scholarly journals Enteric nervous system modulation of luminal pH modifies the microbial environment to promote intestinal health

2021 ◽  
Author(s):  
M. Kristina Hamilton ◽  
Elena S. Wall ◽  
Karen Guillemin ◽  
Judith S. Eisen
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Intestinal Microbiota ◽  
Pathogenic Bacteria ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Wild Type ◽  
Intestinal Health ◽  
Primary Function ◽  
Luminal Ph

AbstractThe enteric nervous system (ENS) controls many aspects of intestinal homeostasis, including parameters that shape the habitat of microbial residents. Previously we showed that zebrafish lacking an ENS, due to deficiency of the sox10 gene, develop intestinal inflammation and bacterial dysbiosis, with an expansion of proinflammatory Vibrio strains. To understand the primary defects resulting in dysbiosis in sox10 mutants, we investigated how the ENS shapes the intestinal environment in the absence of microbiota and associated inflammatory responses. We found that intestinal transit, intestinal permeability, and luminal pH regulation are all aberrant in sox10 mutants, independent of microbially induced inflammation. Treatment with the proton pump inhibitor, omeprazole, corrected the more acidic luminal pH of sox10 mutants to wild type levels. Omeprazole treatment also prevented overabundance of Vibrio and ameliorated inflammation in sox10 mutant intestines. Treatment with the carbonic anhydrase inhibitor, acetazolamide, caused wild type luminal pH to become more acidic, and increased both Vibrio abundance and intestinal inflammation. We conclude that a primary function of the ENS is to regulate luminal pH, which plays a critical role in shaping the resident microbial community and regulating intestinal inflammation.Author SummaryThe intestinal microbiota is an important determinant of health and disease and is shaped by the environment of the gut lumen. The nervous system of the intestine, the enteric nervous system (ENS), helps maintain many aspects of intestinal health including a healthy microbiota. We used zebrafish with a genetic mutation that impedes ENS formation to investigate how the ENS prevents pathogenic shifts in the microbiota. We found that mutants lacking an ENS have a lower luminal pH, higher load of pathogenic bacteria, and intestinal inflammation. We showed that correcting the low pH, using the commonly prescribed pharmacological agent omeprazole, restored the microbiota and prevented intestinal inflammation. Conversely, we found that lowering the luminal pH of wild type animals, using the drug acetazolamide, caused expansion of pathogenic bacteria and increased intestinal inflammation. From these experiments, we conclude that a primary function of the ENS is to maintain normal luminal pH, thereby constraining intestinal microbiota community composition and promoting intestinal health.

scholarly journals The enteric nervous system promotes intestinal health by constraining microbiota composition

PLoS Biology ◽  
2017 ◽  
Vol 15 (2) ◽  
pp. e2000689 ◽  
Author(s):  
Annah S. Rolig ◽  
Erika K. Mittge ◽  
Julia Ganz ◽  
Josh V. Troll ◽  
Ellie Melancon ◽  
...  
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Microbiota Composition ◽  
Intestinal Health

scholarly journals Non-autophagy role of Atg5 and NBR1 in unconventional secretion of IL-12 prevents gut dysbiosis and inflammation

2020 ◽  
Author(s):  
Seth D. Merkley ◽  
Samuel M. Goodfellow ◽  
Yan Guo ◽  
Zoe E.R. Wilton ◽  
Janie R. Byrum ◽  
...  
Keyword(s):  
Intestinal Microbiota ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Myeloid Cells ◽  
Late Endosome ◽  
Gut Dysbiosis ◽  
Cargo Receptor ◽  
Unconventional Secretion ◽  
Genetic Deletion

ABSTRACTIntestinal myeloid cells play a critical role in balancing intestinal homeostasis and inflammation. Here, we report that expression of the autophagy related 5 (Atg5) protein in myeloid cells prevents dysbiosis and excessive intestinal inflammation by limiting IL-12 production. Mice with a selective genetic deletion of Atg5 in myeloid cells (Atg5ΔMye) showed signs of dysbiosis prior to colitis and exhibited severe intestinal inflammation upon colitis induction that was characterized by increased IFNγ production. This increase in IFNγ was due to excess IL-12 secretion from Atg5-deficient myeloid cells. Atg5 functions to limit IL-12 secretion through modulation of late endosome (LE) acidity. Additionally, the autophagy cargo receptor NBR1, which accumulates in Atg5-deficient cells, played a role by delivering IL-12 to LE. Restoration of the intestinal microbiota and alleviation of intestinal inflammation was achieved by genetic deletion of IL-12 in Atg5ΔMye mice. In summary, Atg5 expression in intestinal myeloid cells acts as an anti-inflammatory brake to regulate IL-12 thus preventing dysbiosis and uncontrolled IFNγ-driven intestinal inflammation.

