Medically unexplained somatic problems including chronic diffuse pain and functional gastrointestinal disorders (FGIDs) are persistent, disabling, costly, and seen across all medical settings (1–3). However, their pathophysiology is poorly understood. Increasingly, there is a growing awareness that chronic diffuse pain and FGIDs are highly prevalent among those with a history of trauma or abuse (4, 5). Rates of abuse history tend to be highest among patients in pain and gastroenterology clinics (6) and one study found that of all females referred to a gastroenterology clinic, 67% had experienced sexual or physical abuse (7).

Despite this awareness, a pathophysiological mechanism that links trauma and abuse history to chronic pain and FGIDs is lacking. In this review, we use the framework provided by the Polyvagal Theory, an evolutionary neurophysiological model of the autonomic response to safety and threat (8–11). Within this framework, we outline a pathophysiological mechanism rooted in chronic autonomic threat responses that give rise to systemic changes in the regulation of pain pathways and the gastrointestinal tract. We then apply this framework to converging evidence from medicine, psychiatry, physiology, and neuroscience to provide a plausible model for the origins of post-traumatic chronic diffuse pain and functional gastrointestinal disorders in the absence of organic medical cause. While the pathogenesis described here may apply to a range of functional somatic disorders, this review focuses on fibromyalgia (FM) and irritable bowel syndrome (IBS) due to the wide clinical prevalence and abundant research related to these disorders.

Fibromyalgia is a chronic widespread pain condition impacting muscles, ligaments, and tendons. With a prevalence around 2–3%, it is among the most common types of chronic diffuse pain (12). It is estimated that women are about twice as likely to develop the disorder than men (13). A diagnosis is typically made based on the number of tender points in characteristic locations, chronicity, and exclusion of other disorders that may be causing pain. While the etiology of fibromyalgia is unknown and pathophysiology is poorly understood, there is growing understanding that emotional or physical trauma may trigger or aggravate symptoms (13).

Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterized by chronic abdominal pain and altered bowel habits—diarrhea, constipation, or alternating episodes of both—in the absence of clear anatomical or physiologic abnormalities. The most recent criteria defines irritable bowel syndrome as recurrent abdominal pain, on average, at least 1 day per week in the 3 months before diagnosis that is associated with two more of the following: (a) relation to defecation, (b) association with change in the frequency of stool, (c) association with a change in the form (appearance) of stool (Rome IV criteria) (14, 15). It is the most frequently diagnosed gastro-intestinal condition, accounting for about 30% of all referrals to gastroenterologists (16) and is highly co-morbid with fibromyalgia (17). Based on a meta-analysis of 80 studies involving over 250,000 total subjects, the world-wide prevalence is estimated to be about 11.2% with higher rates in women than men (18). Like fibromyalgia, the etiology and pathophysiology of irritable bowel syndrome remain uncertain although emotional stress intensifies symptoms and hinders positive treatment outcomes (17).

We review evidence for fibromyalgia and irritable bowel syndrome as arising from a chronic autonomic response that may be triggered or exacerbated by evolutionary bio-behavioral processes that regulate the brain and body in response to threat. In pursuit of this, this paper reviews: (1) the elevated prevalence of fibromyalgia and irritable bowel syndrome among sexual abuse and rape survivors, (2) the organizing autonomic threat-response principles drawn from the guiding framework of the Polyvagal Theory that explain the adaptive function of shifts in autonomic state reflected in respiratory sinus arrhythmia (high frequency heart rate variability), (3) the autonomic and neurophysiological systems that regulate pain and gastrointestinal function, (4) empirical evidence of diminished RSA reflecting altered autonomic function in fibromyalgia and irritable bowel syndrome patients, (5) common autonomically-regulated co-morbidities in fibromyalgia and irritable bowel syndrome patients, and (6) evidence for autonomic disruption after trauma. The understanding of fibromyalgia and irritable bowel syndrome as systemic dysfunction produced by a chronic autonomic threat response provides novel opportunities for treatment that targets the brain-body system, including the brain-gut axis, rather than treating individual symptoms.

Sexual and physical abuse in both childhood and adulthood are a widespread problem. Based on a series of large-scale meta-analyses, international prevalence rates are estimated to be 13% for childhood sexual abuse (8% males, 18% females) and 23% for childhood physical abuse (19). In the US, the Centers for Disease Control and Prevention estimate that the lifetime prevalence of rape is 19% in women and 2% in men and intimate partner violence prevalence is 32% in women and 28% in men (with severe intimate partner violence prevalence at 22 and 14%, respectively) (20). Notably, these higher rates of sexual and physical abuse among women are paralleled in the gender-specific prevalence of fibromyalgia and irritable bowel syndrome. Women are about twice as likely to have a fibromyalgia diagnosis (13) and have 1.67 greater odds of having irritable bowel syndrome than men (18).

