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. 2020 Jan;10(1):a034355. doi: 10.1101/cshperspect.a034355

Enteric Neuromodulation for the Gut and Beyond

Yogi A Patel 1, Pankaj J Pasricha 1,2
PMCID: PMC6938660  PMID: 30858329

Abstract

The small intestine is the longest organ in the human body, spanning a length of ∼5 m and compartmentalized into three distinct regions with specific roles in maintenance of comprehensive homeostasis. Along its length exists as a unique and independent system—called the enteric nervous system (ENS)—which coordinates the multitude of functions continuously around the clock. Yet, with so many vital roles played, the functions, relationships, and roles of the small intestine and ENS remain largely elusive. This fundamental hole in the physiology of the small intestine and ENS introduces a substantial number of challenges when attempting to create bioelectronic approaches for treatment of various disorders originating in the small intestine. Here, we review existing therapeutic options for modulating the small intestine, discuss fundamental gaps that must be addressed, and highlight novel methods and approaches to consider for development of bioelectronic approaches aiming to modulate the small intestine.

WHAT IS THE ENTERIC NERVOUS SYSTEM?

The enteric nervous system (ENS) is the functional interconnection between the gastrointestinal (GI) tract and central (CNS) and peripheral nervous systems (PNS), constantly sensing and actuating the state and function of the esophagus, stomach, small and large intestines, liver, pancreas, and gallbladder. In its entirety, the ENS houses more than 100 million neurons and 70% of the body's immune cells, all of which bidirectionally communicate with nearly 100,000 extrinsic nerve endings (Fung et al. 2017). The general architecture of the ENS throughout the GI tract can be broken down inside out as the lumen, epithelium, lamina propria, submucosa, muscularis, serosa, mesentery, and extrinsic innervation. Dependent on consumption of any substance, a harmonious and coordinated series of events take place at the molecular, cellular, and tissue levels to digest, absorb, and excrete the consumed molecules (Gershon and Erde 1981; Gershon 1999; Hansen 2003). Starting at the surface of the lumen, ingested substances are broken down by the microbiome (Moloney et al. 2014; Rea et al. 2016). The products of the microbiome's actions are absorbed, sensed, and protected against by distinct intestinal epithelial cell (IEC) subtypes in the epithelium. Simultaneously, processes arising from intrinsic glia, neurons, and vasculature located in the myenteric and submucosal plexi sense and actuate the IECs. The myenteric plexus is sandwiched between circular and longitudinal muscle layers, whereas the submucosal plexus is located between the muscularis mucosa and circular muscle layers. Intrinsic cells (e.g., neurons, glia) are further innervated by afferent and efferent processes from extrinsic neurons of sympathetic, parasympathetic, or spinal origin. The sympathetic and parasympathetic systems are primarily understood to have inhibitory and excitatory effects, respectively, on secretion and motility in the GI tract (Kunze and Furness 1999; Furness 2008). Communication within and between the intrinsic and extrinsic nervous systems occurs through a large number of neurotransmitters—namely, acetylcholine, nitric oxide (NO), substance P, somatostatin, noradrenaline, and cholecystokinin (CCK). Collectively, the ENS, GI tract, CNS, and PNS—also referred to as the “gut–brain axis”—monitor and regulate organ states and function—such as digestion, absorption, secretion, motility, and local immunity—to maintain homeostasis (Galland 2014; Sharon et al. 2016).

WHY MODULATE THE ENS?

Dysfunction at various levels of the ENS architecture has been shown to play critical roles in functional GI (Gariepy 2001) and metabolic disorders (Fung et al. 2017). In nearly all cases, these clinically can present themselves as dysmotility, visceral hypersensitivity, compromised mucosal and immune function, altered gut microbiota composition, and changes in CNS function. In addition, functional GI disorders are hypothesized to play a role in the development of long-term neurological and psychological disorders such as Parkinson's disorder, depression, anxiety, and other mood-related disorders.

Functional GI Disorders

Under normal GI physiology, motility results from coordinated contractions of smooth muscles, resulting in two distinct electrical activity patterns—slow waves and spike potentials. Similar to other excitable tissues (e.g., brain, nerves, cardiac), the smooth muscle cells of the GI tract maintain a resting membrane potential across their membranes. This resting membrane potential is typically observed to be between −50 and −60 mV but spontaneously fluctuates, a characteristic unique to smooth muscle cells of the GI tract. Because of the electrical coupling between adjacent smooth muscle cells, the spontaneous and induced fluctuations in resting membrane potential spread throughout the tissue, resulting in measurable events called slow waves, occurring with frequencies of 12 cycles per minute (cpm) in the duodenum and 9 cpm in the ileum.

