Abstract
The ENS modulates a variety of physiological functions in the gastrointestinal tract. However, little is known about the regional transcriptomic heterogeneity in the ENS. The pig is a relevant experimental model due to its similarity to the human in nutrition, physiology and metabolic process, particularly in the ENS. This study aims to characterize the transcriptome profile of enteric ganglia and regional differences in the pig colon. Full thickness tissue samples of the proximal, transverse and distal colon (pC, tC, dC) were collected from adult Yucatan minipigs (n=10). We captured 25–40 ganglia/pig using Leica LMD6000 laser microdissection system from inner submucosal and myenteric plexus (ISP, MP), which were processed for RNA sequencing on Hiseq 3000. Pathway enrichment analysis was exploited to identify the biological pathways that were statistically enriched in a series of differentially expressed gene (DEG) lists. The discordance in biological pathways was assessed between two plexi and among the segments. Although both tC and dC displayed the pathways related to the muscular contraction (MC), the regulatory gene networks were different. In the ISP, the top‐ranking ADORA1 (adenosine A1 receptor) interacted with SSTR1 (somatostatin receptor 1) in the tC and ADORA1 or VIP in the dC contributed to MC regulation. While in the MP, we found interaction of top‐ranking ADRA2C (alpha‐2C‐adrenergic receptor) and ADRA1A in the tC and network among ADRA2C, ADRA1A, EDNRA (endothelin receptor type A) and EDNRB in the dC. The pC showed pathway prominence in both MC and inflammatory defense. The regulatory genes involved in inflammation were highly ranked in the DEG lists. Among them, complement C3‐C3aR network in the ISP regulated the inflammatory activities, while in the MP it involved TRPV1‐TRPM4 interaction. A similarity of the pathway popularity stood out in pC‐MP compared to tC‐ or dC‐MP. TRPV1 was highly ranked in pC‐MP rather than in tC‐ or dC‐MP. In addition, ADORA2A and ADORA2B (pC vs tC) and ACHE (acetylcholinesterase) (pC vs dC) in pC‐MP pointed to the anti‐inflammatory effects. When comparing with pC‐MP, major categories of the pathway enrichment were the same between tC‐ and dC‐MP, with CaSR (calcium‐sensing receptor) signaling mediating the neuronal calcium regulation. Surprisingly, the variance in the ISP among segments was strikingly smaller, which was also validated by weighted gene coexpression network analysis. The topmost ranking CHRNA6 (cholinergic receptor nicotinic alpha 6 subunit) and CHRNB3 were referred to as mediation of cholinergic neurotransmission in pC‐ISP (vs dC‐ISP), the component of the renin‐angiotensin system as maintenance of electrolyte homeostasis in tC‐ISP (vs pC‐ISP), and NOS1, P2RY1 (purinergic receptor P2Y1) and NPY2R (neuropeptide Y receptor Y2) as the modulation of colonic motility in dC‐ISP (vs pC‐ISP). Collectively, these data present the transcriptomic profile with distinct patterns in different colonic segments, suggesting that genetic diversity is required for the ENS in orchestrating physiological functions in the colon including regulation of inflammation, ion transport and motility.Support or Funding Information(NIH) SPARC OT2OD023899‐01 grant (P‐QY, YT)
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