Converging evidence across many studies shows that abuse history is a strong predictor of fibromyalgia. In a meta-analysis of 18 studies with a total of over 13,000 combined participants, Häuser and colleagues found that sexual and physical abuse in both childhood and adulthood predicted greater odds of fibromyalgia (odds ratio point estimate range: 1.94–3.07) (21). In their meta-analysis, Paras and colleagues found that rape survivors have especially high odds of fibromyalgia diagnosis (OR = 3.27) (22). These risk factors are higher in fibromyalgia patients than those with rheumatoid arthritis, highlighting the specificity of the role of abuse and trauma in FM pathogenesis compared to a pain disorder with a known organic cause (23).

Rates of gastrointestinal problems such as irritable bowel syndrome are similarly elevated in survivors of abuse. Meta-analytic evidence supports this with childhood sexual abuse being associated with higher risk of gastrointestinal problems (24). It is estimated that individuals with a history of sexual abuse are about twice as likely to develop abdominal pain and gastrointestinal problems than those without an abuse history (25). As seen with fibromyalgia, rape survivors are among those with the highest risk, with meta-analytic methods suggesting their odds of having a functional gastrointestinal disorder are about four times greater than those without an abuse history (22). Those with an abuse history also have higher severity and quantity of GI symptoms and seek medical help more often (26).

Overall, these robust associations suggest that abuse and trauma experiences may be key to understanding the pathogenesis of fibromyalgia and irritable bowel syndrome. However, a comprehensive integrative model to explain the mechanisms through which traumatic experiences affect these chronic disorders is lacking.

The brain-body connection is composed of integrated sensory, interoceptive, and regulatory systems that monitor internal body conditions and the external environment, coordinating homeostatic processes required for maintenance of biological functions as well as responses to threats from inside and out (27–30). Within the body, interoceptive signals continuously provide homeostatic information about the body's physiological condition to the brain. In complement, exteroception (evaluation of external conditions) provides information about environmental challenges and threats, to allow for the flexible shifting of resource allocation to meet external demands. Detection of both internal and external threats or perturbations can disrupt homeostatic processes in the interest of allocating resources for addressing the threat.

The Polyvagal Theory (8–11) provides a neurophysiological framework for understanding the evolutionary history of mammalian nervous system and its relation to the anatomic and functional organization of the human brain-body connection. Over the course of evolution, vertebrate nervous systems have elaborated on and appended to the earliest and most primitive of these brain-body systems. With time, newer systems increased precision, speed, and complexity, as well as evolved new functions that respond to novel environmental and social needs. These newer neurophysiological systems did not replace older systems, but instead became integrated with older functions.

Some of the first of these regulatory systems, observed in the earliest vertebrates, were powered by hormones and facilitated relatively slow, diffuse reactions in the brain and body. However, with time, the evolution of the autonomic system afforded more rapid and targeted control. With the heart serving as a key metabolic structure, the earliest neural regulatory pathways evolved to provide control over its function. These efferent pathways emerged from an area of the brainstem known as the dorsal motor nucleus of the vagus (DMX), adjacent to the target site of the sensory afferent pathways that provides information from the heart and target organs. Together, this coordinated efferent-afferent system formed the dorsal vagal complex (DVC). This regulatory circuit was well developed in early vertebrate evolution and emerged in primitive vertebrates such as cartilaginous fish, integrating information arising from the body and higher brain structures. In humans, this system has few fibers innervating the heart, with most efferent projections innervating organs below the diaphragm, including the gastro-intestinal tract, to regulate digestive and metabolic functions.

The emergence of a spinal sympathetic nervous system (SNS) in bony fish, with its broad scope and target specificity, provided a rapid and coordinated fight/flight system for mobilizing the body in response to threats. This system built on the architecture of the DVC, utilizing information traveling from the body and exteroceptive higher brain regions to coordinate threat-related response needs. In humans, this system regulates a wide range of tissues and structures including the digestive tract, heart, and lungs.