scholarly journals G protein-coupled receptor trafficking and signaling: new insights into the enteric nervous system

2019 ◽  
Vol 316 (4) ◽  
pp. G446-G452 ◽  
Author(s):  
Simona E. Carbone ◽  
Nicholas A. Veldhuis ◽  
Arisbel B. Gondin ◽  
Daniel P. Poole
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
G Protein ◽  
Molecular Mechanisms ◽  
Intestinal Inflammation ◽  
Receptor Expression ◽  
Enteric Neurons ◽  
Future Research ◽  
Detailed Knowledge ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are essential for the neurogenic control of gastrointestinal (GI) function and are important and emerging therapeutic targets in the gut. Detailed knowledge of both the distribution and functional expression of GPCRs in the enteric nervous system (ENS) is critical toward advancing our understanding of how these receptors contribute to GI function during physiological and pathophysiological states. Equally important, but less well defined, is the complex relationship between receptor expression, ligand binding, signaling, and trafficking within enteric neurons. Neuronal GPCRs are internalized following exposure to agonists and under pathological conditions, such as intestinal inflammation. However, the relationship between the intracellular distribution of GPCRs and their signaling outputs in this setting remains a “black box”. This review will briefly summarize current knowledge of agonist-evoked GPCR trafficking and location-specific signaling in the ENS and identifies key areas where future research could be focused. Greater understanding of the cellular and molecular mechanisms involved in regulating GPCR signaling in the ENS will provide new insights into GI function and may open novel avenues for therapeutic targeting of GPCRs for the treatment of digestive disorders.

scholarly journals You Talking to Me? Says the Enteric Nervous System (ENS) to the Microbe. How Intestinal Microbes Interact with the ENS

2020 ◽  
Vol 9 (11) ◽  
pp. 3705
Author(s):  
Mauro Giuffrè ◽  
Rita Moretti ◽  
Giuseppina Campisciano ◽  
Alexandre Barcelos Morais da Silveira ◽  
Vincenzo Maria Monda ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Enteric Nervous System ◽  
Pathogenic Bacteria ◽  
Current Knowledge ◽  
Intestinal Microbes ◽  
The Central Nervous System ◽  
Gut Microorganisms ◽  
Future Concepts ◽  
Suitable Environment

Mammalian organisms form intimate interfaces with commensal and pathogenic gut microorganisms. Increasing evidence suggests a close interaction between gut microorganisms and the enteric nervous system (ENS), as the first interface to the central nervous system. Each microorganism can exert a different effect on the ENS, including phenotypical neuronal changes or the induction of chemical transmitters that interact with ENS neurons. Some pathogenic bacteria take advantage of the ENS to create a more suitable environment for their growth or to promote the effects of their toxins. In addition, some commensal bacteria can affect the central nervous system (CNS) by locally interacting with the ENS. From the current knowledge emerges an interesting field that may shape future concepts on the pathogen–host synergic interaction. The aim of this narrative review is to report the current findings regarding the inter-relationships between bacteria, viruses, and parasites and the ENS.

Role of glial cell-line derived neurotropic factor family receptor α2 in the actions of the glucagon-like peptides on the murine intestine

2007 ◽  
Vol 293 (2) ◽  
pp. G461-G468 ◽  
Author(s):  
Sean C. McDonagh ◽  
Jenny Lee ◽  
Angelo Izzo ◽  
Patricia L. Brubaker
Keyword(s):  
Nervous System ◽  
Substance P ◽  
Enteric Nervous System ◽  
Cell Line ◽  
Glial Cell ◽  
Wild Type ◽  
Intestinal Growth ◽  
Mrna Transcripts ◽  
Neurotropic Factor

The intestinal glucagon-like peptides GLP-1 and GLP-2 inhibit intestinal motility, whereas GLP-2 also stimulates growth of the intestinal mucosa. However, the mechanisms of action of these peptides in the intestine remain poorly characterized. To determine the role of the enteric nervous system in the actions of GLP-1 and GLP-2 on the intestine, the glial cell line-derived neurotropic factor family receptor α2 (GFRα2) knockout (KO) mouse was employed. The mice exhibited decreased cholinergic staining, as well as reduced mRNA transcripts for substance P-ergic excitatory motoneurons in the enteric nervous system (ENS) ( P < 0.05). Examination of parameters of intestinal growth (including small and large intestinal weight and small intestinal villus height, crypt depth, and crypt cell proliferation) demonstrated no differences between wild-type and KO mice in either basal or GLP-2-stimulated mucosal growth. Nonetheless, KO mice exhibited reduced numbers of synaptophysin-positive enteroendocrine cells ( P < 0.05), as well as a markedly impaired basal gastrointestinal (GI) transit rate ( P < 0.05). Furthermore, acute administration of GLP-1 and GLP-2 significantly inhibited transit rates in wild-type mice ( P < 0.05–0.01) but had no effect in GFRα2 KO mice. Despite these changes, expression of mRNA transcripts for the GLP receptors was not reduced in the ENS of KO animals, suggesting that GLP-1 and -2 modulate intestinal transit through enhancement of inhibitory input to cholinergic/substance P-ergic excitatory motoneurons. Together, these findings demonstrate a role for GFRα2-expressing enteric neurons in the downstream signaling of the glucagon-like peptides to inhibit GI motility, but not in intestinal growth.

