Gastroenterology 2016;150:1355–1367

Biopsychosocial Aspects of Functional GastrointestinalDisorders: How Central and Environmental Processes Contributeto the Development and Expression of FunctionalGastrointestinal Disorders

Lukas Van Oudenhove,1 Rona L. Levy,7 Michael D. Crowell,2 Douglas A. Drossman,3

Albena D. Halpert,4 Laurie Keefer,5 Jeffrey M. Lackner,6 Tasha B. Murphy,7 and Bruce D. Naliboff8

1Laboratory for Brain-Gut Axis Studies, Translational Research Center for Gastrointestinal Disorders, University of Leuven,Leuven, Belgium; 2Department of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona; 3Center for Educationand Practice of Biopsychosocial Care LLC, Drossman Gastroenterology PLLC, Chapel Hill, North Carolina; 4Center forDigestive Disorders, Boston Medical Center, Pentucket Medical Associates, Haverhill, Massachusetts; 5Division ofGastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York; 6Behavioral Medicine Clinic, Department ofMedicine, University at Buffalo School of Medicine and Biomedical Sciences, State University of New York, New York;7Behavioral Medicine Research Group, School of Social Work, University of Washington, Seattle, Washington; and8Center for Neurobiology of Stress, Departments of Medicine and Psychiatry and Biobehavioral Sciences, David Geffen Schoolof Medicine at University of California, Los Angeles, California

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We provide a general framework for understanding func-tional gastrointestinal disorders (FGIDs) from a bio-psychosocial perspective. More specifically, we provide anoverview of the recent research on how the complex in-teractions of environmental, psychological, and biologicalfactors contribute to the development and maintenance ofFGIDs. We emphasize that considering and addressing allthese factors is a conditio sine qua non for appropriatetreatment of these conditions. First, we provide an over-view of what is currently known about how each of thesefactors—the environment, including the influence of thosein an individual’s family, the individual’s own psychologicalstates and traits, and the individual’s (neuro)physiologicalmake-up—interact to ultimately result in the generation ofFGID symptoms. Second, we provide an overview ofcommonly used assessment tools that can assist cliniciansin obtaining a more comprehensive assessment of thesefactors in their patients. Finally, the broader perspectiveoutlined earlier is applied to provide an overview of cen-trally acting treatment strategies, both psychological andpharmacological, which have been shown to be efficaciousto treat FGIDs.

Keywords: Adverse Life Events; Anxiety; Depression;Psychological Treatments.

Abbreviations used in this paper: ANS, autonomic nervous system; CBT,cognitive-behavioral treatment; FD, functional dyspepsia; FGID, functionalgastrointestinal disorder; FSS, functional somatic syndromes; GI,gastrointestinal; HPA, hypothalamoLpituitaryLadrenal; IBS, irritablebowel syndrome; SNRI, serotonin noradrenalin reuptake inhibitor; TCA,tricyclic antidepressant.

Most current article

© 2016 by the AGA Institute0016-5085/$36.00

http://dx.doi.org/10.1053/j.gastro.2016.02.027

Biopsychosocial Basis of the FunctionalGastrointestinal Disorders

It is generally accepted that functional gastrointestinaldisorders (FGIDs) result from complex and reciprocal in-teractions between biological, psychological, and socialfactors, rather than from linear monocausal etiopathoge-netic processes. This consensus report, based on anextensive critical literature review by a multidisciplinaryexpert committee, aims to provide a framework for

understanding FGID from a biopsychosocial perspective.Further, we emphasize why and how knowledge of thisbiopsychosocial framework is critical for assessment andtreatment of these difficult-to-treat disorders that ofteninduce uncertainty and frustration in caregivers and pa-tients alike. The many processes that are part of thesecomplex interactions of the individual’s physiology, psy-chology, and environment are illustrated in an overview ofthe biopsychosocial model of FGID (Figure 1) and describedfurther.