The phylogenetically newest autonomic system is the ventral vagal complex (VVC), which emerged during the transition from primitive extinct reptiles to mammals. Like the SNS before it, this system built on the integration of afferent information arising from the body and descending signals from higher brain structures to respond to internal and external needs. Its efferent arm emerged as cell bodies of vagal efferent source nuclei of the DMX migrated ventrally, forming a second and distinct cardioinhibitory nucleus known as the nucleus ambiguus (NA) and became integrated with circuits that regulate the bronchi and muscles of the face and head. Unlike earlier systems, which promoted defense-related survival responses, this new autonomic face-heart connection formed in concert with the mammalian dependence on social-affiliative behaviors. It provided a substrate for communication of defense or affiliative states via vocalization acoustic features (via regulation of the larynx and pharynx) (31, 32) and facial expressions, as well as providing capacity to dampen older survival-based response systems.

In mammals, all three systems contribute to maintaining homeostatic function and coordinating responses to internal and external perturbations. Information from within is integrated in signals arising from afferent pathways and converging on brainstem structures, most prominently the nucleus tractus solitarius (NTS), while top down signals from higher brain regions, including sensory systems, provide information about external threats. This integrated interoceptive and exteroceptive information is projected to higher-level brain structures and to visceral organs via the source nuclei of the motor pathways involved in the DVC, SNS, and VVC to coordinate responses. This integrated information also interacts with neuroception, the subconscious assessment of threat and safety in the environment (named in contrast to consciously experienced sensory perception) (33, 34). Importantly, the non-conscious threat detection that occurs in both the body and higher-level brain centers suggests that individuals may not be aware of threat-response triggers. However, they may consciously experience the threat-related changes in brain and body regulation (e.g., urge to defecate, feelings of anxiety).

The Polyvagal Theory proposes that the evolution and individual anatomical pathways of the DVC, SNS, and VVC give rise to an ordered response hierarchy that promotes coordinated responses to threats. Under normal homeostatic conditions, each system is involved in basal functions for organism maintenance. However, under threat conditions, the function of individual systems can be recruited to regulate metabolic resources as needed. Phylogenetically newer systems are primary responders; older systems are recruited as threat persists. This phylogenetically ordered response hierarchy is consistent with the Jacksonian principle of dissolution (35). First, under threat, the VVC, the most rapidly responsive system, withdraws its inhibitory influence on mobilization. Since a component of HRV, known as respiratory sinus arrhythmia (RSA; see below), is primarily a product of this circuit, it is often used as an index of the strength of this circuit. Second, the SNS can further ramp up mobilization and promote fight/flight behaviors. Finally, when recruited for defense responses, the DVC produces an efferent vagal surge that inhibits metabolic functions by slowing heart rate, reducing digestive processes, and promoting behavioral shut down. Notably, all three autonomic systems feature cardio-regulatory pathways; modulating cardiac function is key to altering metabolic resources for body responses. Calm, affiliative social engagement requires dampening of threat-related bodily mobilization (this mobilization brake must be removed for efficient body mobilization), fight/flight mobilization requires ratcheting up available resources, and behavioral shut down requires reduction of metabolic function.

Though acute neural threat reactions are adaptive and necessary, chronic state shifts that maintain threat responses can be a risk factor for body dysfunction and disease. The brain-body connection is composed of multiple integrated feedback loops and the chronic maintenance of threat responses can lead to a “compromised” functional state. Chronic compromised states may give rise to the emergence of functional gastrointestinal disorders and altered pain signaling as part of a chronic systemic, rather than an event related organ- specific, pathophysiology. These changes in homeostatic functions may be self-maintaining or cascading even after the threat has been lifted due to long-term alterations in set points, learned responses to threat cues, and the symptoms themselves propagating threat-reaction.

In addition to the shared VVC dampening in both fibromyalgia and irritable bowel syndrome, these disorders also share a high co-morbidity and overlap in autonomic symptoms. Fibromyalgia occurs in about 49% of irritable bowel syndrome cases (17). Both diagnoses are also associated with other autonomic and state-regulation problems. Irritable bowel syndrome patients have increased rates of non-digestive pelvic pain, chronic fatigue, sleep problems, syncope and dizziness (67), as well as heightened visceral and cutaneous pain perception (68). Fibromyalgia co-morbidities are similar and include chronic fatigue, sleep problems, elevated rates of visceral pain and sensory hypersensitivities (13). Furthermore, self-reported autonomic problems - including issues with subdiaphragmatic organs, orthostatic, vasomotor, and secretomotor functions - are elevated in fibromyalgia patients and overall severity of fibromyalgia symptoms is associated with severity of these problems (69).

Fibromyalgia and irritable bowel syndrome are both associated with elevated sexual and reproductive system problems that may be a manifestation of general autonomic function. Individuals with irritable bowel syndrome have elevated rates of vulvodynia, dysmenorrhea, amenorrhea, and irregular menstruation (67). Likewise, fibromyalgia is related to increased incidence of dysmenorrhea (13). In addition, women with fibromyalgia experience blunted sexual desire and arousal, fewer experiences of orgasm, and increased pain during intercourse (70).