scholarly journals Specific immune modulation of experimental colitis drives enteric alpha-synuclein accumulation and triggers age-related Parkinson-like brain pathology

2020 ◽  
Author(s):  
Stefan Grathwohl ◽  
Emmanuel Quansah ◽  
Nazia Maroof ◽  
Jennifer A Steiner ◽  
Liz Spycher ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Immune Modulation ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Experimental Colitis ◽  
Alpha Synuclein ◽  
Submucosal Plexus ◽  
Wild Type ◽  
Genetic Ablation ◽  
Dss Colitis

Abstract Background : Intraneuronal accumulation of a-synuclein (αSyn) is key in Parkinson’s disease (PD) pathogenesis. The pathogenic process is suggested to begin in the enteric nervous system decades before diagnosis of PD and then propagate into the brain. The triggers for these events are unclear but, in some patients, colitis might play a critical role. Methods : We administered lipopolysaccharide (LPS) or dextran sulfate sodium (DSS) to assess the effect of different types of experimental colitis on αSyn accumulation in the gut of αSyn transgenic and wild type mice and quantified local gene expression by RT-PCR and level of αSyn accumulation by immunofluorescence imaging. Immune modulation during the DSS colitis paradigm in the αSyn transgenic mice included genetic ablation of Cx3cr1 or treatment with recombinant IL-10. To determine long-term effects of experimental colitis, we induced DSS colitis in young αSyn transgenic mice and aged them under normal conditions up to nine or 21 months before analyzing their brains by immunohistochemistry. In vivo experiments were performed in randomized cohorts. Blinded experimenters performed image analysis and statistical analysis depended on data type (i.e., Student’s t-test, ANOVA, mixed-effects model). Results : We demonstrate that mild sustained or one strong insult of experimental DSS colitis triggers αSyn accumulation in the submucosal plexus of wild type and αSyn transgenic mice, while short-term mild DSS experimental colitis or inflammation induced by LPS does not have such an effect. Lack of macrophage-related Cx3cr1-signalling during DSS colitis increases accumulation of αSyn in the colonic submucosal plexus of αSyn transgenic mice while systemic treatment with immune-dampening IL-10 ameliorates this phenomenon. Additionally, DSS colitis-induced αSyn accumulation in young αSyn transgenic mice persists for months and is exacerbated by lack of Cx3cr1-signaling. Remarkably, experimental colitis at three months of age exacerbates the accumulation of aggregated phospho-Serine 129 αSyn in the midbrain (including the substantia nigra), in 21- but not 9-month-old αSyn transgenic mice. This increase in midbrain αSyn accumulation is accompanied by the loss of tyrosine hydroxylase-immunoreactive nigral neurons. Conclusions : Our data suggest that specific types of intestinal inflammation, mediated by monocyte/macrophage signaling, could play a critical role in the initiation and progression of PD.

scholarly journals PASTA kinase-dependent control of peptidoglycan synthesis via ReoM is required for cell wall stress responses, cytosolic survival, and virulence in Listeria monocytogenes

2021 ◽  
Vol 17 (10) ◽  
pp. e1009881
Author(s):  
Jessica L. Kelliher ◽  
Caroline M. Grunenwald ◽  
Rhiannon R. Abrahams ◽  
McKenzie E. Daanen ◽  
Cassandra I. Lew ◽  
...  
Keyword(s):  
Cell Wall ◽  
Listeria Monocytogenes ◽  
Stress Responses ◽  
Pathogenic Bacteria ◽  
Critical Role ◽  
Wall Stress ◽  
Wild Type ◽  
Comprehensive Overview ◽  
Bacterial Physiology ◽  
Cell Wall Stress

