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The implications of altered gastrointestinal mucus homeostasis in neurological disorders

Neurology
2 months ago, OP Editor

Mucus is an integral part of the gastrointestinal (GI) system that is controlled by the enteric nervous system (ENS). Where dysfunction occurs in the ENS, mucus homeostasis is often altered and results in the change in mucus layer volume, viscosity, porosity and subsequently GI microbial population. As several neurological disorders are associated with an altered mucus homeostasis, this review proposes a new research focus to better understand the mucus structure and function, and their potential effect in exacerbating the core symptoms of neurological diseases.

The ENS is part of the nervous system that controls motor function, local blood flow, mucosal transport and secretions, and modulates immune and endocrine functions.1 The GI system is one such system that is organized and coordinated by the ENS to generate functionally digestive patterns.2 Although patients with neurological disorders are often presented with digestive disorders, it is uncertain if the cause can be attributed to the changes of the nervous system alone.2 A recent review article suggested that alterations of mucus homeostasis may also contribute to GI dysfunction in neurological disorders.2

The intestinal mucus layer is located throughout the gut and is critical in maintaining intestinal homeostasis.2 Mucus is primarily secreted by goblet cells in the intestinal epithelium, where mucus release, movement and renewal are controlled by the ENS.2 As mucus production in the goblet cells is involved in a high level of protein production, protein misfolding is often suspected in the mucus production process which can then trigger the unfolded protein response that is associated with chronic inflammation and autoimmune changes which are common in the neurodegenerative diseases.3 Accordingly, protein misfolding can also alter the production and apoptosis of goblet cells that will affect mucus properties and lead to GI symptoms.2 Certain vesicle-associated proteins in the neurotransmitter system that have been identified as mutated in neurological disorders can also affect mucus vesicular secretions and cause GI symptoms.2

As the key developmental pathways implicated in neurological diseases are involved in goblet cell maturation, mucus production and release, Dr. Hearth and colleagues proposed that the changes in goblet cell number resulting from neurological diseases, as well as the correlating changes in morphology or mucus properties, can contribute to GI symptoms.2 For instance, in patients with cystic fibrosis, GI abnormalities including meconium ileus and distal intestinal obstruction syndrome are often caused by an increase in secreted mucus volume, mucus dehydration and increased viscosity that result in the blockage of the small intestine.4 In patients with Hirschsprung’s Disease, a neuronal loss of goblet cell function and mucus layer properties is often observed.2

While downstream to neurological disorders, alterations in mucus structure and function may also contribute to GI dysfunction by changing the commensal microbial population that may result in dysbiosis.2 As dysbiosis can alter gut barrier function by changing the thickness, a change in mucus structure may contribute to disease progression in various neurological disorders such as autism, Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis.2 In patients diagnosed with autism spectrum disorder, an altered level of mucosa-associated bacterial species are observed along with symptoms of abdominal pain, diarrhea, constipation, and bloating.2 In Parkinson’s diseases, GI disorders are observed prior to the onset of characteristic motor symptoms such as tremor and coordination of complex movement with mucosal samples showing altered level of bacterial population.6 In Alzheimer’s disease, microbial dysbiosis has been implicated to increase gut permeability, causes systemic inflammation and impairs the blood brain barrier.7 In multiple sclerosis, the altered abundance of mucosal microbiome may favour the growth of pathogenic bacteria that alter mucus composition and may exacerbate the core symptoms of the disease.8

As impaired mucus homeostasis is often associated with neurological diseases, Dr. Hearth and colleagues suggest future research to focus on the mucus structure and function in neurological diseases to better understand how the altered mucus properties and subsequent microbial dysbiosis could contribute to the potential exacerbation of the core symptoms observed in various neurological diseases such as autism, Parkinson’s Disease, Alzheimer’s Disease, and multiple sclerosis.2

  1. Costa M et al. Anatomy and physiology of the enteric nervous system. Gut 2000;47:iv15-iv19
  2. Herath et al. The Role of the Gastrointestinal Mucus System in Intestinal Homeostasis: Implications for Neurological Disorders. Front. Cell. Infect. Microbiol. 2020;10:248.
  3. Matus S et al. Protein folding stress in neurodegenerative diseases: a glimpse into the ER. Curr. Opin. Cell Biol. 2011;23:239–252.
  4. Colombo et al. Guidelines for the diagnosis and management of distal intestinal obstruction syndrome in cystic fibrosis patients. J. Cyst. Fibros. 2011;10(Suppl. 2):S24–S28.
  5. Luna RA et al. Distinct microbiome-neuroimmune signatures correlate with functional abdominal pain in children with autism spectrum disorder. Cell Mol. Gastroenterol. Hepatol. 2017;3:218–230.
  6. Heintz-Buschart A et al. The nasal and gut microbiome in Parkinson’s disease and idiopathic rapid eye movement sleep behavior disorder. Mov. Disord. 2018;33:88–98.
  7. Kowalski K and Mulak A. Brain-gut-microbiota axis in alzheimer’s disease. J. Neurogastroenterol. Motil. 2019;25:48.
  8. Buscarinu MC et al. The contribution of gut barrier changes to multiple sclerosis pathophysiology. Front. Immunol. 2019;10:1916.

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