The touchy business of gastrointestinal (GI) mechanosensitivity

Abstract

The gastrointestinal (GI) tract's normal function depends on its ability to propel, mix, and store contents in a highly coordinated fashion. An ability to sense mechanical forces is therefore fundamental to normal GI tract operation. There are several mechanosensory circuits distributed throughout the GI tract. These circuits rely on a range of specialized and non-specialized mechanosensory cells that include epithelial enterochromaffin (EC) cells, both intrinsic and extrinsic sensory neurons, glia, interstitial cells of Cajal (ICC), and smooth muscle cells. While the anatomy of GI mechanosensory circuits is established, the molecular mechanisms and functions are still poorly understood. In this review, we focus on the neuro-epithelial mechanosensory circuit in the gut, composed of epithelial EC cells and sensory neurons, both intrinsic and extrinsic. Intriguingly, this circuit closely resembles the light touch circuit in the skin that is composed of an epithelial Merkel cell and an afferent sensory neuron, suggesting that the basic building blocks are retained in diverse mechanosensory systems. We compare the gross and molecular anatomy and physiology of these circuits and dissect the roles of GI neuroepithelial mechanosensory, or “GI touch” circuit, in GI health and disease.

Graphical abstract

Highlighting the similarities between skin somatosensory light touch and “GI touch.”

Introduction

The digestive system's functions of obtaining nutrients and disposing wastes are crucial for survival. To perform these functions the GI tract has evolved as a highly specialized conduit system which relies heavily on sensation of mechanical forces, or mechanosensitivity. In turn, disruptions in GI mechanosensitivity lead to GI function disturbances in animals ranging from fruit flies (Zhang et al., 2014) to humans (Ritchie, 1973). Given the importance of mechanosensitivity for normal function, the GI tract relies on multiple extrinsic and intrinsic cellular mechanosensors that are distributed throughout its circumference and length (Alcaino et al., 2017). The extrinsic mechanosensors innervate all layers of the GI tract, transmitting sensory information to the spinal cord and vagal nuclei (Brierley et al., 2004). There is also a system of intrinsic mechanosensors comprised of specialized epithelial cells called enterochromaffin (EC) cells, intrinsic primary afferent neurons (IPANs), myenteric neurons, glia, interstitial cells of Cajal (ICCs) and smooth muscle cells (Alcaino et al., 2017). These intrinsic and extrinsic mechanosensors are coordinated into circuits that are essential for normal GI functions (Figure 1).

Figure 1.

Intrinsic and extrinsic GI mechanosensory circuits. Multiple circuits and cells are responsible for processing the mechanosensory stimuli in the GI tract, with mechanosensory cells in red. These include a) vagal afferents that innervate from esophagus to transverse colon, b) thoracic and lumbar afferents that cover most of the GI tract length, and c) pelvic (sacral) afferents innervate the rectum and pelvic floor. In the enteric wall of the GI tract, d) on the epithelium within the mucosa are e) EC cells, which process luminal mechanical cues, and signal to intrinsic sensory neurons in f) myenteric plexus and h) submucosa as well as i) extrinsic sensory neurons. Intrinsic mechanosensors include j) myenteric neurons and intestinofugal neurons, k) glia, l) interstitial cells of Cajal, and m) smooth muscle cells. Extrinsic mechanosensory neurons project to multiple layers of the GI tract, including n) serosa and o) myenteric plexus (intraganglionic laminar endings, IGLEs) and mucosa.

Parallels between somatosensory and GI touch

In studying GI mechanosensitivity it is instructive to examine other specialized mechanosensory systems, such as touch and hearing. Somatosensory touch is one of the most well-understood specialized mechanosensory systems. Light touch mechanosensitivity stems from a specialized neuro-epithelial circuit containing a primary epithelial mechanosensor called a Merkel cell which forms a serotonergic synapse (Chang et al., 2016) with a mechanosensitive epithelial projecting dorsal root ganglion (DRG) neuron (Figure 2A, Table 1). Both the Merkel cell and DRG neuron that innervates it are mechanosensitive and rely on the same specific mechanotransducer, the mechanosensitive ion channel Piezo2, to convert mechanical force into an inward ionic current that initiates an intracellular response (Ranade et al., 2014; Woo et al., 2014). The redundancy of this two mechanoreceptor configuration is advantageous – elimination of Piezo2 from both the Merkel cell and sensory neuron is required to experience substantial light touch deficiency (Ranade et al., 2014).

Figure 2.

Light touch circuitry in the skin and gut. A) Skin light touch circuit is a two-receptor system, composed of the Merkel cell at the interface between epidermis and dermis, that relies on Piezo2 for mechanosensation and it uses synaptic 5-HT signaling to communicated with a mechanosensitive DRG neuron that also relies of Piezo2 for mechanosensation. (B) “GI touch” circuitry is composed of a mechanosensitive epithelial EC cell that may also rely on Piezo2 for mechanosensation and it is proposed to form a 5-HT synapse with a potentially mechanosensitive sensory neuron (either intrinsic IPAN or extrinsic that leads to the DRG or vagal nuclei).