Environmental InfluencesChildhood environmental factors: parental beliefs

and behaviors. There is familial aggregation of childhoodFGID.1 Children of adult irritable bowel syndrome (IBS)patients make more health care visits than the children ofnon-IBS parents. This pattern is not confined to gastroin-testinal (GI) symptoms2 and holds for maternal andpaternal symptoms.3,4 Although there is ongoing researchinto a genetic explanation for these familial patterns, whatchildren learn from parents can make an even greatercontribution to the risk for developing an FGID thangenetics.5 The basic learning principle of positive rein-forcement or reward, defined as an event following somebehavior that increases the likelihood of that behavioroccurring in the future, is a likely contributor to how thiscan occur. Children whose mothers reinforce illness

Figure 1. Biopsychosocial Model of IBS. Genetic and environmental factors, such as early life experiences, trauma, and sociallearning, influence both the brain and the gut, which in turn interact bidirectionally via the autonomic nervous system and theHPA axis. The integrated effects of altered physiology and the person’s psychosocial status will determine the illnessexperience and ultimately the clinical outcome. Furthermore, the outcomes will in turn affect the severity of the disorder. Theimplication is that psychosocial factors are essential to the understanding of IBS pathophysiology and the formulation of aneffective treatment plan. Figure adapted from Drossman et al,109 with permission.

Figure 2. Associations between maternal reinforcement andparental IBS, and illness behavior. In addition to increasedreported severity, children whose mothers strongly reinforceillness behavior also experience more school absences thanother children. Figure adapted from Levy et al,6 withpermission.

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behavior experience more severe stomachaches and moreschool absences than other children6 (Figure 2). Inaddition, when parents were asked to show positive orsympathetic responses to their children’s pain in alaboratory, the frequency of pain complaints was higherthan when parents are instructed to ignore them.7 Finally, alarge randomized clinical trial of children with functionalabdominal pain found that cognitive-behavioral treatment(CBT) targeting coping strategies, as well as parents’ andchildren’s beliefs about, and responses to, children’s paincomplaints, induced greater baseline to follow-updecreases in pain and GI symptoms compared with aneducational intervention controlling for time andattention,8 and that this effect was mediated by changes inparents’ cognitions about their child’s pain.9

There is also a strong association between parentalpsychological status, particularly anxiety, depression, andsomatization, and children’s abdominal symptoms.4,10,11

This association could be occurring through modeling—children observing and learning to display the behaviorsthey observe, in this case, possibly heightened attention to,or catastrophizing about, somatic sensations. However, theeffect of parental traits on children’s symptoms could alsooccur through reinforcement. Parents with certain traits orbeliefs, such as excessive worry about pain, might paymore attention to, and thereby reward, somatic complaints.

Parents’ catastrophizing cognitions about their own painpredicted responses to their children’s abdominal pain thatencouraged illness behavior, which in turn predicted childfunctional disability.12

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Environmental stressors in childhood and adultlife. Adverse life events (including sexual, physical, andemotional abuse). Compared with controls, IBS patientsreport a higher prevalence of adverse life events in general,and physical punishment, emotional abuse, and sexualabuse in particular13; such history is related to FGIDseverity and clinical outcomes, such as psychologicaldistress, and daily functioning.14 This in turn leads toincreased health care seeking, which could explain thehigher association of abuse histories with GI illness inreferral centers compared with primary care.14 Population-based studies have led to more conflicting results with re-gard to the association between self-reported FGIDs andabuse history.15,16 Further, it should be noted that highfrequencies of childhood abuse (approaching 50%) are notunique to patients with FGID, as similar figures are found inpatients with non-GI functional somatic syndromes (FSS, eg,pelvic pain, headaches, and fibromyalgia).17

The onset of FGIDs has been associated with the expe-rience of severely threatening events, such as the breakup ofan intimate relationship. In one study, two-thirds of patientshad experienced such an event compared with one-quarterof healthy controls.18

Prospective studies have demonstrated that the experi-ence of stressful life events is associated with symptomexacerbation and frequent health care seeking among adultswith IBS.19,20 Chronic life stress is the main predictor of IBSsymptom intensity over 16 months, even after controllingfor relevant confounders.21