The co-occurrence of fibromyalgia and irritable bowel syndrome with their overlapping autonomic co-morbidities suggest a role for a general systemic dysfunction as an underlying pathophysiology that gives rise to chronic diffuse pain and functional gastrointestinal problems. This points to the possibility that integrated brain-body reactions may produce long-term systemic changes that give rise to chronic disease and dysfunction related to evolutionary threat responses. Abuse or psychological trauma provides an especially potent experience that may re-tune the nervous system toward a chronic threat response.

As reviewed above, the human autonomic nervous system is tuned to rapidly respond to a wide range of external and internal conditions. Many mild events that challenge the nervous system's resources are part of everyday life and trigger adaptive acute reactions. However, traumatic experiences may be especially potent in re-calibrating the autonomic nervous system toward a state that supports chronic defense responses. These long-term chronic changes, which affect autonomic regulation and the function of the brain and body, are observed across a range of traumatic events, including physical and sexual abuse in both childhood and adulthood.

These traumatic experiences may trigger a chronic threat-related brain-body response. A recent meta-analysis showed that RSA is dampened in individuals with Post-Traumatic Stress Disorder (PTSD) (71). This is consistent with a model of dampened VVC activity, as part of a chronic threat response, being implicated in long term effects following a trauma. Emerging evidence also suggests that a range of interventions including biofeedback and mindfulness that improve PTSD symptoms also increase heart rate variability (72–74). Importantly, however, VVC regulation may be dampened and trigger somatic problems even in the absence of a PTSD diagnosis. Although empirical research in this domain is currently scant, one study found that women with an abuse history have low RSA compared to health controls even when they do not meet diagnostic criteria for PTSD (75).

Anxiety disorders and depression are common sequelae following traumatic events. Both fibromyalgia and irritable bowel syndrome co-occur with panic disorder, generalized anxiety disorder, and PTSD (13, 76). It is estimated that 30–50% of fibromyalgia patients also have anxiety and/or depression at the time of diagnosis (12). A meta-analysis shows that across studies, depression symptoms are elevated in fibromyalgia and irritable bowel syndrome and anxiety is elevated in irritable bowel syndrome (77). Patients with GI dysfunctions, who have an abuse history, have higher rates of panic symptoms and depression as well as autonomically-related somatic symptoms such as sleep disturbance and pelvic pain than those without abuse history (26), suggesting a higher likelihood of systemic brain-body dysfunction.

The reviewed converging evidence, viewed through the lens of organizing principles derived from Polyvagal Theory, proposes a plausible pathway through which chronic subdiaphragmatic organ disease and pain may be based in the evolutionary neurophysiological defensive states elicited by abuse and life threat. These chronic systemic functional problems are reflected in regulation of the heart by the VVC (as measured by RSA), providing a portal for identifying disorders of visceral organ function. This novel model describes a possible mechanism through which trauma may lead to the pathophysiology of chronic pain and functional gastrointestinal disorders. When organic cause is not evident, functional GI problems or chronic diffuse pain may be a marker of a traumatized nervous system.

Although the link between sexual and physical abuse is well documented, there are many other experiences that may trigger chronic neurophysiological defense responses in chronic pain and FGIDs. Other traumas that trigger defense states, including invasive surgical procedures, may have similar effects. Many infants born prematurely require chronic intensive medical interventions to survive. These interventions, although enhancing survival, are marked by repeated pain-inducing procedures, surgery, medication, and maternal separation at a time when the regulation of the autonomic nervous system, particularly the VVC, is still developing. These experiences may all have the capacity to trigger a life-threat challenge to the nervous system, which may alter ANS function in the long term. Adolescents who were born premature have more tender points and lower tender thresholds than those born full term (78) and a recent study found that 62% of female fibromyalgia patients reported a gestation of <38 weeks (this gestational age cut off is based on the study sample median and provides preliminary evidence for the proposed model until a study with more clinically meaningful criteria is conducted) (79).

Our review has focused on the chronic pain disorder fibromyalgia, since it is among the most common types of chronic diffuse pain and has been widely researched. However, at least 10% of the general population has chronic diffuse pain that is not diagnosed as fibromyalgia, with little specific disease or obvious abnormality to explain symptoms (12). Notably, sexual abuse history is also associated with elevated rates of pelvic and nonspecific chronic pain (22). It is possible that these non-specific pain problems may have an underlying autonomic mechanism involving both vagal efferent and afferent pathways conveying information between the brainstem and subdiaphragmatic organs.

