journal article·2021-12-16Open access

The Enteric Nervous System and the Microenvironment of the Gut: The Translational Aspects of the Microbiome-Gut-Brain Axis

Fruzsina Mogor, Tamás Kovács, Zoltan Lohinai, David Dora

Applied Sciences· Volume 11· Issue 24

Abstract

The proper functioning of the gastrointestinal tract is essential for digestion, absorption and the elimination of waste products. It protects us against pathogens, allergens and toxins, continuously monitoring and regulating the internal environment. The vast majority of these tasks are carried out by the nervous and immune systems of the gut in close cooperation by constantly adapting to internal and external stimuli, maintaining its homeostasis. In this review, we would like to summarize the most recent findings about the cytoarchitecture and functional microanatomy of the enteric nervous system and the immune microenvironment of the gut highlighting the essential role and inevitable molecular crosstalk between these two highly organized networks. Gut neuroimmunology is a rapidly evolving field and might help us to understand the etiology of inflammatory bowel disease and the systemic consequences of chronic intestinal inflammation. Finally, we also included a brief outlook to present the most recent research depicting the multifaceted role of the gut microbiome, its contribution to the gut-brain axis and human disease.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: Gastrointestinal motility and disorders · Gut microbiota and health · IL-33, ST2, and ILC Pathways

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Anatomy, Histology and Embryology, Semmelweis University, Tuzolto St. 58, 1094 Budapest, Hungary

National Korányi Institute of Pulmonology, 1094 Budapest, Hungary

References (100+)