Finally, stress can affect FGID treatment outcomes—onestudy demonstrated that the presence of a single stressorwithin 6 months before participation in an IBS treatmentprogram was directly associated with poor outcomes andhigher symptom intensity at 16-month follow-up whencompared with patients without exposure to such astressor.22

Social support. Quality or lack of social support isrelated to many aspects of IBS.23 Patients report findingsocial support as a way to help overcome IBS.24 Relatedly,perceived adequacy of social support is associated with IBSsymptom severity, putatively through a reduction in stresslevels.25 However, negative social relationships marked byconflict and adverse interactions are more consistently andstrongly related to IBS outcomes than social support.23

Illustrative of the role of social support and clinicallyimportant, a supportive patient�practitioner relationshipsignificantly improved symptomatology and quality of life inpatients with IBS.26

Culture. Cultural beliefs, norms, and behaviors affectall aspects of what has been discussed in this section: in-teractions within the family, with other support systems,and the world at large. For more extensive discussion, seethe article in this issue regarding multicultural aspects ofFGIDs.

Psychological DistressPsychological distress is an important risk factor for the

development of FGIDs and, when present, can perpetuate or

exacerbate symptoms. Further, it affects the doctor�patientrelationship and negatively impacts treatment outcomes.However, psychological distress can also be a consequencerather than a cause of disease burden.

Comorbid anxiety and depression are independent pre-dictors of post-infectious IBS and functional dyspepsia (FD)but, at the same time, also occur as a consequence of bodilysymptoms and related quality of life impairment. Theabsence of formal psychiatric comorbidity does not excludea role of dysfunctional cognitive and affective processes notcaptured by the current psychiatric classification system(s)(in the sense of not reaching the threshold for a psychiatricdisorder or not being included in the classification system,eg, in the case of symptom-specific anxiety, which is relevantin the context of FGID but does not constitute a psychiatricdisorder).

Mood disorders. Overlap between depression andFGID is about 30% in primary care settings and slightlyhigher in tertiary care.27 Depression can impact the numberof functional GI symptoms experienced or the number ofFGID diagnoses.28,29 Suicidal ideation is present in between15% and 38% of patients with IBS, and has been linked tohopelessness associated with symptom severity, interfer-ence with life, and inadequacy of treatment.30 Comorbiddepression has been linked to poor outcomes, including highhealth care utilization and cost, functional impairment, poorquality of life, and poor treatment engagement andoutcomes.25,31

Anxiety disorders. Anxiety disorders are the mostcommon psychiatric comorbidity, occurring in 30%�50% ofFGID patients. They may initiate or perpetuate FGID symp-toms through their associated heightened autonomicarousal (in response to stress) or at the level of the brain,which can interfere with GI sensitivity and motor function.Vulnerability to anxiety disorders might share similarpathways as vulnerability to FGIDs, particularly withrespect to anxiety sensitivity, body vigilance, and ability totolerate discomfort.

Somatization, somatic symptom disorder, andfunctional somatic syndromes. The Diagnostic andStatistical Manual of Mental Disorders, 5th edition dis-carded the concept of somatization, originally defined as“a tendency to experience and communicate somaticsymptoms unaccounted for by pathological findings inresponse to psychosocial stress and seek medical help forit,”32 but often operationalized in a descriptive way,measuring somatization by simply quantifying the numberof (medically unexplained) symptoms, in favor of somaticsymptom disorder.33 In the new diagnostic category, so-matic symptoms may or may not be medically unex-plained, but are distressing and disabling and associatedwith excessive and disproportionate thoughts, feelings,and behaviors for more than 6 months.34 This approachshifts the experience of medically unexplained symptomsfrom (unconscious) manifestations of psychologicaldistress toward abnormal cognitive�affective processes(eg, excessive illness worry, body preoccupation, and hy-pochondriasis), both as contributors to, and consequencesof, symptoms.35

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Somatization is associated with GI sensorimotor pro-cesses, including gastric sensitivity and gastric emptying,symptom severity,36 and impaired quality of life in FD.37

Further, somatization is associated with health care useand predicts a poor response to treatment, includingincreasing one’s likelihood of discontinuing medication dueto perceived adverse effects.38 Therefore, assessing soma-tization by checking severity of multiple somatic symptomsremains clinically useful.

