Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact

Citations to this article

Building a second brain in the bowel
Marina Avetisyan, … , Ellen Merrick Schill, Robert O. Heuckeroth
Marina Avetisyan, … , Ellen Merrick Schill, Robert O. Heuckeroth
Published February 9, 2015
Citation Information: J Clin Invest. 2015;125(3):899-907. https://doi.org/10.1172/JCI76307.
View: Text | PDF
Review Series Article has an altmetric score of 3

Building a second brain in the bowel

  • Text
  • PDF
Abstract

The enteric nervous system (ENS) is sometimes called the “second brain” because of the diversity of neuronal cell types and complex, integrated circuits that permit the ENS to autonomously regulate many processes in the bowel. Mechanisms supporting ENS development are intricate, with numerous proteins, small molecules, and nutrients that affect ENS morphogenesis and mature function. Damage to the ENS or developmental defects cause vomiting, abdominal pain, constipation, growth failure, and early death. Here, we review molecular mechanisms and cellular processes that govern ENS development, identify areas in which more investigation is needed, and discuss the clinical implications of new basic research.

Authors

Marina Avetisyan, Ellen Merrick Schill, Robert O. Heuckeroth

×

Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2009 Total
Citations: 6 5 9 6 10 8 4 7 3 8 5 1 72
Citation information
This citation data is accumulated from CrossRef, which receives citation information from participating publishers, including this journal. Not all publishers participate in CrossRef, so this information is not comprehensive. Additionally, data may not reflect the most current citations to this article, and the data may differ from citation information available from other sources (for example, Google Scholar, Web of Science, and Scopus).

Citations to this article (72)