Show source-provided references
1. Cells of the innate and adaptive immunity and their interactions in inflammatory bowel disease10.1016/j.advms.2016.09.001 ↗
2. Functional specializations of intestinal dendritic cell and macrophage subsets that control TH -17 and T regulatory responses is dependent on the T:APC ratio, source of mouse strain and regional localization10.4049/jimmunol.1002701 ↗
3. Innate lymphoid cells: 10 years on10.1016/j.cell.2018.07.017 ↗
4. Mucosal innate immune cells regulate both gut homeostasis and intestinal inflammation10.1002/eji.201343782 ↗
5. Regulatory immune cells in regulation of intestinal inflammatory response to microbiota10.1038/mi.2015.49 ↗
6. Luminal bacteria recruit CD103+ dendritic cells into the intestinal epithelium to sample bacterial antigens for presentation10.1016/j.immuni.2013.01.009 ↗
7. Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1+ macrophages to CD103+ dendritic cells10.1016/j.immuni.2013.12.012 ↗
8. Origin, Differentiation, and function of intestinal macrophages10.3389/fimmu.2018.02733 ↗
9. Mechanisms of oral tolerance10.1007/s12016-018-8680-5 ↗
10. CD8α + and CD11b + dendritic cell-restricted MHC class II controls Th1 CD4+ T cell immunity10.4049/jimmunol.171.10.5077 ↗
11. Intestinal microbial diversity during early-life colonization shapes long-term IgE levels10.1016/j.chom.2013.10.004 ↗
12. Microbiota regulation of inflammatory bowel disease and colorectal cancer10.1016/j.semcancer.2013.09.002 ↗
13. Microbiome Dependent regulation of tregs and Th17 cells in mucosa10.3389/fimmu.2019.00426 ↗
14. Innate lymphoid cells-a proposal for uniform nomenclature10.1038/nri3365 ↗
15. The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin10.1146/annurev-pathol-011110-130318 ↗
16. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens10.1038/nm1720 ↗
17. Immunomodulation of human CD19 + CD25 high regulatory B cells via Th17/Foxp3 regulatory T cells and Th1/Th2 cytokines10.1016/j.humimm.2019.05.011 ↗
18. IL-10-producing regulatory B cells induced by IL-33 (BregIL-33) effectively attenuate mucosal inflammatory responses in the gut10.1016/j.jaut.2014.01.032 ↗
19. Macrophages in intestinal inflammation and resolution: A potential therapeutic target in IBD10.1038/s41575-019-0172-4 ↗
20. Intestinal resident macrophages: Multitaskers of the gut10.1111/nmo.13843 ↗
21. Evidence of a myenteric plexus barrier and its macrophage-dependent degradation during murine colitis: Implications in enteric neuroinflammation10.1016/j.jcmgh.2021.07.003 ↗
22. Macrophages in intestinal homeostasis and inflammation10.1111/imr.12192 ↗
23. Tissue-resident macrophages in the intestine are long lived and defined by Tim-4 and CD4 expression10.1084/jem.20180019 ↗
24. Self-maintaining gut macrophages are essential for intestinal homeostasis10.1016/j.cell.2018.07.048 ↗
25. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility10.1016/j.cell.2014.04.050 ↗
26. Neuro-immune interactions drive tissue programming in intestinal macrophages10.1016/j.cell.2015.12.023 ↗
27. Macrophages associated with the intrinsic and extrinsic autonomic innervation of the rat gastrointestinal tract10.1016/j.autneu.2012.02.004 ↗
28. TRPV4 channel signaling in macrophages promotes gastrointestinal motility via direct effects on smooth muscle cells10.1016/j.immuni.2018.04.021 ↗
29. Morphological classifications of enteric neurons—100 years after Dogiel10.1007/s004290050267 ↗
30. Two types of neurones in the Myenteric Plexus of duodenum in the guinea-pig10.1113/jphysiol.1974.sp010436 ↗
31. Intracellular recording from the Myenteric Plexus of the guinea-pig ileum10.1113/jphysiol.1973.sp010244 ↗
32. Intracellular study of electrical activity of Auerbach’s Plexus in guinea-pig small intestine10.1007/BF00585604 ↗
33. Identification of neuron types in the submucosal ganglia of the mouse ileum10.1007/s00441-009-0773-2 ↗
34. Immunohistochemical analysis of neuron types in the mouse small intestine10.1007/s00441-008-0684-7 ↗
35. Nestor-Kalinoski, A., Smith-Edwards, K.M., Meerschaert, K., Margiotta, J.F., Rajwa, B., Davis, B.M., and Howard, M.J. (2021). Unique neural circuit connectivity of mouse proximal, middle, and distal colon defines regional colonic motor patterns. Cell. Mol. Gastroenterol. Hepatol., ahead of print.10.1016/j.jcmgh.2021.08.016 ↗
36. The enteric network: Interactions between the immune and nervous systems of the gut10.1016/j.immuni.2017.05.011 ↗
37. Activation of GABAA receptors in colon epithelium exacerbates acute colitis10.3389/fimmu.2018.00987 ↗
38. Classes of enteric nerve cells in the guinea-pig small intestine10.1002/1097-0185(20010101)262:1<58::AID-AR1011>3.0.CO;2-V ↗
39. Neurochemical classification of myenteric neurons in the guinea-pig ileum10.1016/0306-4522(96)00275-8 ↗
40. Neurochemical classification of enteric neurons in the guinea-pig distal colon10.1007/s004410000260 ↗
42. Vanden regional complexity in enteric neuron wiring reflects diversity of motility patterns in the mouse large intestine
43. Classification of human enteric neurons10.1007/s00418-021-02002-y ↗
44. The human enteric nervous system10.1111/j.1743-3150.2004.00476.x ↗
45. Robust, 3-dimensional visualization of human colon enteric nervous system without tissue sectioning10.1053/j.gastro.2020.02.035 ↗
46. Intrinsic primary afferent neurons of the intestine10.1016/S0301-0082(97)00051-8 ↗
47. Enteric nervous system: Sensory transduction, neural circuits and gastrointestinal motility10.1038/s41575-020-0271-2 ↗
48. Mechanosensory S-neurons rather than AH-neurons appear to generate a rhythmic motor pattern in guinea-pig distal colon10.1113/jphysiol.2004.063586 ↗
49. Combinatorial transcriptional profiling of mouse and human enteric neurons identifies shared and disparate subtypes in situ10.1053/j.gastro.2020.09.032 ↗
50. Diversification of molecularly defined myenteric neuron classes revealed by single-cell RNA eequencing10.1038/s41593-020-00736-x ↗
