Intestinal microbiota influence the early postnatal development of the enteric nervous system
Abstract
BACKGROUND: Normal gastrointestinal function depends on an intact and coordinated enteric nervous system (ENS). While the ENS is formed during fetal life, plasticity persists in the postnatal period during which the gastrointestinal tract is colonized by bacteria. We tested the hypothesis that colonization of the bowel by intestinal microbiota influences the postnatal development of the ENS. METHODS: The development of the ENS was studied in whole mount preparations of duodenum, jejunum, and ileum of specific pathogen-free (SPF), germ-free (GF), and altered Schaedler flora (ASF) NIH Swiss mice at postnatal day 3 (P3). The frequency and amplitude of circular muscle contractions were measured in intestinal segments using spatiotemporal mapping of video recorded spontaneous contractile activity with and without exposure to lidocaine and N-nitro-L-arginine (NOLA). KEY RESULTS: Immunolabeling with antibodies to PGP9.5 revealed significant abnormalities in the myenteric plexi of GF jejunum and ileum, but not duodenum, characterized by a decrease in nerve density, a decrease in the number of neurons per ganglion, and an increase in the proportion of myenteric nitrergic neurons. Frequency of amplitude of muscle contractions were significantly decreased in the jejunum and ileum of GF mice and were unaffected by exposure to lidocaine, while NOLA enhanced contractile frequency in the GF jejunum and ileum. CONCLUSIONS & INFERENCES: These findings suggest that early exposure to intestinal bacteria is essential for the postnatal development of the ENS in the mid to distal small intestine. Future studies are needed to investigate the mechanisms by which enteric microbiota interact with the developing ENS.
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Animal studies suggest that the GM plays a crucial role in regulating early brain development.
“Animal studies suggest that the GM plays a crucial role in regulating early brain development (19, 45, 60, 114–117).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [114]
The gut microbiota is essential for the development of the ENS.
“recent findings indicating that the gut microbiota is essential for the development of the ENS (Collins et al., 2014; Obata and Pachnis, 2016).”
From Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism (2017) · cites this paper as Collins et al., 2014
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Enteric nervous system: the bridge between the gut microbiota and neurological disorders
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“A general reduction in the myenteric plexus density has been observed in both the jejunum and the ileum of postnatal germfree (GF) mice, but not in the duodenum; this suggests that early exposure to gut microbes is essential for the postnatal development of the ENS (Collins et al., 2014).”
BackgroundYarandi, S. S., Kulkarni, S., Saha, M., Sylvia, K. E., Sears, C. L., & Pasricha, P. J. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.03.050 · Cited by 138 · see citing works
Autism Spectrum Disorder as a Brain-Gut-Microbiome Axis Disorder
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Psychobiotics and the gut–brain axis: in the pursuit of happiness
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“The myenteric plexus of the jejunum and ileum of GF mice showed an unorganized lattice-like appearance, with fewer ganglia, and thinner nerve fibers.(24) Intestinal motility, measured as frequency of spontaneous muscle contractions, was decreased in GF mice, as was the amplitude of muscle contractions in GF mice compa…”
InfluentialGut microbiota regulates lacteal integrity by inducing VEGF‐C in intestinal villus macrophages
Suh, S. H., Choe, K., Hong, S. P., Jeong, S., Mäkinen, T., Kim, K. S., Alitalo, K. K., Surh, C. D., Koh, G. Y., & Song, J. (2019) · EMBO Reports · doi:10.15252/embr.201846927 · Cited by 133 · see citing works
“Similarly, gut microbiota governs development of the enteric nervous system only in the jejunum and ileum but not the duodenum [28,51].”
Enteric neuroimmune interactions coordinate intestinal responses in health and disease
Wang, H., Foong, J. P. P., Harris, N. L., & Bornstein, J. C. (2021) · Mucosal Immunology · doi:10.1038/s41385-021-00443-1 · Cited by 128 · see citing works
Gut microbiome and anticancer immune response: really hot Sh*t!
Viaud, S., Daillère, R., Boneca, I. G., Lepage, P., Langella, P., Chamaillard, M., Pittet, M. J., Ghiringhelli, F., Trinchieri, G., Goldszmid, R., et al. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2014.56 · Cited by 123 · see citing works
“Finally, intestinal bacteria are essential for the postnatal development of the enteric nervous system in the mid-distal SI.(18)”
BackgroundBicknell, B. T., Liebert, A. D., Borody, T. J., Herkes, G., McLachlan, C. S., & Kiat, H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119577 · Cited by 129 · see citing works
“In germ-free animal models, many aspects of neurodevelopment have been shown to be compromised, including neurogenesis and myelination [103] and dendritic spine development [104], as well as abnormal ENS development [105], which can be reversed by the post-natal transplant of a normal microbiome.”