This rhythmic activity is initiated by the interstitial cells of Cajal (ICC), which initiates smooth muscle contractions that then propagate along the length of the muscle (Furness 2000; Ward and Sanders 2001). When the initiated slow wave passes through a smooth muscle region that has been primed by a local release of acetylcholine from motor neurons within the ENS, spike potentials are generated and result in smooth muscle contractions, which propagate along the length of the intestinal tract. The primary purpose of the rhythmic and tonic contractions in the small intestine is to help transport a bolus through the GI tract over time (Hulzinga et al. 1995; Ward et al. 1998). As the bolus comes into contact with the luminal wall, mechanoreceptors are activated and, in turn, activate the peristaltic reflex, which creates a contraction proximal to the site of the bolus and a relaxation distal to the site of the bolus to allow translocation of the bolus through the intestine.

Failure to maintain both slow waves and spike potential generated contractions results in disorders such as functional dyspepsia (FD) in the small intestine or irritable bowel syndrome (IBS) in the large intestine, both of which cause abdominal pain, nausea, and bloating (Drossman et al. 1990; Gershon 2005; Drossman 2006). Characterization of these disorders in patients has traditionally been through clinical symptoms with the belief that no histopathological abnormalities were present; however, recent studies suggest functional abnormalities in motility, sensation, permeability, and inflammation can be observed, with stress playing a critical role in disease onset (Lomax et al. 2005, Zhou et al. 2009; Öhman and Simrén 2010; Mayer et al. 2014a; Piche 2014; Kelly et al. 2015; Foster et al. 2017).

Metabolic Disorders

Slow waves and spike potential–evoked contractions shadow a multitude of functions continuously performed by the small intestine and ENS. Digestion (duodenum) and absorption (jejunum, ileum) are two of the most basic, yet fundamental, roles of the small intestine. These compartments of the small intestine and their functions have been suggested as playing critical roles in maintenance of metabolic homeostasis, and failure of these mechanisms is believed to be a pivotal driver of growing pandemics such as type 2 diabetes mellitus (T2DM) (Zheng et al. 2018). At present, two critical components of the small intestine are believed to play a causal or correlative role in the development of T2DM—the gut microbiota (Turnbaugh and Gordon 2009; Mayer et al. 2014b; Ridlon et al. 2014; Shreiner et al. 2015) and duodenum.

The effects of the gut microbiota on metabolic activity are widely accepted with the microbiota composition impacting the ability to digest and produce biologically active substances usable by the host to store and use energy efficiently.

The duodenum, which is the first compartment of the small intestine, has specifically been implicated in metabolic disorders with supporting data from preclinical and clinical studies. For surgical interventions, the Roux-en-Y gastric bypass (RYGB) is the mainstay of surgical intervention for metabolic disorders, in which case the stomach volume is reduced, the length of the jejunum and ileum are shortened, and the duodenum is almost completely bypassed (Buchwald 2014). This permanent restructuring of the GI tract has been shown to reduce hyperglycemia and be effective at hindering the development of obesity. Less severe methods have been explored, such as liners that coat the surface of the duodenum or ablation of the duodenal surface, and shown to provide similar benefits in treating hyperglycemia in T2DM. The metabolic benefits achieved through surgical interventions are likely to benefit from a number of causes—including remodeling of the intrinsic and extrinsic nervous system pathways. In the metabolic surgery conditions, it is hypothesized that remodeling of vagal afferents leads to the observed benefits in energy homeostasis and metabolism.

Emotion, Cognition, and Stress

Growing scientific and clinical evidence suggests that functional GI and metabolic disorders may be linked to the development of short- and long-term psychiatric and mood disorders (Cryan and O'Mahony 2011; Luna and Foster 2015; Mayer et al. 2015; Foster et al. 2017). Dysbiosis within the microbiota has been observed in metabolic syndrome, obesity, and IBS patients, leading to the hypothesis that the state of the gut microbiota may be the link between disorders of the GI tract and nervous system (Collins 2014; Hackett and Steptoe 2017). The true nature of the relationship between the gut microbiota and numerous systems—either causal or correlative—is difficult to delineate because of methodological challenges and variability in characterizing the composition of the microbiota. However, a general principle has emerged that is critical for studies attempting to develop bioelectronic medicine—the gut microbiota can affect multiple central and peripheral functions and, in turn, many central and peripheral functions can affect the gut microbiota.