51. ScRNA-seq reveals new enteric nervous system roles for GDNF, NRTN, and TBX310.1016/j.jcmgh.2020.12.014 ↗
52. Molecular architecture of the mouse nervous system10.1016/j.cell.2018.06.021 ↗
53. Macrophages in the external muscle layers of mammalian intestines
54. Muscularis macrophage development in the absence of an enteric nervous system10.1073/pnas.1802490115 ↗
55. Intraganglionic macrophages: A new population of cells in the enteric ganglia10.1111/joa.12863 ↗
56. Adult enteric nervous system in health is maintained by a dynamic balance between neuronal apoptosis and neurogenesis10.1073/pnas.1619406114 ↗
57. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages10.1038/ni.2419 ↗
58. Profiling peripheral nerve macrophages reveals two macrophage subsets with distinct localization, transcriptome and response to injury10.1038/s41593-020-0618-6 ↗
59. MHC-positive, ramified macrophages in the normal and injured rat peripheral nervous system10.1007/BF01191724 ↗
60. Properties of the enteric nervous system: Limitation of access of intravascular macromolecules to the myenteric plexus and muscularis externa10.1002/cne.901800305 ↗
61. Vascular permeability in the peripheral autonomic and somatic nervous systems: Controversial aspects and comparisons with the blood-brain barrier10.1002/(SICI)1097-0029(19961001)35:2<122::AID-JEMT3>3.0.CO;2-S ↗
62. The multiple faces of inflammatory enteric glial cells: Is Crohn’s Disease a gliopathy?10.1152/ajpgi.00016.2018 ↗
63. Enteric neuroplasticity and dysmotility in inflammatory disease: Key players and possible therapeutic targets10.1152/ajpgi.00206.2019 ↗
64. Targeting enteric neurons and plexitis for the management of inflammatory Bowel disease10.2174/1389450121666200516173242 ↗
65. Enteric nervous system development: A crest cell’s journey from neural tube to colon10.1016/j.semcdb.2017.01.006 ↗
66. Origin of the lamina propria dendritic cell network10.1016/j.immuni.2009.08.010 ↗
67. Pleiotropic Effects of the bone morphogenetic proteins on development of the enteric nervous system10.1002/dneu.22002 ↗
68. BMP Signaling is necessary for neural crest cell migration and ganglion formation in the enteric nervous system10.1016/j.mod.2005.03.003 ↗
69. Smad-dependent and smad-independent pathways in TGF-β family signalling10.1038/nature02006 ↗
70. Effect of the normal microbial flora on gastrointestinal motility10.3181/00379727-126-32430 ↗
71. Gut microbial products regulate murine gastrointestinal motility via toll-like receptor 4 signaling10.1053/j.gastro.2012.06.034 ↗
72. 6-Hydroxydopamine-mediated release of norepinephrine increases faecal excretion of salmonella enterica serovar typhimurium in pigs10.1051/vetres/2010040 ↗
73. An intestinal organ culture system uncovers a role for the nervous system in microbe-immune crosstalk10.1016/j.cell.2017.02.009 ↗
74. Pavlov, I.P. (1904). Conditioned Reflexes: An Investigation of the Physiological Activity of the Cerebral Cortex, Dover Publications.
75. Effect of probiotics on central nervous system functions in animals and humans: A systematic review10.5056/jnm16018 ↗
76. Targeting gut flora to treat and prevent disease
77. The role of microbiome in central nervous system disorders10.1016/j.bbi.2013.12.015 ↗
78. Why does the microbiome affect behaviour?10.1038/s41579-018-0014-3 ↗
79. Microbiota is essential for social development in the mouse10.1038/mp.2013.65 ↗
80. Normal gut microbiota modulates brain development and behavior10.1073/pnas.1010529108 ↗
81. Microbiome influences prenatal and adult microglia in a sex-specific manner10.1016/j.cell.2017.11.042 ↗
82. Antibiotics in the first year of life and subsequent neurocognitive outcomes10.1111/apa.13613 ↗
83. The microbiome and host behavior10.1146/annurev-neuro-072116-031347 ↗
84. Microbiota regulates visceral pain in the mouse10.7554/eLife.25887 ↗
85. The microbiome: Stress, health and disease10.1007/s00335-013-9488-5 ↗
86. The effects of probiotics on depressive symptoms in humans: A systematic review10.1186/s12991-017-0138-2 ↗
87. Obsessive-compulsive-like behaviors in house mice are attenuated by a probiotic (Lactobacillus Rhamnosus GG)10.1097/FBP.0000000000000013 ↗
88. The microbiome, immunity, and Schizophrenia and Bipolar Disorder10.1016/j.bbi.2016.12.010 ↗
89. Microbiome and anticancer immunosurveillance10.1016/j.cell.2016.03.001 ↗
90. The lung mycobiome: An emerging field of the human respiratory microbiome10.3389/fmicb.2015.00089 ↗
91. The gut-lung axis in health and respiratory diseases: A place for inter-organ and inter-kingdom crosstalks10.3389/fcimb.2020.00009 ↗
92. The role of lung and gut microbiota in the pathology of asthma10.1016/j.immuni.2020.01.007 ↗
93. Gut microbiome modulates efficacy of immune checkpoint inhibitors10.1186/s13045-018-0592-6 ↗
94. The gut microbiome and response to immune checkpoint inhibitors: Preclinical and clinical strategies10.1186/s40169-019-0225-x ↗
95. Oral administration of bifidobacterium breve promotes antitumor efficacy via dendritic cells-derived Interleukin 1210.1080/2162402X.2020.1868122 ↗
96. The commensal microbiome is associated with Anti–PD-1 efficacy in metastatic melanoma patients10.1126/science.aao3290 ↗
97. Regulation of the immune system by biodiversity from the natural environment: An ecosystem service essential to health10.1073/pnas.1313731110 ↗
98. Maintaining health by balancing microbial exposure and prevention of infection: The hygiene hypothesis versus the hypothesis of early immune challenge10.1016/S0195-6701(13)60007-9 ↗
99. Gut microbiota, bacterial translocation, and interactions with diet: Pathophysiological links between major depressive disorder and non-communicable medical comorbidities10.1159/000448957 ↗
100. Gut microbiome modulates response to Anti-PD-1 immunotherapy in melanoma patients10.1126/science.aan4236 ↗