Abstract
The enteric nervous system (ENS) poses the intrinsic innervation of the gastrointestinal tract and plays a critical role for all stages of postnatal life. There is increasing scientific and clinical interest in acquired or age-related gastrointestinal dysfunctions that can be manifested in diseases such as gut constipation or fecal incontinence. In this study, we sought to analyze age-dependent changes in the gene expression profile of the human ENS, particularly in the myenteric plexus. Therefore, we used the laser microdissection technique which has been proven as a feasible tool to analyze distinct cell populations within heterogeneously composed tissues. Full biopsy gut samples were prepared from children (4–12 months), middle aged (48–58 years) and aged donors (70–95 years). Cryosections were histologically stained with H&E, the ganglia of the myenteric plexus identified and RNA isolated using laser microdissection technique. Quantitative PCR was performed for selected neural genes, neurotransmitters and receptors. Data were confirmed on protein level using NADPH-diaphorase staining and immunohistochemistry. As result, we demonstrate age-associated alterations in site-specific gene expression pattern of the ENS. Thus, in the adult and aged distal parts of the colon a marked decrease in relative gene expression of neural key genes like NGFR, RET, NOS1 and a concurrent increase of CHAT were observed. Further, we detected notable regional differences of RET, CHAT, TH, and S100B comparing gene expression in aged proximal and distal colon. Interestingly, markers indicating cellular senescence or oxidative stress (SNCA, CASP3, CAT, SOD2, and TERT) were largely unchanged within the ENS. For the first time, our study also describes the age-dependent expression pattern of all major sodium channels within the ENS. Our results are in line with previous studies showing spatio-temporal differences within the mammalian ENS.
Highlights
The gut is comprised of three distinct tissue regions i.e., the mucosa, submucosa, and muscle layers, which are innervated by the diverse network of the enteric nervous system (ENS)
The same was true for nitric oxide synthase 1 (NOS1), which catalyzes the generation of nitric oxide, the most important non-cholinergic non-adrenergic inhibitory neurotransmitter
Our study has confirmed that age-associated alterations in sitespecific gene expression patterns occur within the ENS
Summary
The gut is comprised of three distinct tissue regions i.e., the mucosa, submucosa, and muscle layers, which are innervated by the diverse network of the enteric nervous system (ENS). Typical age-related diseases such as gut constipation can be correlated with alterations and decreased regenerative potential in the ENS (Saffrey, 2013). This is emphasized by manifestation of diseases such as slowtransit constipation, chronic intestinal pseudo-obstruction, achalasia, or inflammatory enteric neuropathies (Talley et al, 1992; Majumdar et al, 1997; Ratnaike, 1999; De Lillo and Rose, 2000)
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