J. S., Cook, E. H., & Veenstra-VanderWeele, J. M. (2017) · Autism Research · doi:10.1002/aur.1791 · Cited by 25
“Indirect effects of blood serotonin on the brain are also possible, since serotonin plays an important role in gut function and immune regulation, with potential downstream effects on the brain [Baganz & Blakely, 2013; Gershon, 2013; Arreola et al., 2015; Margolis et al., 2016].”
Self-citationSerotonergic Control of Gastrointestinal Development, Motility, and Inflammation
Najjar, S. A., Hung, L. Y., & Margolis, K. G. (2023) · Comprehensive physiology · doi:10.1002/cphy.c220024 · Cited by 53
Self-citationThe enteric nervous system deficits in autism spectrum disorder
Wang, X., Tang, R., Wei, Z., Zhan, Y., Lu, J., & Li, Z. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1101071 · Cited by 25
“As observed in human patients, a knock-in mouse model overexpressing the most common SERT variant (Gly56Ala) in ASD children not only exhibits ASD-like behaviors but also displays abnormalities in the ENS (Margolis et al., 2016).”
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Self-citationMaterial Engineering in Gut Microbiome and Human Health
Yang, L., Hung, L. Y., Zhu, Y., Ding, S., Margolis, K. G., & Leong, K. W. (2022) · Research · doi:10.34133/2022/9804014 · Cited by 24
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“In addition, a growing number of studies in patients and animal models of autism have demonstrated an association between autism and gastrointestinal imbalances such as altered gut microbiome composition [14–18], faecal short chain fatty acid levels [19], increased gut permeability [20, 21], changes in villi architect…”
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Ellegood, J., Yee, Y., Kerr, T. M., Muller, C. L., Blakely, R., Henkelman, R. M., Veenstra-VanderWeele, J. M., & Lerch, J. P. (2018) · Molecular Autism · doi:10.1186/s13229-018-0210-z · Cited by 18
“ing functional and developmental effects in the gut [67].”
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Self-citationTryptophan hydroxylase and serotonin synthesis regulation
Kuhn, D. M., & Hasegawa, H. (2020) · Handbook of behavioral neuroscience · doi:10.1016/b978-0-444-64125-0.00012-8 · Cited by 16
Quinlan, M. A., Krout, D., Katamish, R. M., Robson, M. J., Nettesheim, C., Gresch, P. J., Mash, D. C., Henry, L. K., & Blakely, R. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00689 · Cited by 16
Self-citationLoss of ASD-related molecule Cntnap2 affects colonic motility in mice
Robinson, B. G., Oster, B. A., Robertson, K., & Kaltschmidt, J. A. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1287057 · Cited by 15
The Emerging Role of the Gut–Brain–Microbiota Axis in Neurodevelopmental Disorders
Hosie, S., Abo-Shaban, T., Lee, C. Y. Q., Matta, S. M., Shindler, A. E., Gore, R., Sharna, S. S., Herath, M., Crack, P. J., Franks, A. E., et al. (2022) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-05843-1_14 · Cited by 16
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“A similar mechanism may be active in some monogenic forms of ASD [84, 85], although the existence of an association between serotonin blood level and gastrointestinal symptoms in iASD is controversial [86–88].”
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“The neurotransmitter serotonin can regulate the central and enteric nervous systems, influencing gastrointestinal movement and emotions [38, 39].”
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Posttraumatic Stress Disorder and the Gut Microbiome
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Serotonin - Neurotransmitter and Hormone of Brain, Bowels and Blood
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Unlocking the Mysteries: Serotonin Receptor Networks Explored
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Development of the Enteric Nervous System: A Genetic Guide to the Perplexed
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Self-citationCecal motility and the impact of Lactobacillus in feather pecking laying hens
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“In addition, the treatment of pregnant mice with pharmacologic compounds that alter 5-HT bioavailability can exert effects on aspects of both the CNS and ENS [70,71].”
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“Prominent among these are enteric nervous system hypoplasia, decreased GI motility, and reduced peri-stalsis (Margolis et al., 2016).”
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“Since 5-HT promotes gut motility, we investigated whether deficiency of adipocyte TPH2 modulated nutrient absorption (27, 28).”
Metadata
- Authors
- Margolis, K. G., Li, Z., Stevanovic, K., Saurman, V., Israelyan, N., Anderson, G. M., Snyder, I., Veenstra-VanderWeele, J., Blakely, R. D., & Gershon, M. D.
- Affiliations
- Columbia University (US)
- Yale University (US)
- Vanderbilt University (US)
- Corresponding author
- Margolis, Kara Gross
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2016-04-25
- Volume
- 126
- Issue
- 6
- Pages
- 2221-2235
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC4887174
- OpenAlex
- W2343547480
- Cited by
- 139
- References
- 77
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 12 · 2023: 23 · 2022: 17 · 2021: 15 · 2020: 16 · 2019: 17 · 2018: 10 · 2017: 11 · 2016: 4
- FWCI
- 8.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Autism Research Institute (NS15547, DK093786)
- National Institutes of Health (5r01ns015547-39, NS15547, MH096972)
- National Institute of Mental Health (P50MH096972, R01MH094604)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK093786)
- National Institute of Neurological Disorders and Stroke (R01-NS015547)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- autism spectrum disorder, serotonin transporter, gastrointestinal dysfunction, fluoxetine, 5-HT4 receptor agonist, peristalsis, gut-brain axis, mouse model
- MeSH terms
- Autism Spectrum Disorder, Animals, Female, Gastrointestinal Motility, Humans, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Pregnancy, Serotonin, Genetic Variation, Enteric Nervous System, Mice, Knockout, Models, Animal, Gastrointestinal Tract, Serotonin Plasma Membrane Transport Proteins, Mice, Neurogenesis, Mice, 129 Strain
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