Antibiotic-induced dysbiosis of the microbiota impairs gut neuromuscular function in juvenile mice
Caputi, V., Marsilio, I., Filpa, V., Cerantola, S., Orso, G., Bistoletti, M., Paccagnella, N., De Martin, S., Montopoli, M., Dall'Acqua, S., et al. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13965 · Cited by 124 · see citing works
“In mammals, young adulthood represents a critical and dynamic phase for differentiation and maturation of neural circuits in the gut (Collins et al., 2014).”
BackgroundResultHost‐microbe interaction in the gastrointestinal tract
Parker, A., Lawson, M. A., Vaux, L., & Pin, C. (2017) · Environmental Microbiology · doi:10.1111/1462-2920.13926 · Cited by 123 · see citing works
“Feature Altered phenotype in germ-free Model References Transit of luminal contents Delayed gastric emptying and prolonged transit Mouse (Abrams and Bishop, 1967; Iwai et al., 1973) Chicken (Palmer and Rolls, 1981; Furuse and Okumura, 1994) Crypt-villus morphology Thinner villi with shallower crypts, reduced thickness…”
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“Motility has been studied in some detail in the small intestine of GF mice (13, 33, 57, 58), yet few studies have reported on motility of the colon in these mice.”
BackgroundTargeting the gut to treat multiple sclerosis
Ghezzi, L., Cantoni, C., Pinget, G. V., Zhou, Y., & Piccio, L. (2021) · Journal of Clinical Investigation · doi:10.1172/jci143774 · Cited by 114 · see citing works
“Gut microbiota influence both CNS and ENS development, as evident in GF mice, whose myenteric plexus is structurally abnormal, exhibiting decreased nerve density and number of neurons per ganglion (86).”
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“The effect of microbiota on the formation of neural circuits in the mammalian gut is highlighted by studies of germ-free mice that demonstrated that these animals have altered spontaneous circular muscle contractions and decreased nerve density in the jejunum and ileum (101).”
The Gut Microbiome as Therapeutic Target in Central Nervous System Diseases: Implications for Stroke
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“absence of microorganisms is not fully developed, and GFmice have an altered intestinal motility [22].”
BackgroundSwine gut microbiota and its interaction with host nutrient metabolism
Wang, H., Xu, R., Zhang, H., Su, Y., & Zhu, W. (2020) · Animal nutrition · doi:10.1016/j.aninu.2020.10.002 · Cited by 109 · see citing works
“This multi-lateral network of communication between the gut microbiota and the central nervous system (CNS, representing the headquarters of the body) is mediated by the autonomic nervous system (ANS), enteric nervous system, immune system and bacterial metabolites (Junges et al., 2018).”
BackgroundInfluentialEnteric nervous system and intestinal epithelial regulation of the gut-brain axis
Dowling, L. R. C., Strazzari, M. R., Keely, S., & Kaiko, G. E. (2022) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2022.07.015 · Cited by 110 · see citing works
Gut microbiota, nutrient sensing and energy balance
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“Moreover, both development of the enteric nervous system and excitability of primary afferents in the myenteric plexus are altered in GF mice [64,65], furthering the possibility that the microbiota can have a direct influence on intestinal nutrient-sensing mechanisms.”
BackgroundThe Use of Defined Microbial Communities To Model Host-Microbe Interactions in the Human Gut
Elzinga, J., John van der, O. O. S. T., de Vos, W. M., & Smidt, H. (2019) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00054-18 · Cited by 101 · see citing works
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Roles of gut microbiome in epilepsy risk: A Mendelian randomization study
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“Investigations have shown that GMs play a vital role in the development of the enteric nervous system, blood–brain barrier, and glial cells, which are all important for cognitive development and behavior regulation (Braniste et al., 2014; Collins et al., 2014).”
BackgroundPekmez, C. T., Dragsted, L. O., & Brahe, L. K. (2018) · Clinical Nutrition · doi:10.1016/j.clnu.2018.02.014 · Cited by 94 · see citing works
Brun, P., Gobbo, S., Caputi, V., Spagnol, L., Schirato, G., Pasqualin, M., Levorato, E., Palù, G., Giron, M. C., & Castagliuolo, I. (2015) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2015.03.018 · Cited by 92 · see citing works
“Derangement in the composition of the gut microbial community is a central or a contributing cause ofmanyGI diseases possibly by altering the intestinal neurotransmission pathways (Collins et al., 2014).”