It is widely accepted that the hypothalamic-pituitary-adrenal (HPA) axis is impaired in states of heightened emotion or depression and the increased presence of inflammatory biomarkers such as interleukin (IL)-6, tumor necrosis factor (TNF), and C reactive protein (Gotlib et al. 2008; Pariante and Lightman 2008). These local and systemic changes have been shown to alter the composition of the gut microbiota. Sudo (2006) showed the effects to be bidirectional by investigating the HPA axis in germ-free (GF), specific pathogen-free (SPF), and mice with a single bacterium. By evoking a stress response, Sudo found that GF mice experienced an elevated stress response determined by measuring adrenocorticotropic hormone (ACTH) and corticosterone levels. The elevated HPA axis response in the GF mice could be reversed by introducing a single bacterium, showing the interplay between the HPA axis and state of the gut microbiota.

In addition to elevating stress responses, the state of the gut microbiota can also influence neural signaling and processing, contributing to development of psychiatric and mood disorders. By feeding Lactobaccillus species orally, Kamiya et al. (2006) showed complete inhibition of distension-evoked visceral pain perception in anesthetized rats. Kunze et al. (2009) showed that the presence of Lactobaccillus consistently activated calcium-activated potassium channels in sensory neurons in the myenteric plexus, with further work from Rousseaux et al. (2007) showing receptor expression changes in the IECs leading to increased analgesic functions. These brief examples show the local and systemic modulation that the gut microbiota can have on the functions of the CNS, PNS, and ENS, and emphasize why the state of the gut microbiota must be considered when developing and evaluating the effects of bioelectronic modulation.

WHERE, WHEN, AND HOW TO MODULATE THE ENS?

With a length of ∼5 m, there are multiple targets through which the ENS, and thus organ function, can be modulated (Fig. 1). Starting at the pylorus, the duodenum extends ∼25 cm, followed by the jejunum (2 m) and then the ileum (3 m), which empties into the colon at the ileocecal valve. The epithelium of the small intestine is folded to a high degree, making the true epithelial surface ∼32 m2, with each compartment having distinct pH and temperature profiles to accommodate their unique function.

Figure 1.

Figure 1.

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Graphical depiction of the enteric nervous system (ENS) connectome with sources of intrinsic and extrinsic innervation. Various anatomical locations exist for modulating ENS function and ultimately providing therapeutic benefits for small intestine–related disorders. Extrinsic stimulation activates nerves that terminate on various cell types, including interstitial cells of Cajal (ICC) cells (yellow), macrophages (magenta), neurons (green), and smooth muscle cells (gray)—resulting in pathway-specific activation. Intrinsic stimulation activates all cells near the lumen and can result in direct activation of any cell type or pathway nearby.

In general, the ENS can be modulated by targeting either the intrinsic or extrinsic nervous systems, or direct organ stimulation. There exists a range of commercial bioelectronic medicine therapies for treatment of functional GI disorders; however, the mechanisms and specific targets through which the observed benefits are achieved remains unclear. Here, we discuss the different targets and their advantages and disadvantages in the context of bioelectronic modulation of the intestine.

Targeting the Intrinsic Nervous System

Targeting the intrinsic nervous system means identifying and targeting specific elements within the ENS, which stands as a functional unit of the nervous system with its own complex architecture consisting of muscle layers and a multitude of unique cell types, including but not limited to macrophages, neurons, and glia. Targeting specific elements within this complex architecture has the highest degree of difficulty but may provide the highest degree of spatial and functional selectivity. Achieving this level of selectivity with bioelectronic modulation is complicated by many obstacles—including charge spread during electrical stimulation, variability in tissue characteristics in disease states, as well as gaps in knowledge about unique cell types and their role(s) in detection, processing, and actuating tissue function under different physiological stimuli. Recent small animal studies have shown the ability to engage specific cell types within the ENS using optogenetics (Boesmans et al. 2018). However, to the best of our knowledge, no existing bioelectronic approach directly attempts or aims to engage the ENS.

