자율신경성 소화장애

Functional gastrointestinal disorders (FGID) and gastroesophageal reflux (GERD) disease affect a large global population and incur substantial health care costs. Impairment in gut-brain communication is one of the main causes of these disorders. The central nervous system (CNS) provides its inputs to the enteric nervous system (ENS) by modulating the autonomic nervous system (ANS) to control the gastrointestinal functions. Therefore, GERD and FGID’s might be associated with autonomic dysfunction, which can be identified via heart rate variability (HRV). FGIDs may be treated by restoring the autonomic dysfunction via neuromodulation. This article reviews the roles of HRV in the assessment of autonomic function and dysfunction in (i) gastroesophageal reflux (GERD), and the following FGIDs: (ii) functional dyspepsia (FD) and gastroparesis, (iii) irritable bowel syndrome (IBS) and (iv) constipation. The roles of HRV in the assessment of autonomic responses to various interventions were also reviewed. We used PUBMED, Web of Science, Elsevier/Science direct and Scopus to search the eligible studies for each disorder, which also included the keyword ‘heart rate variability’. The retrieved studies were screened and filtered to identify the most suitable studies using HRV parameters to associate the autonomic function with any of the above disorders. Studies involving both human and animal models were included. Based on analyses of HRV, GERD as well as the FGIDs were found to be associated with decreased parasympathetic activity and increased sympathetic nervous system activity with the autonomic balance shifted towards the sympathetic nervous system. In addition, the HRV methods were also reported to be able to assess the autonomic responses to various interventions (mostly neuromodulation), typically the enhancement of parasympathetic activity. In summary, GERD and FGIDs are associated with impaired autonomic dysfunction, mainly due to suppressed vagal and overactive sympathetic tone, which can be assessed noninvasively using HRV.

3.1. Gastroesophageal Reflux and Autonomic Nervous System: A total of 861 individuals were included in all the 15 studies selected for the gastroesophageal reflux group. Seven out of the 15 studies compared the autonomic nervous system activity of the patients to that of healthy controls, while in the other seven studies, the comparison was carried out among different patient groups; three studies were conducted on newborn babies or kids while the rest were conducted on adults.

Four studies used short term HRV (≤5 min); seven studies used long term HRV (12–24 h); four studies did not mention the duration of the ECG recording. One study used only time domain parameters (SDNN, SDNNi, RMSSD, pNN50%) for the ANS activity assessment and one study used heart ratios (max HR/Min HR) during postural change, Valsalva, hand grip, and deep breathing to record the variability in heart rate instead of time or frequency domain parameters. Seven studies used only frequency domain parameters, HF and LF powers, and their ratios for the ANS assessment, and in the remaining six studies, both time and frequency parameters were implemented.

Based on the HRV parameter values, six studies concluded that patients had low overall heart rate variability compared to controls, as the HRV parameters (PNS and SNS parameters) were lowered in patients. Four studies reported a decreased parasympathetic activity and enhanced sympathetic tone with the autonomic balance shifted towards the SNS in patients compared to controls. One study compared two groups of patients and tried to differentiate alcoholic non cardiac chest pain patients with and without depression and alexithymia using HRV and could not find any difference. Nowak et al. concluded that the children suffering from IBS had no significant differences in their autonomic activity compared to controls.

Djeddi et al. studied the autonomic activity before, during, and after the gastroesophageal reflux event and found that the PNS activity is significantly suppressed prior to the reflux event. Jones et al. indicated that the autonomic neuropathy, which was believed to be the cause of gastroesophageal reflux, could be reversed if treated.

Three studies assessed the effect of esophageal electric stimulation on the autonomic nervous system in patients with GERD. Two of the three reported that transcutaneous electric acustimulation (stimulation delivered via acupoints) decreased the SNS and promoted the PNS activity in patients with GERD. The other showed that electrical esophageal stimulation (EOS; 200 μs, 0.2 Hz., 25 stimuli) applied 5 cm above the lower esophageal sphincter altered ANS such that the sympathetic outflow (LF peak power) was decreased and the cardiovagal activity (HF peak power) was increased in patients with GERDS, but not in healthy controls. This might be attributed to the fact that the baseline ANS activity in the healthy controls was already in a homeostatic state, hence the electric stimulations did not modulate it much, contrary to patients.

The detailed information on the population, study design, HRV parameters used, results, and conclusion in the 15 studies is summarized in Table 2.

3.2. Functional Dyspepsia, Gastroparesis and Autonomic Nervous System: Out of the total 19 studies included for the “functional dyspepsia and gastroparesis” group, six were animal studies, which included five studies on rats/rodents and one study carried out on dogs. In the 13 human studies, a total of 873 participants took part, which includes 154 healthy controls and 719 patients. Further details about the participants (gender, average age, pathophysiology of each group) are given in Table 3 below.

Thirteen studies utilized frequency domain parameters (HF power, LF power, LF/HF ratio, HFa, LFa, LFa/HFa) for autonomic assessment while five studies used both time (SDNN, SDANN, pNN50%, RMSSD, E/I, Valsalva ratio) and frequency domain parameters, and one study used only the time domain parameters for the ANS assessment.

While Kumar et al. did not find any abnormality in the autonomic nervous system function in patients with delayed gastric emptying, all other human studies have found at least one abnormal HRV parameter value in patients with functional dyspepsia or gastroparesis compared to healthy controls. Only one study reported that patients with FD had a high parasympathetic tone and a lowered LF/HF ratio and that symptoms were more severe in patients with impaired PNS activity. All other studies demonstrated that both FD and gastroparesis were associated with a decreased vagal tone and/or an increased sympathetic activity. Three human studies have shown that the suppressed vagal activity can be enhanced (increase in HF power) and SNS can be decreased by gastric electrical stimulation or gastric neuromodulation, transcutaneous auricular vagus nerve stimulation, and epalrestat (an aldose reductase inhibitor, used for treating diabetic neuropathy) administration.