Somatization has been thought to explain the frequentextraintestinal symptoms of IBS, and the high co-occurrencebetween FGID and other FSS,39 and is a term that iscommonly used in the medical literature to refer to medi-cally unexplained syndromes (in parallel with the psychi-atric terminology outlined here). There is extensive overlapamong FSS—two-thirds of FGID patients experience symp-toms of other FSS, including interstitial cystitis, chronicpelvic pain, headaches, and fibromyalgia,40 independent ofpsychiatric comorbidity, but the question whether thedifferent FSS represent truly distinct disorders (“splitter”view) or different manifestations of a common underlyingpathophysiological process (“lumper” view) remains unre-solved at present and falls outside the scope of this article.

CognitiveLaffective processes. Overlapping psy-chological constructs, including health anxiety (gastroin-testinal) symptom-specific anxiety, attentional bias,symptom hypervigilance, and catastrophizing, have beenlinked to FGID independent of psychiatric comorbidity, andare important treatment targets for CBT (see PsychologicalTreatments section)41 (Figure 3). An overview of theseprocesses and their roles in FGID is provided in Table 1.

Mechanisms: The Neurophysiological Basis ofthe Biopsychosocial Model

Here we give an overview of the neurophysiologicalmechanisms that explain the link between psychologicalprocesses, psychiatric comorbidity, and FGID symptomsdescribed in the previous sections. Specifically, the criticalrole of bidirectional signaling mechanisms between the GItract and the central nervous system are discussed,including the central processes involved in modulation ofvisceral afferent signals and the influence of efferent outputof central stress and emotional�arousal circuits on motor,barrier, and immune functions of the GI tract. Finally, theemerging evidence on bidirectional communication betweenthe gut microbiota and the (emotional) brain is outlinedbriefly.

BrainLgut processing. The “brain�gut axis” is thebidirectional neurohumoral communication system be-tween the brain and the gut that is continuously signalinghomeostatic information about the physiological conditionof the body to the brain through afferent neural (spinal andvagal) and humoral “gut�brain” pathways.42 Under normalphysiological conditions, most of these interoceptive gut�brain signals are not consciously perceived. However, thesubjective experience of visceral pain results from theconscious perception of salient gut�brain signals inducedby noxious stimuli, which indicate a potential threat to

homeostasis, thereby requiring a behavioral response. In thebrain, [visceral afferent] interoceptive signals are processedin a homeostatic�afferent network (brainstem sensorynuclei, thalamus, posterior insula) and integrated with andmodulated by emotional�arousal (locus coeruleus, amyg-dala, subgenual anterior cingulate cortex) and cortical�modulatory (prefrontal cortex and anterior insula, peri-genual anterior cingulate cortex) neurocircuits. Key regionsin these emotional�arousal and cortical�modulatory cir-cuits project in a “top-down” fashion to brainstem areas,such as the periaqueductal gray and the rostral ventrolat-eral medulla, which, in turn, send descending projections tothe dorsal horn of the spinal cord, where pain transmissionis modulated (descending modulatory system) (Figure 4).Thus, [visceral] pain perception does not display a linearrelationship with the intensity of peripheral afferent input,but rather emerges from a complex psychobiological pro-cess whereby visceral afferent input is processed andcontinuously modulated by cognitive and affective circuitsat the level of the brain and through descending modulatorypathways. These mechanisms help understand the influenceof the cognitive and affective processes outlined in theprevious section on GI symptom perception in FGID pa-tients, as well as the therapeutic effect of interventionstargeting these processes, and constitute the basis for amodel of FGID as disorders of gut�brain signaling. Morespecifically, dysfunction of these modulatory systems mightallow physiological (non-noxious) stimuli to be perceived aspainful or unpleasant (visceral hypersensitivity), which canlead to chronic visceral pain and/or discomfort, hallmarksymptoms of FGID. The results of functional brain imagingstudies in FGID will be outlined and should be interpretedwithin this framework.