Chandrasekharan, B., Saeedi, B. J., Alam, A., Houser, M., Srinivasan, S., Tansey, M., Jones, R., Nusrat, A., & Neish, A. S. (2019) · Gastroenterology · doi:10.1053/j.gastro.2019.03.045 · Cited by 94 · see citing works
Neuro-immune regulation of mucosal physiology
Chesné, J., Cardoso, V., & Veiga‐Fernandes, H. (2018) · Mucosal Immunology · doi:10.1038/s41385-018-0063-y · Cited by 92 · see citing works
Targeting the gut microbiota to influence brain development and function in early life
Wang, S., Harvey, L., Martı́n, R., van der Beek, E. M., Knol, J., Cryan, J. F., & Renes, I. B. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.09.002 · Cited by 92 · see citing works
Gut-Brain Axis in the Early Postnatal Years of Life: A Developmental Perspective
Jena, A., Montoya, C. A., Mullaney, J. A., Dilger, R. N., Young, W., McNabb, W. C., & Roy, N. C. (2020) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2020.00044 · Cited by 92 · see citing works
The microbiota-gut-brain axis: Focus on the fundamental communication pathways
Bistoletti, M., Bosi, A., Banfi, D., Giaroni, C., & Baj, A. (2020) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2020.08.012 · Cited by 88 · see citing works
Cellular Organization of Neuroimmune Interactions in the Gastrointestinal Tract
Margolis, K. G., Gershon, M. D., & Bogunovic, M. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.05.003 · Cited by 86 · see citing works
“Germ-free mice exhibit significant ENS abnormalities, including a decline in the myenteric, particularly nitrergic, neurons in the jejunum, ileum, and colon [61,62].”
BackgroundNeuroimmune Interactions in the Intestine
Wallrapp, A., & Chiu, I. M. (2024) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101921-042929 · Cited by 91 · see citing works
O’Donovan, S. M., Crowley, E. K., Brown, J. R. ‐., O’Sullivan, O., O’Leary, O. F., Timmons, S., Nolan, Y. M., Clarke, D. J., Hyland, N. P., Joyce, S. A., et al. (2020) · Neurogastroenterology & Motility · doi:10.1111/nmo.13726 · Cited by 86 · see citing works
Enteric nervous system assembly: Functional integration within the developing gut
Hao, M. M., Foong, J. P. P., Bornstein, J. C., Li, Z. L., Berghe, P. V., & Boesmans, W. (2016) · Developmental Biology · doi:10.1016/j.ydbio.2016.05.030 · Cited by 82 · see citing works
Sanchez, J. B., & Kadrofske, M. M. (2019) · Neurogastroenterology & Motility · doi:10.1111/nmo.13569 · Cited by 81 · see citing works
Aktar, R., Parkar, N., Stentz, R., Baumard, L., Parker, A., Goldson, A. J., Brion, A., Carding, S. R., Blackshaw, L. A., & Peiris, M. (2020) · Gut Microbes · doi:10.1080/19490976.2020.1766936 · Cited by 80 · see citing works
“Studying germ-free (GF) mice has shown host–microbe interactions and the influence of the microbiome on neuron size, architecture and colon function.(5,6) However, despite these advances, there is no suggestion of how specific bacteria induce these changes.”
BackgroundMicrobiome, Parkinson’s Disease and Molecular Mimicry
Miraglia, F., & Colla, E. (2019) · Cells · doi:10.3390/cells8030222 · Cited by 81 · see citing works
Padhi, P., Worth, C., Zenitsky, G. D., Jin, H., Sambamurti, K., Anantharam, V., Kanthasamy, A., & Kanthasamy, A. G. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.836605 · Cited by 80 · see citing works
Gut microbiota and microbial metabolites for osteoporosis
Zheng, X.-Q., Wang, D.-B., Jiang, Y., & Song, C. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2437247 · Cited by 89 · see citing works
The gut microbiome in disorders of gut–brain interaction
Kraïmi, N., Ross, T., Pujo, J., & Palma, G. D. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2360233 · Cited by 86 · see citing works
“18 26–34 Indeed, it is now well known that the gut microbiome is beneficial to multiple aspects of host function, from host-metabolism, biochemical regulation of processes such as gluconeogenesis, lipogenesis, and cholesterol synthesis, 35 to healthy aging.”
BackgroundSpontaneous body contractions are modulated by the microbiome of Hydra
Murillo‐Rincón, A. P., Klimovich, A. V., Pemöller, E., Taubenheim, J., Mortzfeld, B. M., Augustin, R., & Bosch, T. C. G. (2017) · Scientific Reports · doi:10.1038/s41598-017-16191-x · Cited by 77 · see citing works
Gut-microbiota derived bioactive metabolites and their functions in host physiology
Debnath, N., Kumar, R., Kumar, A., Mehta, P. K., & Yadav, A. K. (2021) · Biotechnology and Genetic Engineering Reviews · doi:10.1080/02648725.2021.1989847 · Cited by 77 · see citing works
The Influence of Early Life Nutrition on Epigenetic Regulatory Mechanisms of the Immune System
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Systems-level metabolism of the altered Schaedler flora, a complete gut microbiota
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“ASF-colonized mice are commercially available and widely used (Singer and Nash, 2000; SarmaRupavtarm et al., 2004; Ge et al., 2006; Stehr et al., 2009; Collins et al., 2014; Henderson et al., 2015; Moghadamrad et al., 2015; Shen et al., 2015).”