Similarly, our review of functional GI disorders has been limited to irritable bowel syndrome since this is the most widely reported and studied GI disorder. However, it is possible that the range of functional gastrointestinal disorders lacking obvious anatomical or physiologic causes that do not meet irritable bowel syndrome criteria—including functional constipation, diarrhea, abdominal bloating, and distension (15)—may have a pathophysiology rooted in chronic defense states. For instance, functional dyspepsia, a disorder marked by bloating, upper abdominal pain or discomfort, and indigestion in the absence of organic disease, may also be part of a chronic subdiaphragmatic immobilization or shut down response. Notably, the risk of functional dyspepsia is elevated among childhood sexual abuse and war survivors (80), co-occurs with elevated rates of depression and anxiety (77), is marked by a lack of the typical gastric antral motility reactivity to mental stress exhibited by healthy controls (81), is associated with decreased RSA (81, 82), and successful symptom treatment by acupuncture concurrently increases RSA (83).

A conceptualization of pain and GI regulation as part of an integrated nervous system that is capable of dynamic state-related shifts provides an optimistic opportunity for new treatment targets. Rather than focusing on disease symptoms as organ, tissue, or pathway-specific, the understanding of the organizing principles through which the nervous system regulates visceral organs and afferent signals may lead to novel approaches that draw on evolutionary neurophysiological feedback loops. Treatments that target the autonomic nervous system, rather than the digestive system or a pain source, provide a direct test of the proposed model. With the rising availability of vagus nerve stimulation devices, there is increasing evidence that targeting ANS function can indeed improve symptoms.

Recent applications of electrical vagus nerve stimulation show promise for both treatment of pain and functional gastrointestinal disorders. These treatments stimulate afferent vagal signaling, rather than the GI tract or painful regions. This signaling may increase VVC regulation and strengthen the body's natural safety-related feedback loops that inhibit pain signaling and promote efficient GI function. A pilot study showed that an implanted vagal nerve stimulator had positive effects in a small sample of treatment-resistant fibromyalgia (84). This suggests that vagal nerve stimulation likely influences general noxious- and pain-related pathways and may have benefits for a range of neurophysiologically-linked problems. Promising results have been observed for respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) in chronic pelvic pain patients, which include reductions in anxiety (85). Benefits have also been observed for GI function. In healthy participants, non-invasive transcutaneous electrical vagal nerve stimulation (t-VNS) with deep slow breathing increased both musculoskeletal pain threshold and gastroduodenal motility (86). The stimulation also increased heart rate variability, consistent with a model of VVC activation inhibiting pain pathways and stimulating efficient gastrointestinal functions. In addition, a randomized, sham-controlled double-blind study found that an ear-attached cranial nerve stimulator (which includes the vagus nerve as a target) improved GI pain symptoms in adolescents with pain-related FGIDs (87). These studies provide preliminary experimental evidence for the proposed model of ANS afferent signaling as a part of the pathophysiology of FGIDs and FM.

Beyond vagus nerve stimulation, a polyvagal approach also predicts that evolutionary cues that trigger neurophysiological safety responses and remove threat cues may likewise have treatment potential. Empirical work based on these evolutionary neurophysiological cues is needed. However, there is mounting evidence that mammalian safety-cueing acoustic features are embedded in frequency bands and spectro-temporal modulation (31, 32) and preliminary work demonstrates that these properties may be effective in promoting VVC activation for clinical applications (88). Other sensory modalities may also offer promising non-invasive portals for influencing nervous system function.

The evolutionary neurophysiological framework of the polyvagal theory provides a plausible model for post-traumatic chronic pain and functional gastrointestinal disorders based on systemic brain-body responses to safety and threat. This framework provides an integrative perspective that unites multiple co-occurring phenomena across perceptual and neurophysiological reports, though much individual variability still remains. While FM and IBS share a neurophysiological substrate with threat-response systems, symptom heterogeneity is the rule rather than the exception, which likely reflects interactions with higher level brain structures, neuroendocrine, and immune processes [e.g., 89)]. However, this review highlights the potential for the autonomic nervous system to be the basis for the organization and synthesis of observations made made by physicians, mental health practitioners, and neuroscientists to piece together the mechanisms that link traumatic experiences, threat-related nervous system function, and multiple somatic disorders. Conversations about trauma history between patients and medical practitioners may be critical for interpreting symptoms and developing treatment plans, but these conversations are rare (26). By building a better understanding of the systemic chronic nervous system alterations that can be induced by trauma, the medical community can move toward explaining co-morbidities and developing targeted treatments.

JK and SWP both contributed to the conceptualization and writing of this work.