Functional gastrointestinal disorders. Behavioralstudies on psychosocial influences on perception ofgastrointestinal distension. The exact nature of the visceralhyperalgesia or hypersensitivity found in a substantialsubset of IBS and FD patients remains unclear. The conceptof “visceral hypersensitivity” is operationalized as lowerpain thresholds during visceral sensory testing, that is,reporting pain at lower pressures or volumes duringrepeated ascending inflations of a GI balloon catheter.However, as we have outlined, it is becoming increasinglyclear that psychological processes and psychosocial factorscan influence visceral perceptual sensitivity.

Several studies suggest that an increased psychologicaltendency to report pain, which can be driven by hypervig-ilance, underlies the decreased pain thresholds in IBS pa-tients, rather than increased neurosensory sensitivity.43

Studies on the effects of stressors on perception of colo-rectal distention in healthy subjects and IBS patients haveproduced somewhat inconsistent findings, due to variationsamong the stressors used or potential confounders, such asdistraction. However, a study that controlled for distractiondemonstrated that IBS patients, but not healthy subjects,rated rectal distension more intense and unpleasant duringdichotomous listening stress compared with relaxation.44

In addition, anxiety and depression levels are associatedwith increased pain ratings but not increased rectal

Figure 3.Gastrointestinal-symptom specific anxiety: when normal becomes threatening. Gastrointestinal symptom-specificanxiety is an important perpetuating factor of FGID and is characterized by worry and hypervigilance around GI sensationsthat can range from normal bodily functions (hunger, satiety, gas) to symptoms related to an existing GI condition (abdominalpain, diarrhea, urgency). The worry and hypervigilance usually generalize into fear regarding the potential for sensations orsymptoms to occur and/or the contexts in which they may be most likely to present. Gastrointestinal symptom-specific anxietycan result in avoidance and behaviors out of proportion to symptoms.

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sensitivity in IBS.45 Further, several studies have demon-strated a relationship between psychosocial status on theone hand, and gastric discomfort thresholds or symptomreporting in FD on the other.46 In the next section, we willdiscuss the emerging evidence from functional brain imag-ing studies clarifying the mechanisms underlying thesepsychological influences on rectal sensitivity in IBS.

Visceral stimulation studies. A recent meta-analysis ofrectal distension studies demonstrated that IBS patientsshowed greater brain responses than healthy subjects inhomeostatic�afferent brain regions. Further, IBS patientsshowed engagement of emotional�arousal regions thatlacked consistent activity in healthy subjects and lessinvolvement of key cortical�modulatory regions.47 Thisresponse pattern is consistent with the increased sympa-thetic arousal, anxiety, and vigilance often associated withIBS. Similarly, FD patients activate homeostatic�afferentand sensory brain regions at significantly lower intragastricballoon pressures than healthy controls, with these lower-intensity levels of gastric stimulation, inducing similarlevels of perception (gastric hypersensitivity). During pain-ful gastric distension, FD patients did not activate the per-igenual anterior cingulate cortex, a key region of thedescending modulatory system, and this lack of activationwas correlated with anxiety levels.48

A few studies have also examined the brain response toanticipation of a visceral stimulus in both healthy subjectsand IBS patients. In IBS patients, the anticipatory responsein the locus coeruleus is predictive of both the subjectiveand brain response to subsequent noxious rectal disten-tion.49 In FD, during anticipated gastric distension, patientsfail to deactivate the amygdala, a key emotional arousal

region involved in pain modulation, which is paralleled byhigher pain ratings during anticipation.48

Taken together, these results are consistent with themodel of FGID as disorders of gut�brain signaling outlinedhere: anxiety-related impairment of the descending modu-latory system causes defective sensory filtering, dependenton which physiological levels of gastric distension areperceived as painful.