Table 1.

Somatosensory light touch versus “GI touch.”

	Somatosensory Light Touch	“GI touch”
Epithelial Mechanosensor	Merkel cell	Enterochromaffin cell
Developmentally relevant genes	Atoh1, Gfi1, Isl1, Insm1	Atoh1, Gfi1, Isl1, Insm1
Mechanotransducer(s)	Piezo2	Piezo2?
Neurotransmitter(s)	5-HT	5-HT
Endocrine function	?	Yes
Peripheral Sensory Neuron	Aβ DRG neuron	Mucosal afferent/efferent DRG neuron Vagal neuron
Mechanotransducer(s)	Piezo2	?
Functions	Light touch	Secretion, motility, visceral sensation
Diseases	Neuropathy (diabetes, chemotherapy)	Irritable bowel syndrome (IBS), Inflammatory bowel disease (IBD), Slow transit constipation

The GI mucosal mechanosensory circuitry bears striking similarity to the light touch system described above (Figure 2B, Table 1). In the GI tract, luminal pressure leads to serotonin (5-hydroxytryptamine, 5-HT) release from the EC cell which, similar to the Merkel cell in the skin, serves as the primary mechanotransducer in the epithelium (Bulbring and Crema, 1959; Linan-Rico et al., 2016; Wang et al., 2017). The Merkel and EC cells have notable developmental and functional parallels. Despite being derived from different stem cell populations, both Merkel and EC cells share transcriptional regulators of specification (Atoh1) and differentiation (Gfi1, Isl1, Insm1) (Haeberle et al., 2004; May and Kaestner, 2010; Shroyer et al., 2005; Wright et al., 2015; Yang et al., 2001). They use the same neurotransmitter (5-HT) to communicate with the epithelial projecting sensory neurons (Bellono et al., 2017; Chang et al., 2016), and selectively express Piezo2 (Wang et al., 2017; Woo et al., 2014).

However, unlike the substantial progress in the understanding of Merkel cell mechanotransduction, critical questions remain about EC cell mechanotransduction. Though work in an EC cell model (QGP-1) has established an important role for Piezo2 in mechanotransduction and 5-HT release, it is currently unknown if Piezo2 serves as the primary mechanotransducer in native EC cells. If it does, it will be important to determine how Piezo2 activation couples to mechanosensitive 5-HT release in native EC cells, and whether previously established signaling molecules, such as purines and ATP, may be involved (Linan-Rico et al., 2016). We expect that answers to these questions may allow targeted approaches to modulate GI mechanosensitivity directly through the EC cell.

We may next examine the relationships between the EC cell and its sensory neurons to determine whether there are similarities between somatosensory touch and the GI neuro-epithelial mechanosensory circuit, or “GI touch” (Figure 2B). The EC cell communicates with both extrinsic mucosal and intrinsic primary afferent neurons (IPANs), and these interactions allow the integration of mechanical signals to sense the state of the system and to influence multiple GI functions (Bellono et al., 2017; Mawe and Hoffman, 2013). The extrinsic mucosal sensory neurons (Brookes et al., 2013; Williams et al., 2016) and IPANs are also mechanosensitive (Kunze et al., 2000), but little is known beyond this. We do not know whether, like the touch sensory neurons, GI mucosal sensory neurons use mechanosensitive ion channels for mechanotransduction, and whether “GI touch” requires coordination of multiple mechanoreceptors like somatosensory light touch.

Elucidating “GI touch” functions

It may be informative to compare the functions of the two neuro-epithelial circuits. The skin's touch system provides a sensory interaction with the environment to protect against injury and to tune locomotor activity. On the other hand, “GI touch” is thought not to be consciously sensed, and therefore its functions are more difficult to determine. Yet, we do know that “GI touch” is critical for normal GI tract function. For example, we know that an increase in mucosal pressure leads to 5-HT release from the EC cell (Bertrand, 2006; Bulbring and Crema, 1959) and activation of 5-HT receptors on IPANs, which then leads to an increase in fluid secretion and initiation and modulation of propagating colonic motility (Bulbring and Lin, 1958; Frieling et al., 1992; Heredia et al., 2009; Heredia et al., 2013). When 5-HT synthesis is abolished specifically in EC cells, colonic pellets are larger and colonic motility is abnormal, suggesting that an important sensory-motor circuit originates directly from EC cells (Heredia et al., 2013). In contrast, experiments as dramatic as removing the GI mucosa find colonic motility to be mostly intact, questioning the role of EC cells in colonic motility (Keating and Spencer, 2010; Spencer et al., 2011). Thus, a spirited debate on this topic persists (Smith and Gershon, 2015; Spencer et al., 2015). It is possible that both points of view are right, and, like skin's light touch, “GI touch” involves multiple mechanoreceptors. Such an arrangement would afford the GI mechanosensory system with the redundancies required to maintain function in a range of challenging circumstances, including inflammation and infection. It would follow that major functional abnormalities would require disruption to multiple mechanosensors.

