Unraveling the Intricacies of Colon Mechanosensation: A Step Closer to Understanding GI Physiology and Pathophysiology


Colon mechanosensation is a crucial aspect of gastrointestinal (GI) physiology and plays a significant role in both normal function and pathophysiological conditions.

However, our understanding of colonic sensory neurons and their functions has been limited due to the lack of genetic access to colon-innervating sensory neurons.

In a recent study, researchers overcame this limitation by labeling distinct transcriptionally defined subtypes of dorsal root ganglion (DRG) afferents specifically innervating the colon, thus enabling selective genetic access to these colon-innervating sensory neuron subtypes.

The study’s approach involved characterizing nearly all Aδ- and C-fiber populations identified in single-cell sequencing experiments, leading to the identification of five distinct colon-innervating populations. Two of these populations, TrkB+ colon-innervating DRGs and TH+ colon-innervating DRG neurons, were found to be low-threshold mechanoreceptors (LTMRs).

Colon mechanosensation is the ability of the colon to sense mechanical stimuli, such as distension, contraction, and movement. This is important for a number of functions, including:

  • Perception of pain: The colon is a sensitive organ, and mechanical stimuli can cause pain. This is important for detecting damage to the colon, such as from infection or inflammation.
  • Regulation of bowel movements: The colon contracts rhythmically to move food and waste through the digestive tract. Mechanosensation helps to coordinate these contractions, ensuring that food and waste move through the colon at a healthy pace.
  • Absorption of nutrients: The colon absorbs water and some nutrients from food. Mechanosensation helps to regulate the absorption of these nutrients, ensuring that they are absorbed in the right amounts.

The colon has a number of specialized cells that are responsible for mechanosensation. These cells are located in the lining of the colon and contain mechanoreceptors, which are proteins that detect mechanical stimuli. When the colon is distended or contracted, the mechanoreceptors send signals to the brain, which interprets these signals as pain, pressure, or other sensations.

There are a number of factors that can affect colon mechanosensation, including:

  • Inflammation: Inflammation can damage the mechanoreceptors in the colon, making it more sensitive to mechanical stimuli. This can lead to pain and other symptoms, such as diarrhea.
  • Irritable bowel syndrome (IBS): IBS is a chronic condition that affects the digestive system. People with IBS often have increased sensitivity to mechanical stimuli in the colon, which can lead to abdominal pain, bloating, and changes in bowel habits.
  • Medications: Some medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs), can damage the mechanoreceptors in the colon. This can lead to pain and other symptoms.

The TrkB+ neurons responded to low-threshold colon distension in a rapidly adapting (RA) manner, while the TH+ afferents exhibited low force thresholds and slow conduction velocities, resembling C-LTMRs. The other three populations were characterized by their expression of the neuropeptide CGRP (calcitonin gene-related peptide) and were labeled as Bmpr1b+ CGRP, Sstr2+ CGRP, and Adra2a+ CGRP subtypes.

The Bmpr1b+ CGRP subtype, which formed simple intraganglionic laminar endings (IGVEs) with 1-2 myenteric wrappings, responded to high-threshold colon distension in a slow-adapting (SA) manner, and had slightly faster optogenetic latencies than C-LTMRs. This implied its function as Aδ-HTMRs (high-threshold mechanoreceptors).

The Sstr2+ CGRP subtype exhibited endings branching into the myenteric plexus, submucosa, or mucosa, and responded to high-threshold colon distension and intracolonic capsaicin in an SA manner, establishing its function as C-HTMRs. The Adra2a+ CGRP neurons formed IGVEs with few myenteric wrappings or branched into the submucosal layer; however, their specific physiological properties remained to be determined in future studies.

Interestingly, the study highlighted a conservation of response properties between certain colon-innervating DRG populations and their counterparts in the skin.

For example, the TrkB+ neurons in the colon shared response properties with Aδ-LTMRs that innervate hairy skin, while the TH+ afferents in the colon resembled C-LTMRs that innervate hairy skin.

This suggests that the genetic composition of a mechanosensory neuron type dictates its force thresholds and adaptation to sustained stimuli, regardless of the organ it innervates.

One surprising finding was the responsiveness of TrpV1+ DRG afferents in the colon to both high-threshold colon distension and intracolonic capsaicin, while these neurons were considered mechanically insensitive but heat-responsive in the skin. The reasons for this dichotomy are not yet fully understood and may be attributed to the distinct microenvironments of the skin and colon or genetic heterogeneity within the Sstr2-expressing population.

The study also revealed that colon-innervating DRG afferents rely significantly on the mechanosensitive ion channel Piezo2 for their mechanosensitivity, similar to their cutaneous counterparts. However, some high-threshold force sensitivity in colon-innervating DRG afferents was found to be Piezo2 independent, suggesting the involvement of other high-threshold mechanosensitive ion channels or tissue damage responses mediated by other signals.

The study’s findings also hinted at potential overlapping innervation between the colon and skin. Some TrkB+ Aδ-LTMRs were found to respond to both colonic distension and skin pinch, implying the possibility of neurons innervating both organs. This observation contrasts with an accompanying study, raising questions about the factors contributing to these differences, such as experimental techniques and recording locations.

Additionally, the researchers discovered that the ablation of Bmpr1b+ Aδ-HTMRs prolonged colon motility, indicating the important role of this HTMR population in normal physiological function, particularly in sensing contents and promoting expulsion. Furthermore, the study shed light on the potential involvement of Bmpr1b+ Aδ-HTMRs in colon inflammation and hypersensitivity.

After inflammation, these HTMRs became more sensitive and mediated pathophysiological responses to colon distension, suggesting their potential as therapeutic targets for treating abdominal pain associated with colon inflammation.

Despite the significant insights gained from this study, there are some limitations that need to be addressed in future research.

Firstly, although five colon-innervating DRG populations were identified and extensively characterized, additional studies are required to understand whether subtypes without specific mouse tools also innervate the colon and if there are still unidentified subtypes involved in colon mechanosensation.

Secondly, the functional characterization of the Adra2a+ CGRP subtype was limited due to sparse labeling with the Adra2aCreER line, necessitating further investigation to understand its role in colon sensation. Lastly, while the study focused on the responses of these populations to colon mechanosensation, additional work is needed to explore their responses to other colonic stimuli.

In conclusion, this groundbreaking study provides valuable insights into the genetic identity, morphological and physiological properties, and functions of colon-innervating DRG populations. The findings have important implications for our understanding of colon mechanosensation in both normal physiology and pathological conditions, such as inflammatory bowel disease. Further research in this area is warranted to uncover potential therapeutic targets for treating abdominal pain and other GI disorders associated with colon innervation.

reference link : https://www.cell.com/cell/fulltext/S0092-8674(23)00740-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867423007407%3Fshowall%3Dtrue#secsectitle0075


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