Brain networks. Compared with healthy subjects, IBSpatients show up-regulated connectivity within theemotional�arousal circuitry, and altered serotonergicmodulation of this circuitry appears to play a role in visceralhypersensitivity in female IBS patients.50 Additionally, theimportance of descending pain modulatory circuitry hasbeen demonstrated in IBS patients and healthy controls.51

Structural imaging. IBS is associated with decreasedgray matter density in cortical�modulatory prefrontal andparietal regions, as well as in emotional circuits.52 Control-ling for anxiety and depression, several of the affective re-gions no longer differed between IBS patients and controls,whereas the differences in prefrontal and posterior parietalcortices remained. These findings are consistent with theclose relationship of IBS to mood disorders. In anotherstudy, pain catastrophizing was negatively correlated withdegree of cortical thickness in the prefrontal cortex.53

Similarly, gray matter density in sensory and homeo-static�afferent regions, as well as cortical pain modulatoryareas is decreased in FD patients compared with healthycontrols, and most of these differences disappear whencontrolling for anxiety and depression scores.54

It remains unknown whether these changes are pre-existing risk factors for disease or whether they are

Table 1.Cognitive�Affective Processes Influencing the Symptom Experience in Functional Gastrointestinal Disorders

Term Definition Association with FGID Outcomes Management

Illness anxiety Global tendency to worry aboutcurrent and future bodilysymptoms, formerly referred to ashypochondriasis

Low insightExtensive research into what is wrongNot easily reassured,Lack of acceptanceRisk factor for development of FGID

ChronicitySocial dysfunction, occupational

difficulties,High health costs,Negative doctor�patient relationship,Poor treatment response

Responsive to CBT

Symptom-specificanxiety

Worry/hypervigilance around thelikelihood/presence of specificsymptoms and the contexts inwhich they occur

Belief that normal gut sensations areharmful or will lead to negativeconsequences

Promotes GI symptoms

Drives health care useNegatively impacts treatment

response

Aerophagia improved with distractionMay be differentially responsive to

interoceptive exposure-basedbehavior therapy

Hypervigilance/attentional bias

Altered attention toward, andincreased engagement with,symptoms and reminder ofsymptoms

IBS patients showed higher recall ofpain words and GI wordscompared with healthy controls

NCCP patients hypervigilant towardcardiopulmonary sensations

Dismiss signs of improvementIgnore information suggesting that

their FGID is not serious

Responsive to CBT

Catastrophizing 2-pronged cognitive process in whichan individual magnifies theseriousness of symptoms andconsequences whilesimultaneously viewingthemselves as helpless

Results in symptom amplificationIncreased painInhibits pain inhibitionNegatively affects interpersonal

relationshipsLeads to increased worry, suffering,

disability

High symptom reportingReduced quality of lifeCan impact patient self-reportBurdens provider

Improves with CBTMediates outcome

NCCP, noncardiac chest pain.

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Figure 4. Overview of pathways through which psychological processes exert their role in functional gastrointestinal disorders.The “emotional motor system” consists mainly of subcortical and brain stem areas (amygdala, hypothalamus, and peri-aqueductal gray matter) that are crucial in relaying descending modulatory output from affective and cognitive cortical cir-cuitry, as well as regulating autonomic and HPA axis output. CRF, corticotrophin-releasing factor. Figure adapted from VanOudenhove and Aziz46 and Naliboff and Rhudy,110 with permission.

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secondary changes, and what the underlying biologicalsubstrates are.

Resting state functional imaging. Female IBS subjectshave greater high-frequency power in the insula and low-frequency power in the sensorimotor cortex than male IBSsubjects during task-free rest. Correlations were observedbetween resting-state activity and IBS symptoms.55 Itshould be emphasized, however, that these new findings,although interesting, are preliminary. Specifically, it remainsto be determined whether these findings are specific to IBS,or a feature of FSS in general, and to what extent thesechanges are driven by comorbid psychiatric disorders.