Title and authors Publication Year
Unraveling the Connections: Eating Issues, Microbiome, and Gastrointestinal Symptoms in Autism Spectrum Disorder
Tomaszek N, Urbaniak AD, Bałdyga D, Chwesiuk K, Modzelewski S, Waszkiewicz N
Nutrients 2025
Autism gene variants disrupt enteric neuron migration and cause gastrointestinal dysmotility
McCluskey KE, Stovell KM, Law K, Kostyanovskaya E, Schmidt JD, Exner CR, Dea J, Brimble E, State MW, Willsey AJ, Willsey HR
Nature Communications 2025
Imaging the enteric nervous system
Hazart D, Moulzir M, Delhomme B, Oheim M, Ricard C
Frontiers in Neuroanatomy 2025
Metabolomics Insights into Gut Microbiota and Functional Constipation
Zheng F, Yang Y, Lu G, Tan JS, Mageswary U, Zhan Y, Ayad ME, Lee YY, Xie D
Metabolites 2025
Aqueous extract of Solanum americanum Mill. relieves functional constipation by modulating the enteric nervous system and gut micro-ecosystems
Gao X, Li Y, Hu Y, Yang W, Peng L, Sheng J, Tian Y, Yao L, Zhao Y
Frontiers in Nutrition 2025
Flow Cytometric Analysis and Sorting of Murine Enteric Nervous System Cells: An Optimized Protocol
Karkala F, de Bosscher I, Windster JD, Stroebel S, van Zanten L, Alves MM, Sacchetti A
International Journal of Molecular Sciences 2025
The Potential Application of Aloe Barbadensis Mill. as Chinese Medicine for Constipation: Mini-Review.
Huang WR, Fang QH, Yu XB, Ge WH, Yu Y
Drug design, development and therapy 2024
From diversity to disease: unravelling the role of enteric glial cells
Santhosh S, Zanoletti L, Stamp LA, Hao MM, Matteoli G
Frontiers in immunology 2024
Microplastic and the Enteric Nervous System: Effect of PET Microparticles on Selected Neurotransmitters and Cytokines in the Porcine Ileum
Gałęcka I, Całka J
International Journal of Molecular Sciences 2024
The emerging roles of neuroactive components produced by gut microbiota.
Dezfouli MA, Rashidi SK, Yazdanfar N, Khalili H, Goudarzi M, Saadi A, Kiani Deh Kiani A
Molecular biology reports 2024
Essential roles of the unfolded protein response in intestinal physiology
Hetz C, Silva-Agüero JF, Ellerby LM
eGastroenterology 2024
Label-free, fast, 2-photon volume imaging of the organization of neurons and glia in the enteric nervous system
Hazart D, Delhomme B, Oheim M, Ricard C
Frontiers in neuroanatomy 2023
Microbiota-Gut-Brain Axis in Major Depression: A New Therapeutic Approach.
Kim IB, Park SC, Kim YK
Advances in experimental medicine and biology 2023
Up-Regulation of microRNA-424 Causes an Imbalance in AKT Phosphorylation and Impairs Enteric Neural Crest Cell Migration in Hirschsprung Disease
Xu Z, Yan Y, Gu B, Cai W, Wang Y
International journal of molecular sciences 2023
Interstitial Cells of Cajal and Enteric Nervous System in Gastrointestinal and Neurological Pathology, Relation to Oxidative Stress
López-Pingarrón L, Almeida H, Soria-Aznar M, Reyes-Gonzales MC, Rodríguez-Moratinos AB, Muñoz-Hoyos A, García JJ
Current issues in molecular biology 2023
History of childhood physical abuse is associated with gut microbiota diversity among adult psychiatric inpatients
Rohr JC, Bourassa KA, Thompson DS, Fowler JC, Frueh BC, Weinstein BL, Petrosino J, Madan A
Journal of Affective Disorders 2023
Loss of ASD-related molecule Cntnap2 affects colonic motility in mice
Robinson BG, Oster BA, Robertson K, Kaltschmidt JA
Frontiers in neuroscience 2023
Loss of ASD-Related Molecule Cntnap2 Affects Colonic Motility in Mice
Robinson BG, Oster BA, Robertson K, Kaltschmidt JA
2023
Sequencing Reveals miRNAs Enriched in the Developing Mouse Enteric Nervous System
Pai C, Sengupta R, Heuckeroth RO
Non-Coding RNA 2023
Pcgf1 gene disruption reveals primary involvement of epigenetic mechanism in neuronal subtype specification in the enteric nervous system
Putra BP, Ito K, Cirillo C, Sunardi M, Koseki H, Uesaka T, Enomoto H
Development, Growth & Differentiation 2023
Development, Diversity, and Neurogenic Capacity of Enteric Glia
W Boesmans, A Nash, K Tasnády, W Yang, L Stamp, M Hao
Frontiers in Cell and Developmental Biology 2022
Age-dependent aggregation of α-synuclein in the nervous system of gut-brain axis is associated with caspase-1 activation
Q Hu, M Hong, M Huang, Q Gong, X Zhang, V Uversky, F Pan-Montojo, T Huang, H Zhou, S Zhu
Metabolic Brain Disease 2022
Resveratrol in Intestinal Health and Disease: Focusing on Intestinal Barrier
Y Wang, C Hong, Z Wu, S Li, Y Xia, Y Liang, X He, X Xiao, W Tang
Frontiers in Nutrition 2022
Transepithelial Effect of Probiotics in a Novel Model of Gut Lumen to Nerve Signaling
Piletz JE, Cooper J, Chidester K, Erson K, Melton S, Osemeka A, Patterson M, Strickland K, Wan JX, Williams K
Nutrients 2022
Embelin and levodopa combination therapy for improved Parkinson’s disease treatment