Targeting the Extrinsic Nervous System

Bioelectronic modulation of the intestine through the extrinsic nervous system refers to modulation of activity at the level of either autonomic nerves, ganglia, the spinal cord, or the CNS, which then results in a functional change in the intestine. Similar to intrinsic neuromodulation, extrinsic bioelectronic modulation can be used to actuate tissue function through modulation of efferent or afferent signaling. Depending on the selected target, the ability to achieve functional or pathway-specific selectivity may be limited with traditional bioelectronic medicine approaches.

Direct Organ Stimulation

The intestine is constructed of layers of smooth muscle cells, which provide it with a set of unique functional behaviors (e.g., peristalsis, segmentation, propulsion). Adding to this, the ENS provides an interconnect for relaying information about the organ's state and its luminal contents to the CNS. Bioelectronic medicine that directly stimulate organs, as has been performed with intestinal electrical stimulation, are likely to simultaneously engage smooth muscle cells, extrinsic nerve fiber terminals, and excitable cells within the ENS. This approach has been shown to treat a myriad of clinical conditions such as dumping syndrome (Xu et al. 2007), short-bowel syndrome (Yin and Chen 2010), obesity (Liu et al. 2005; Yin et al. 2007), and intestinal hypomotility (Yin and Chen 2010). However, it is unclear what is being targeted or engaged with intestinal electrical stimulation in all of these conditions.

It has been suggested that pulse width can be used to engage specific cell types (Yin and Chen 2010) with long pulse widths being more effective at engaging smooth muscle cells, which have longer time constants than neuronal elements such as extrinsic nerve fiber terminals or somas. However, this is unlikely to be an effective strategy for achieving selective target engagement as long pulse widths will inevitably depolarize or hyperpolarize cells with short time constants in the process of exciting smooth muscle cells, leading to a widespread release of a number of neurotransmitters, and triggering multiple inherent reflexes and pathways. A more likely explanation is that intestinal electrical stimulation overrides ongoing spontaneous activity at the level of the tissue (e.g., slow waves, spiking), ENS, and extrinsic inputs leading to therapeutic benefit in such a wide array of disconnected clinical conditions. It may also be possible that direct organ stimulation provides therapeutic benefit through modulation of afferent inputs, altering inherent circuit reflexes, synaptic gains, or simply desynchronize the gut–brain axis.

CURRENT CHALLENGES ON THE ROAD TO DEVELOPING BIOELECTRONIC MEDICINE

Unraveling the ENS Connectome

Much of our existing understanding of the structure and function of the ENS is pieced together from in vitro or cell culture–based studies, both of which are isolated from the effects of extrinsic innervation, the state of the gut microbiota, and inherent interorgan reflexes. This has resulted in valuable knowledge about unique cell types and their functional roles in sensing, processing, and actuating tissue function, but how the ENS and its unique cell types respond in harmony under different stimuli remains unclear (Ye and Liddle 2017), that is, understanding the different states of the ENS with respect to the functions of the small intestine (e.g., peristalsis, segmentation) and the luminal contents driving the intrinsic and extrinsic neural circuitry (Furness 2012).

One approach to determining the underlying activity of the ENS is use of optogenetics, either in transgenic or virally transfected animal models, to selectively engage specific cell types and measure the temporal and spatial patterns of activation using fluorescent voltage or calcium indicators or high-density multielectrode recordings of extracellular activity. The measured activation profiles can then be registered with high-resolution images of the ENS to obtain first-degree connectivity maps of the stimulated and unstimulated network states. The representative maps can be used to derive mathematical models of the ENS circuitry, which in turn enables rapid computational and experimental testing of hypotheses about specific cell types and their roles and functions under different stimuli and network states. Applying the same approach to disease states would enable identification of key failure points in the ENS architecture and target to be modulated by bioelectronic approaches.

Interfaces for Moving Targets

Approaches within the scope of bioelectronic medicine can be invasive—through implanted devices—and noninvasive, and disorders of the small intestine and ENS may benefit from both types of treatments. Chronic disease conditions in which symptoms such as visceral pain, motility, or metabolic conditions are to be treated may require implanted devices, whereas intermittent symptoms such as nausea and bloating may benefit from noninvasive approaches that provide temporary relief. Invasive devices allow targeting of structures with temporal and spatial precision; however, they have a significant patient cost and require surgery. Noninvasive devices and approaches significantly reduce the patient burden, but substantially limit the ability to target structures deep within the body or achieve spatiotemporal precision. Because of these aforementioned pros and cons, bioelectronic approaches targeting the small intestine and other elements of the GI tract are likely to be invasive. Although spatiotemporal precision can be achieved through invasive devices, other related challenges that must be addressed are anatomical variability and ensuring long-term stability of the neural interfaces.