In FD, using 18F-fluorodeoxyglucose positron-emissiontomography, increased activity was found in homeo-static�afferent and sensory regions, but also in the peri-genual anterior cingulate cortex, a key pain modulatoryarea. The activity in the homeostatic�afferent regionscorrelated with dyspepsia symptom levels.56 Further, FDpatients with comorbid anxiety and depression are charac-terized by altered activity in homeostatic�afferent andsensory regions, as well as a number of other regionscompared with patients without such comorbidity.57 Usingradioligand positron-emission tomography, highercannabinoid-1 receptor availability was found in FDcompared with matched controls, in virtually all of theseregions, indicating that altered endocannabinoid function

can underlie the differences in resting state brain activityfound in FD.58 Several recent resting-state functional mag-netic resonance imaging studies in FD demonstrated alteredfunctional connectivity at rest, including in the “defaultmode network”59 (a set of coherent brain processes inmedial prefrontal, temporal, and parietal regions that isactive during self-referential and reflective activity at rest,without attention being allocated to a particular intero- orexteroceptive stimulus), pain modulatory networks, as wellas homeostatic�afferent circuits. The dysfunctional con-nectivity patterns correlate with dyspepsia symptomseverity, as well as comorbid anxiety and depressionlevels.60

Taken together, these findings indicate that patients withIBS and FD are not only characterized by abnormal brainresponses to visceral pain stimuli, but also by abnormalbrain activity and connectivity at rest. These abnormalitiesseem to be at least partly related to comorbid anxiety anddepression.

White matter tract imaging. IBS patients have whitematter tract alterations in multiple areas, including thal-amus basal ganglia and sensory/motor association/inte-gration regions compared with healthy controls.61 Anotherstudy showed that white matter changes in IBS are relatedto symptom severity and psychological variables of traitanxiety and catastrophizing.62 Zhou et al63 demonstrated

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abnormalities in a number of white matter tracts in FDpatients vs healthy controls, but again, most of these dif-ferences were accounted for by comorbid anxiety anddepression.63

Psychosocial influences on gut function throughefferent output of central emotionalLarousalcircuits. Brain�gut interfaces: the autonomic nervousand stress-hormone systems. In addition to their modu-latory influences on the processing of visceral afferentinput, psychological processes and distress can influencevarious aspects of GI function through efferent brain�gutpathways. More specifically, emotional�arousal braincircuits control output of the efferent autonomicnervous system (ANS) (ortho/parasympatheticbalance) as well as the stress hormone system(hypothalamo�pituitary�adrenal [HPA] axis), both ofwhich can alter GI motor, immune, or barrier function,which can in turn influence visceral afferent signaling.The “emotional motor system,” consisting of keysubcortical nodes of the emotional�arousal circuit(hypothalamus, amygdala, and periaqueductal gray)plays a key role in these processes64 (Figure 4). Thecorticotrophin-releasing factor transmitter system, bothcentrally (at the level of the dorsal motor nucleus of thevagus, hypothalamus, and amygdala) and peripherally(at the level of the GI tract/enteric nervous system), is ofmajor importance here as it influences autonomicoutflow as well as stimulates the HPA axis resulting inadrenocorticotropic hormone and cortisol secretion.65

Studies of stress influences on motor, barrier,and immune functions of the gastrointestinaltract. Gastric motility. Evidence on the influence of stresson gastric motility is mixed, although most older studiespoint toward a stress-induced reduction in antral motilityand/or gastric emptying.46 More recent studies demon-strated impairment of gastric accommodation during exper-imentally induced anxiety in healthy subjects,66 as well as anassociation between both state anxiety and comorbid anxietydisorders and impaired accommodation in FD.58

Colonic motility. IBS patients show exaggerated motilityresponses to physical and psychological stress, as well asintravenous injection of corticotrophin-releasing factor.67 Acritical role for motility disturbances in producing symp-toms, especially pain, in a majority of IBS patients has,however, not been clearly demonstrated, except for stoolfrequency and consistency,68 abdominal distension, anddissatisfaction with bowel movements.69