In addition to the intrinsic GI neuro-epithelial circuit involved in “GI touch,” recent studies suggest that enteroendocrine cells, and EC cells specifically, synapse with extrinsic afferent and efferent extrinsic neurons (Bellono et al., 2017; Bohorquez et al., 2015; Williams et al., 2016). In these circuits, the EC cells presumably collect and integrate information, both chemical and mechanical, and set up a two-way communication system with both afferent and efferent extrinsic neurons that engage the CNS. However, the function of these circuits is unclear. Future studies are needed to elucidate important brain-GI cross talk that could play roles in a range of physiologic phenomena. Possible intriguing examples range from functions in modulating food intake behaviors, like neuro-epithelial taste circuits, to sensing and modulating the external environment, like the microbiome.

In addition to the similarities, there are also important differences between somatosensory touch and “GI touch” systems. In contrast to the somatosensory light touch, the EC cell has a clear endocrine function. EC cells are the major source of systemic serotonin, which is involved in regulation of a broad range of physiologic functions, from fasting metabolic adaptation between meals (Sumara et al., 2012) to long-term maintenance of bone health (Yadav et al., 2010). We do not yet know whether the EC cell endocrine and neuro-epithelial functions are differentially engaged, and whether the cellular signaling pathways downstream from chemical or mechanical stimulation are different. Regardless of their mode of engagement, an intriguing hypothesis is that synaptic connections influence GI physiology (Bellono et al., 2017; Bohorquez et al., 2015), similar to somatosensory touch tuning motor output, while endocrine secretions modulate systemic physiology, including cardiovascular (Cote et al., 2003) and metabolic (Sumara et al., 2012; Yadav et al., 2010) functions.

“GI touch” and disease

The diseases that involve the somatosensory touch and “GI touch” systems also have similarities. Peripheral neuropathy is an example of a somatosensory touch dysfunction commonly caused by some forms of chemotherapy, such as cisplatin, which manifests as numbness, abnormal sensations, and occasionally pain. Interestingly, GI symptoms are commonly associated with chemotherapy, and studies are beginning to show that some chemotherapeutic agents, such as cisplatin, which causes peripheral neuropathy, also causes ENS neuropathy and dysmotility (Uranga et al., 2017). A limitation to progress in the field of enteric neuropathy is that while there are well-defined clinical symptoms and pathophysiologic classifications of somatosensory disturbances in peripheral neuropathy, symptoms associated with “GI touch” pathologies are unclear because we presume that “GI touch” does not involve conscious sensation. However, strong evidence exists that “GI touch” abnormalities and abnormal 5-HT signaling are indeed involved in functional GI pathologies. For example, we know that the GI secretomotor and sensory functions affected by mucosal mechanical stimuli are disturbed in the highly prevalent functional GI diseases, such as IBS, functional dyspepsia and chronic constipation/diarrhea (Mawe and Hoffman, 2013). Studies have also suggested that epithelial 5-HT may contribute to abdominal pain in IBS (Cremon et al., 2011). Indeed, EC cell 5-HT release induced by norepinephrine or isovalerate increased the frequency of mechanically induced neuronal firing, which could alter both motility and sensation (Bellono et al., 2017). Importantly, drugs targeting the receptors downstream of mucosal mechanical stimulation, such as serotonin receptors, have been some of the most promising therapies for functional GI disorders. Unfortunately, given the widespread distribution of these receptors most of these drugs have encountered significant side effects, requiring their removal from the marketplace. A goal of future work should be to understand how the “GI touch” circuitry contributes to the range of symptoms that patients describe, such as bloating, cramps, urge, nausea, and pain and as we better understand the “GI touch” mechanisms, opportunities may emerge to target them directly to provide novel therapeutic options.

Conclusions

In summary, “GI touch” has important functional roles in GI physiology, and has developmental, structural and functional similarities to the somatosensory light touch. However, the molecular mechanisms and precise functional significance of the “GI touch” system are still not clearly established. Given the physiologic importance of this system and its potential disruption in GI diseases, further characterization of “GI touch” function in health and disease will likely produce novel diagnostic and therapeutic approaches.

Highlights.

• Gastrointestinal (GI) mechanosensation is critical to normal GI function.

• Multiple mechanosensitivity circuits exist in the GI tract.

• Enterochromaffin cells & sensory neurons make up the GI neuro-epithelial circuit.

• GI neuro-epithelial circuit is like the skin's light touch circuit.

• “GI touch” is important in GI physiology and pathophysiology.

Abbreviations

GI

gastrointestinal

ENS

enteric nervous system

5-HT

5-hydroxytryptamine

DRG

dorsal root ganglion

IPAN

intrinsic primary afferent neuron