Pathogenic bacteria rely on protein phosphorylation to adapt quickly to stress, including that imposed by the host during infection. Penicillin-binding protein and serine/threonine-associated (PASTA) kinases are signal transduction systems that sense cell wall integrity and modulate multiple facets of bacterial physiology in response to cell envelope stress. The PASTA kinase in the cytosolic pathogen Listeria monocytogenes, PrkA, is required for cell wall stress responses, cytosolic survival, and virulence, yet its substrates and downstream signaling pathways remain incompletely defined. We combined orthogonal phosphoproteomic and genetic analyses in the presence of a β-lactam antibiotic to define PrkA phosphotargets and pathways modulated by PrkA. These analyses synergistically highlighted ReoM, which was recently identified as a PrkA target that influences peptidoglycan (PG) synthesis, as an important phosphosubstrate during cell wall stress. We find that deletion of reoM restores cell wall stress sensitivities and cytosolic survival defects of a ΔprkA mutant to nearly wild-type levels. While a ΔprkA mutant is defective for PG synthesis during cell wall stress, a double ΔreoM ΔprkA mutant synthesizes PG at rates similar to wild type. In a mouse model of systemic listeriosis, deletion of reoM in a ΔprkA background almost fully restored virulence to wild-type levels. However, loss of reoM alone also resulted in attenuated virulence, suggesting ReoM is critical at some points during pathogenesis. Finally, we demonstrate that the PASTA kinase/ReoM cell wall stress response pathway is conserved in a related pathogen, methicillin-resistant Staphylococcus aureus. Taken together, our phosphoproteomic analysis provides a comprehensive overview of the PASTA kinase targets of an important model pathogen and suggests that a critical role of PrkA in vivo is modulating PG synthesis through regulation of ReoM to facilitate cytosolic survival and virulence.

scholarly journals Butyric and Citric Acids and Their Salts in Poultry Nutrition: Effects on Gut Health and Intestinal Microbiota

2021 ◽  
Vol 22 (19) ◽  
pp. 10392
Author(s):  
Mebratu Melaku ◽  
Ruqing Zhong ◽  
Hui Han ◽  
Fan Wan ◽  
Bao Yi ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Organic Acids ◽  
Growth Performance ◽  
Pathogenic Bacteria ◽  
Intestinal Inflammation ◽  
Farm Animals ◽  
Gut Health ◽  
Intestinal Health ◽  
Poultry Products ◽  
Poultry Nutrition

Intestinal dysfunction of farm animals, such as intestinal inflammation and altered gut microbiota, is the critical problem affecting animal welfare, performance and farm profitability. China has prohibited the use of antibiotics to improve feed efficiency and growth performance for farm animals, including poultry, in 2020. With the advantages of maintaining gut homeostasis, enhancing digestion, and absorption and modulating gut microbiota, organic acids are regarded as promising antibiotic alternatives. Butyric and citric acids as presentative organic acids positively impact growth performance, welfare, and intestinal health of livestock mainly by reducing pathogenic bacteria and maintaining the gastrointestinal tract (GIT) pH. This review summarizes the discovery of butyric acid (BA), citric acid (CA) and their salt forms, molecular structure and properties, metabolism, biological functions and their applications in poultry nutrition. The research findings about BA, CA and their salts on rats, pigs and humans are also briefly reviewed. Therefore, this review will fill the knowledge gaps of the scientific community and may be of great interest for poultry nutritionists, researchers and feed manufacturers about these two weak organic acids and their effects on intestinal health and gut microbiota community, with the hope of providing safe, healthy and nutrient-rich poultry products to consumers.

scholarly journals The Enteric Nervous System in Intestinal Inflammation

1996 ◽  
Vol 10 (5) ◽  
pp. 335-341 ◽  
Author(s):  
Keith A Sharkey ◽  
Edward J Parr
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Animal Studies ◽  
Intestinal Inflammation ◽  
Normal Pattern ◽  
Potential Therapeutic Target ◽  
Neuroactive Drugs ◽  
Inflammatory Bowel ◽  
Local Release

Since about the 1950s nerves in the wall of the intestine have been postulated to play a role in the pathogenesis of inflammatory bowel disease (IBD). Human and animal studies examining the role of nerves in intestinal inflammation are the focus of this review. Consideration is given to two possible ways that nerves are involved in IBD. First, nerves may play a role in the development or maintenance of inflammation through local release of transmitters. Second, once initiated (by whatever means), the processes of inflammation may disrupt the normal pattern of innervation and the interactions of nerves and their target tissues. Many of the functional disturbances observed in IBD are likely due to an alteration in the enteric nervous system either structurally through disruptions of nerve-target relationships or by modifications of neurotransmitters or their receptors. Finally, it appears that the enteric nervous system may be a potential therapeutic target in IBD and that neuroactive drugs acting locally can represent useful agents in the management of this disease.

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