Rodent studies showed that delayed gastric emptying was associated with a low HF power and high LF/HF ratio (sympathovagal balance) compared to controls, which was improved with sacral nerve stimulations, electroacupuncture at ST36 with implanted electrodes, or auricular electroacupuncture. Similar findings were reported in dogs with electroacupuncture at ST36.

Table 3 summarizes the population, study design, HRV parameters used, results, and conclusions of all 16 studies in functional dyspepsia and gastroparesis.

3.3. Irritable Bowel Syndrome and Autonomic Nervous System: All 19 studies included for the “Irritable Bowel Syndrome” group in this review were carried out on human participants. There was a total of 2163 participants included in all of the studies, combined with 1494 patients suffering from irritable bowel syndrome and 669 healthy controls. Further details about the participants (gender, average age, subgroups) are given in Table 4.

Thirteen studies implemented the frequency domain parameters (HF power, LF power, LF/HF ratio, HFnu, LFnu, VLFnu), one study used peak HF and LF powers, two studies used the natural log of HF and LF power, and one study used the percentage HF and LF powers. Two studies used both time and frequency domain parameters for the ANS assessment.

While eight studies demonstrated a high sympathetic tone (increased value of LF power and/or LF/HF ratio) and low parasympathetic tone (lower value of HF power) in patients with irritable bowel syndrome compared to adult healthy controls, Jarrett et al. reported no difference in HRV parameters in children with functional abdominal pain (FAP) related to IBS compared to healthy children. Orr et al. showed that the difference in the autonomic activity of IBS patients is only abnormal during rapid eye sleep and during walking. Kano et al. and Adeyemi et al. reported opposite results, showing a low ln(LF/HF) ratio and a higher ln(HF power) in patients compared to controls. However, an inflatable bag was placed inside the rectum during the experiment of Kano et al. which was inflated during the experiment, which might have caused the opposite autonomic response. Jarrett et al. tried to use HRV parameters to differentiate the IBS patients with diarrhea (IBS-D) and with constipation (IBS-C) while Robert et al. compared the HRV of IBS patients with and without depressive symptoms. Both of their results showed no difference in the HRV of between the compared groups. Jarrett et al. reported that the IBS patients with high sympathetic tone were less benefitted from cognitive therapies while, according to Jung et al., HRV parameters could be used to study the effect of cognitive therapies for IBS. Cai et al. reported that only the IBS patient with severe gut pain had high sympathetic tone and low parasympathetic tone. Tanaka et al. established a strong correlation between adrenaline and HRV upon corticotropin release in healthy controls, which was absent in IBS patients. Similarly, Pellissier et al. reported that healthy controls could be differentiated from the IBS patients based on the fact that, in controls, a higher HFnu value correlated with a lower evening salivary cortisol level, while this correlation was absent in the patients.

3.4. Constipation and Autonomic Nervous System: Of the 15 studies included for the “Constipation” group, three were animal studies which included two studies in rats and one study in dogs. The 12 human studies consisted of 197 healthy controls and 634 patients with constipation. Further details about the participants (gender, average age, pathophysiology of each group) are given in Table 5.

Ten studies only implemented the frequency domain parameters (HF power, LF power, LF/HF ratio, HFnu, LFnu) for the autonomic assessment, while five studies used both time (RMSSD, SDNN, pNN50%, sympathetic index) and frequency domain parameters (HF power, RSA, LF power, LF/HF ratio). It is noteworthy that three studies implemented the sympathetic index (SI) for sympathetic nervous system assessment instead of the LF power and two studies used SI/RSA or SI/RMSSD for recording autonomic balance.

The studies involving human participants can be divided into three subgroups. The first subgroup (n = 4) focused on identifying the autonomic function/dysfunction in constipated patient. Lijun et al., Miyagi et al., and J. Liu et al. have concluded that constipation is associated with high sympathetic tone (high SI) and low parasympathetic tone (decreased HF or RSA) and the autonomic balance shifted towards SNS activity (low LF/HF); they concluded that both SNS and PNS were impaired. Gondim et al. only reported a higher SNS tone in constipated patients. Enevoldsen et al. tried to corelate GI transit time with HRV parameters and found no correlation.

Ding et al. tested biofeedback a method to improve autonomic nervous system activity in constipated patients, but they could not establish biofeedback as a way to treat constipation by modulating the ANS. The remaining six human studies tested neuromodulation as a method to treat chronic constipation via modulating vagal and/or sympathetic activity. In an earlier study, neuromodulation of lumbar and sacral autonomic nerves by low level laser therapy was reported to modulate the autonomic nervous system such that PNS activity was enhanced and SNS activity was decreased in patients with GI disorders predominantly constipations. Z. Liu et al. modulated the ANS via transcutaneous electric acustimulation (TEA) and successfully increased the HF power, decreased the LF power as well as LF/HF ratio. While J. Liu et al. found that ANS was modulated with both actual and sham TEA when both combined with Macrogol 4000 Powder (MAC) and adaptive biofeedback, whereas MAC alone did not modulate the ANS. Zhang et al., Wu et al., and Chen et al. have successfully modulated the ANS activity using neuromodulation as an effort to treat the chronic constipation

Similarly in animal studies, Wang et al. demonstrated that Loperamide-induced constipation in rats could be treated by electroacupuncture (EA), which increased the HF power and decreased the LF/HF ratio. Similar findings on autonomic modulation were reported with sacral nerve stimulation in the same rodent model of constipation. Jin et al. found that impaired colonic motility induced by rectal distension in dogs was associated with a significant decrease in the HF power, which was reinstated by EA at ST36.