He, Y., Wang, K., Su, N., Yuan, C., Zhang, N., Hu, X., Fu, Y., & Zhao, F. (2024) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.70099 · Cited by 73 · see citing works
“69 Many investigations have established that the network density of the jejunal and ileal interosseous plexus was dramatically reduced in GF mice compared to SPF animals, as well as the number of neurons in the interosseous ganglion, resulting in structural abnormalities of the jejunal and ileal…”
BackgroundGut-liver axis: Recent concepts in pathophysiology in alcohol-associated liver disease
Raya Tonetti, F., Eguileor, A., Mrdjen, M., Pathak, V., Travers, J., Nagy, L. E., & Llorente, C. (2024) · Hepatology · doi:10.1097/hep.0000000000000924 · Cited by 78 · see citing works
Antibiotics and the nervous system: More than just the microbes?
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Dairy probiotics: Beyond the role of promoting gut and immune health
Ζουμποπούλου, Γ., Pot, B., Tsakalidou, E., & Papadimitriou, K. (2016) · International Dairy Journal · doi:10.1016/j.idairyj.2016.09.010 · Cited by 70 · see citing works
Neuron–Glia Interaction in the Developing and Adult Enteric Nervous System
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“Consequently, antibiotic treatments impaired glial homeostasis [77,78].”
Nerves in gastrointestinal cancer: from mechanism to modulations
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Does the Gut Microbiota Influence Immunity and Inflammation in Multiple Sclerosis Pathophysiology?
Adamczyk-Sowa, M. H., Medrek, A., Madej, P., Michlicka, W., & Dobrakowski, P. P. (2017) · Journal of Immunology Research · doi:10.1155/2017/7904821 · Cited by 67 · see citing works
“[30] reported that the adult intestinal flora is mainly composed of four main clusters: Firmicutes, Bacteroidetes, Actinobacteria, andProteobacteria.”
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Parathan, P., Wang, Y., Leembruggen, A. J. L., Bornstein, J. C., & Foong, J. P. P. (2019) · Developmental Biology · doi:10.1016/j.ydbio.2019.10.011 · Cited by 64 · see citing works
Visceral Pain and Gastrointestinal Microbiome
Chichlowski, M., & Rudolph, C. (2015) · Journal of Neurogastroenterology and Motility · doi:10.5056/jnm15025 · Cited by 65 · see citing works
“The frequency and amplitude of muscle contractions also were fewer in GF mice.(29) GF mice also differ from conventional mice in the expression of brain-derived neurotrophic factor in the cor-”
Gut microbiota and neuropsychiatric disorders: Implications for neuroendocrine-immune regulation
Ge, T., Yao, X., Zhao, H., Yang, W., Zou, X., Peng, F., Li, B., & Cui, R. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105909 · Cited by 62 · see citing works
- Authors
- Collins, J., Borojevic, R., Verdu, E. F., Huizinga, J. D., & Ratcliffe, E. M.
- Affiliations
- McMaster University (CA)
- Corresponding author
- Ratcliffe, E. M.
- Venue
- Neurogastroenterology & Motility
- Publisher
- Wiley
- Published
- 2013-10-08
- Volume
- 26
- Issue
- 1
- Pages
- 98-107
- ISSN
- 1350-1925 (ISSN-L)
- 1365-2982
- OpenAlex
- W1976582565
- Cited by
- 318
- References
- 37
- Citations by year
- 2026: 17 · 2025: 19 · 2024: 28 · 2023: 18 · 2022: 34 · 2021: 43 · 2020: 31 · 2019: 21 · 2018: 28 · 2017: 20 · 2016: 30 · 2015: 15 · 2014: 12 · 2013: 1 · 2012: 1
- FWCI
- 18.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurogastroenterology & Motility (publishedVersion)
- PubMed (publishedVersion)
- Funders
- McMaster University
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
- Keywords
- gut microbiota, enteric nervous system, postnatal development, germ-free mice, myenteric plexus, nitrergic neurons, intestinal motility, smooth muscle contraction, L-NNA, lidocaine, small intestine, gut-brain axis
- MeSH terms
- Animals, Animals, Newborn, Duodenum, Female, Gastrointestinal Motility, Ileum, Jejunum, Pregnancy, Enteric Nervous System, Mice, Microbiota
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