Ramachandra VH, Sivanesan S, Koppal A, Anandakumar S, Howell MD, Sukumar E, Vijayaraghavan R
Translational Neuroscience 2022
Equine Stomach Development in the Foetal Period of Prenatal Life—An Immunohistochemical Study
Poradowski D, Chrószcz A
2022
Cell-autonomous retinoic acid receptor signaling has stage-specific effects on mouse enteric nervous system
Tao Gao, Elizabeth C. Wright-Jin, Rajarshi Sengupta, Jessica B. Anderson, Robert O. Heuckeroth
JCI Insight 2021
Phenotypic and functional comparison of rat enteric neural crest-derived cells during fetal and early-postnatal stages
DH Tian, CH Qin, WY Xu, WK Pan, YY Zhao, BJ Zheng, XL Chen, Y Liu, Y Gao, H Yu
NEURAL REGEN RES 2021
Action Mode of Gut Motility, Fluid and Electrolyte Transport in Chronic Constipation
Q Zhao, YY Chen, DQ Xu, SJ Yue, RJ Fu, J Yang, LM Xing, YP Tang
Frontiers in pharmacology 2021
Motor Stereotypic Behavior Was Associated With Immune Response in Macaques: Insight From Transcriptome and Gut Microbiota Analysis
X Pan, F Liu, Y Song, H Wang, L Wang, H Qiu, M Price, J Li
Frontiers in microbiology 2021
The enteric nervous system in gastrointestinal disease etiology
AM Holland, AC Bon-Frauches, D Keszthelyi, V Melotte, W Boesmans
Cellular and Molecular Life Sciences 2021
Immunohistochemical expression and neurochemical phenotypes of huntingtin-associated protein 1 in the myenteric plexus of mouse gastrointestinal tract
AM Tarif, N Islam, MR Jahan, A Yanai, K Nozaki, K Masumoto, K Shinoda
Cell and Tissue Research 2021
Enteric glial biology, intercellular signalling and roles in gastrointestinal disease
L Seguella, BD Gulbransen
Nature Reviews Gastroenterology & Hepatology 2021
Effect of Paroxetine Combined with Probiotics in Patients with Type 2 Diabetes Mellitus Complicated with Gastrointestinal Dysfunction and Liver Cancer
Y Peng, X Yang, Y Wang, MW Khan
Journal of Oncology 2021
GWAS of peptic ulcer disease implicates Helicobacter pylori infection, other gastrointestinal disorders and depression
Y Wu, GK Murray, EM Byrne, J Sidorenko, PM Visscher, NR Wray
Nature Communications 2021
Abdominal Massage Alleviates Skeletal Muscle Insulin Resistance by Regulating the AMPK/SIRT1/PGC-1α Signaling Pathway
Y Han, Z Lu, S Chen, C Zhong, M Yan, H Wang, M Meng, M Liu
Cell Biochemistry and Biophysics 2021
Enteric glia as a source of neural progenitors in adult zebrafish
S McCallum, Y Obata, E Fourli, S Boeing, CJ Peddie, Q Xu, S Horswell, RN Kelsh, L Collinson, D Wilkinson, C Pin, V Pachnis, TA Heanue
eLife 2020
Robust, 3-Dimensional Visualization of Human Colon Enteric Nervous System Without Tissue Sectioning
KD Graham, SH López, R Sengupta, A Shenoy, S Schneider, CM Wright, M Feldman, E Furth, F Valdivieso, A Lemke, BJ Wilkins, A Naji, EJ Doolin, MJ Howard, RO Heuckeroth
Gastroenterology 2020
MicroRNA-4516-mediated regulation of MAPK10 relies on 3′ UTR cis -acting variants and contributes to the altered risk of Hirschsprung disease
Y Wang, Q Jiang, A Chakravarti, H Cai, Z Xu, W Wu, B Gu, L Li, W Cai
Journal of medical genetics 2020
Bi‐Layered Tubular Microfiber Scaffolds as Functional Templates for Engineering Human Intestinal Smooth Muscle Tissue
Y Chen, C Guo, E Manousiouthakis, X Wang, DM Cairns, TT Roh, C Du, DL Kaplan
Advanced Functional Materials 2020
Seven facts and five initiatives for gut microbiome research
D Li, C Gao, F Zhang, R Yang, C Lan, Y Ma, J Wang
Protein & Cell 2020
Apoptotic and Degenerative Changes in the Enteric Nervous System Following Exposure to Fluoride During Pre- and Post-natal Periods
S Sarwar, JA Quadri, M Kumar, S Singh, P Das, TC Nag, A Shariff
Biological Trace Element Research 2020
Quantitative analysis of enteric neurons containing choline acetyltransferase and nitric oxide synthase immunoreactivities in the submucosal and myenteric plexuses of the porcine colon
M Mazzoni, F Caremoli, L Cabanillas, J de los Santos, M Million, M Larauche, P Clavenzani, RD Giorgio, C Sternini
Cell and Tissue Research 2020
Changes in the Population Size of Calbindin D-28k-Immunoreactive Enteric Neurons in the Porcine Caecum under the Influence of Bisphenol A: A Preliminary Study
I Gonkowski, S Gonkowski, E Dzika, J Wojtkiewicz
Toxics 2020
Down Syndrome Mouse Models have an Abnormal Enteric Nervous System
Ellen Schill, Christina Wright, Alisha Jamil, Jonathan LaCombe, Randall J Roper, Robert Heuckeroth
JCI Insight 2019
Regional complexity in enteric neuron wiring reflects diversity of motility patterns in the mouse large intestine
Z Li, MM Hao, CV den Haute, V Baekelandt, W Boesmans, PV Berghe
eLife 2019
Downregulation of Protein Tyrosine Phosphatase Receptor Type R Accounts for the Progression of Hirschsprung Disease