Patient-to-patient anatomy can vary significantly, especially when considering targets such as nerves, which can have different branching patterns, exposable lengths, and surrounding tissues. Under these conditions, investigations developing bioelectronic medicine need to consider how the efficacy of their approach may be impacted, positively or negatively, by such variabilities. For example, the cervical vagus nerve has been shown to be highly variable between right and left vagi, with branching patterns not observed in all patients (Hammer et al. 2015). Such anatomical variability has to be accounted for and normalized when developing bioelectronic strategies to ensure correct surgical placement of the electrodes and appropriate engagement of the correct neurophysiological pathways. These studies should also aim to characterize the anatomical differences and variability of their target structures within and between preclinical and clinical samples.

In a similar vein, tissue structure and composition are variabilities that should be accounted for in conditions in which the target is direct organ stimulation. Furthermore, as discussed earlier, all GI tissues have ongoing rhythmic activity in normal and diseased states. This constant motion of the organs brings about a significant challenge associated with ensuring not only correct placement but also maintenance of that placement. In the context of the small intestine and ENS, placement of electrodes around the serosa or within the lumen should ideally conform with the tissue to maintain appropriate contact with the target structure but also to not obstruct the organs’ basal functions or impede the transit of luminal contents. Traditionally, devices such as gastric pacemakers and studies in preclinical animal models have used wire-based electrode leads, which are inserted into the target organ to an arbitrary depth and distance apart. This approach is prone to substantial variability and can lead to activation of target and nontarget elements within the tissue as well as introduce mechanical mismatches. Accounting for the mechanical mismatches and motion of the tissues is likely to benefit from novel materials that are soft and programmable, and can respond to unique physiological conditions, such as temperature and pH, as well as withstand constant exposure to external mechanical forces.

Ingestibles: A New Paradigm for Neuromodulation

Advances in material science and small-scale electronics also introduce novel methods for modulating the small intestine and ENS, such as revolutionizing the modern-day pill. As has been shown by previous investigations, sensors and actuators can be developed to monitor and regulate GI tract functions for predetermined periods of time. To date, studies have shown the ability to measure and wirelessly communicate temperature and pH within the GI tract. These electric pills are swallowed and can be programmed to turn on when they reach specific locations within the GI tract. Dependent on reaching the target location, the pill turns on and can perform a myriad of functions such as locally deliver drugs or measure luminal contents. In addition, incorporation of cameras enables wireless endoscopies in which snapshots are taken of the GI tract and available for real-time visualization and characterization of transit times and motility patterns. Electric pills hold great promise as a new method for modulating the small intestine and ENS, and will benefit from ongoing investigations that aim to improve energy-harvesting efficiency, new sensing modalities, and a more comprehensive understanding of the ENS connectome.

Change Requires Change

Implanted bioelectronic devices face a number of factors that influence the achieved therapeutic benefit. Changes at the electrode–tissue interface, the state of the tissue at the time of the therapy (e.g., segmentation vs. contraction, slow wave present or absent), and the disease state all contribute to the achieved effect. For example, in the field of pain neuromodulation, in which patients are implanted with devices for stimulation of various neural structures to reduce the perception of chronic pain, patients routinely undergo procedures to optimize stimulation parameters and protocols. Although this is performed through subjective pain scores, the parameter optimizations ensure that patients receive maximum therapeutic benefit. This example highlights that the need to develop systems and methods that autonomously adapt stimulation strategies will be required.

CONCLUSION

The small intestine and ENS are complex and integrative systems that play a critical role in homeostasis. Multiple unknowns still exist about the relationship between the gut and its various components and functional and physiological states. Application of bioelectronic methods to the small intestine and ENS may enable unique and targeted approaches that ultimately result in restoration of lost function and homeostasis.

Footnotes

Editors: Valentin A. Pavlov and Kevin J. Tracey

Additional Perspectives on Bioelectronic Medicine available at www.perspectivesinmedicine.org

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