J Tian, C Zeng, Z Tian, Y Lin, B Wang, Y Pan, Z Shu, X Jiang
Frontiers in molecular neuroscience 2019
Irritable Bowel Syndrome: News from an Old Disorder
AI Ferreira, M Garrido, F Castro-Poças
GE Portuguese Journal of Gastroenterology 2019
Hirschsprung disease — integrating basic science and clinical medicine to improve outcomes
RO Heuckeroth
Nature Reviews Gastroenterology & Hepatology 2018
Enteric nervous system development: what could possibly go wrong?
M Rao, MD Gershon
Nature Reviews Neuroscience 2018
Recognizing Depression from the Microbiota–Gut–Brain Axis
S Liang, X Wu, X Hu, T Wang, F Jin
International journal of molecular sciences 2018
Gastrointestinal symptoms in postural tachycardia syndrome: a systematic review
SE Mehr, A Barbul, CA Shibao
Clinical Autonomic Research 2018
Distribution and Neurochemistry of the Porcine Ileocaecal Valve Projecting Sensory Neurons in the Dorsal Root Ganglia and the Influence of Lipopolysaccharide from Different Serotypes of Salmonella spp. on the Chemical Coding of DRG Neurons in the Cell Cultures
A Mikołajczyk, A Kozłowska, S Gonkowski
International journal of molecular sciences 2018
The influence of experimental inflammation and axotomy on leucine enkephalin (leuENK) distribution in intramural nervous structures of the porcine descending colon
S Gonkowski, K Makowska, J Calka
BMC veterinary research 2018
‘Neurasthenia gastrica’ revisited: perceptions of nerve-gut interactions in nervous exhaustion, 1880–1920
K Lillestøl
Microbial Ecology in Health and Disease 2018
Neuroimmune regulation during intestinal development and homeostasis
H Veiga-Fernandes, V Pachnis
Nature Immunology 2017
Defining the transcriptomic landscape of the developing enteric nervous system and its cellular environment
S Roy-Carson, K Natukunda, H Chou, N Pal, C Farris, SQ Schneider, JA Kuhlman
BMC Genomics 2017
Age-Dependent Alpha-Synuclein Accumulation and Phosphorylation in the Enteric Nervous System in a Transgenic Mouse Model of Parkinson’s Disease
CB Zhong, QQ Chen, C Haikal, W Li, A Svanbergsson, M Diepenbroek, JY Li
Neuroscience Bulletin 2017
A Novel Zebrafish ret Heterozygous Model of Hirschsprung Disease Identifies a Functional Role for mapk10 as a Modifier of Enteric Nervous System Phenotype Severity
TA Heanue, W Boesmans, DM Bell, K Kawakami, PV Berghe, V Pachnis, RM Hofstra
PLoS genetics 2016
Characterization and transplantation of enteric neural crest cells from human induced pluripotent stem cells
W Li, L Huang, J Zeng, W Lin, K Li, J Sun, W Huang, J Chen, G Wang, Q Ke, J Duan, X Lai, R Chen, M Liu, Y Liu, T Wang, X Yang, Y Chen, H Xia, AP Xiang
Molecular Psychiatry 2016
The Role of the Vagal Nucleus Tractus Solitarius in the Therapeutic Effects of Obesity Surgery and Other Interventional Therapies on Type 2 Diabetes
C Blasi
Obesity Surgery 2016
Gastrointestinal hormones and the gut connectome:
L Ye, RA Liddle
Current opinion in endocrinology, diabetes, and obesity 2016
The bowel and beyond: the enteric nervous system in neurological disorders
M Rao, MD Gershon
Nature Reviews Gastroenterology & Hepatology 2016
Gene-environment interactions and the enteric nervous system: Neural plasticity and Hirschsprung disease prevention
RO Heuckeroth, KH Schäfer
Developmental Biology 2016
Delivery of enteric neural progenitors with 5-HT4 agonist-loaded nanoparticles and thermosensitive hydrogel enhances cell proliferation and differentiation following transplantation in vivo
R Hotta, LS Cheng, HK Graham, N Nagy, J Belkind-Gerson, G Mattheolabakis, MM Amiji, AM Goldstein
Biomaterials 2016
Regeneration: Stem cells make the bowel nervous
RO Heuckeroth
Nature 2016
Hirschsprung disease, Down syndrome and missing heritability: too much collagen slows migration
Robert Heuckeroth
Journal of Clinical Investigation 2015
The gut connectome: making sense of what you eat
Diego Bohórquez, Rodger Liddle
Journal of Clinical Investigation 2015
Neural reflex pathways in intestinal inflammation: hypotheses to viable therapy
RA Willemze, MD Luyer, WA Buurman, WJ de Jonge
Nature Reviews Gastroenterology & Hepatology 2015
Optical Tools to Investigate Cellular Activity in the Intestinal Wall
W Boesmans, MM Hao, PV Berghe
Journal of Neurogastroenterology and Motility 2015
Motility: Hirschsprung disease — laying down a suitable path
HM Young, SJ McKeown
Nature Reviews Gastroenterology & Hepatology 2015
Pulmonary surfactant: an immunological perspective
ZC Chroneos, Z Sever-Chroneos, VL Shepherd
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2009

← Previous 1 2 3 Next →

Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 2 X users
On 1 Facebook pages
188 readers on Mendeley
See more details