Colonic mucosal permeability and low-grade mucosaland systemic inflammation. A subset of IBS patients (notlimited to post-infectious IBS) are characterized by impairedcolonic mucosal integrity and low-grade mucosal and evensystemic inflammation. These alterations, although notconfirmed in all studies, may be related to rectal hyper-sensitivity and pain symptom levels.70 Animal studies havedemonstrated the influence of stress on colonic perme-ability, as well as mucosal and systemic inflammation,mediated by the ANS (eg, the vagal efferent cholinergic anti-inflammatory pathway) and HPA axis.71 In humans, indirectevidence comes from studies in IBS linking HPA axis

hyperactivity (cross-sectionally) to increased systemicinterleukin 6 levels.72 Anxiety and depression levels havebeen linked to production of tumor necrosis factor�a andother pro-inflammatory cytokines,73,74 as well as to numberof mast cells in the mucosa.75 In addition, psychologicalmorbidity or stressful life events at the moment of acutegastroenteritis predict the development of post-infectiousIBS, although this has not been confirmed in all studies.76

Finally, both public speech stress and intravenous injec-tion of corticotrophin-releasing factor increase small intes-tinal permeability through activating the HPA axis (and/orinfluencing ANS outflow), in a mast cell-dependentfashion.77

Autonomic nervous system and hypothalamoLpituitaryLadrenal axis function in functionalgastrointestinal disorders. Autonomic nervous sys-tem. There is only limited support for robust differences inautonomic function measured using cardiovascular (eg,heart rate variability) or circulating (eg, catecholamine)indices of sympathetic and parasympathetic function, bothat rest and in response to stress, between patients withFGID and healthy controls. The evidence suffers from limi-tations, including small sample sizes not allowing conclu-sions on subgroups or sex differences, inappropriate controlof confounders, and reliance on non-GI measures. However,autonomic dysregulation does seem to occur in subgroupsof patients and might influence various processes relevantto FGID pathophysiology.78–80

Hypothalamic-pituitary-adrenal axis. Similarly, there islimited evidence for robust alterations in HPA-axis functionin FGID, but there are suggestions that some aspects of HPAfunction might be compromised in some IBS subgroups,especially under stressful conditions.81–85

Microbiome�Gut�Brain AxisThe microorganisms in the gut (gut microbiota) engage

in bidirectional communication with the brain via neural,endocrine, and immune pathways with significant conse-quences for behavioral disorders, including anxiety,depression, and cognitive disorders, as well as chronicvisceral pain.86 Although much of what is known in this areais based on animal studies, there is also a small, but growingnumber of relevant human studies. For example, in initialstudies, IBS symptoms have been associated with alter-ations in microbiota composition (although larger studiesallowing to control for more potential confounders areclearly needed),87 probiotics have shown promise in treat-ing symptoms in IBS,88 and deficiency in Bifidobacteria hasbeen associated with greater abdominal pain and bloating ina healthy population.89 In addition, administration of aprobiotic alters central processing of emotional stimuli, aswell as resting brain connectivity in sensory and affectivebrain circuits.90

Based on these findings, the hypothesis of amicrobiome�gut�brain axis is emerging, with the possi-bility that modulation of the gut microbiota may be a targetfor new therapeutics for stress and pain-related disorders,including FGID.

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Psychosocial AssessmentClinical Assessment

Psychosocial assessment is a critical part of patient carein FGID. As a general rule, primary care clinicians and gas-troenterologists should approach psychosocial assessmentfrom a screening perspective with the goal to identify pa-tients at risk for refractory symptoms, poor treatmentresponse or low quality of life. In the absence of frankpsychopathology and moderate to severe symptoms, onemight also assess visceral-specific anxiety, catastrophizing,somatization, and quality of life to determine whether acomprehensive evaluation by a health psychologist or psy-chiatrist would be indicated.

We suggest that clinicians include a brief psychosocialassessment of each FGID patient, in addition to a fullclinical assessment of the presenting symptoms. This re-quires a satisfactory patient�doctor relationship, estab-lished during the early part of the consultation, and a fewspecific questions about key psychosocial processes inte-grated into routine history taking. If the patient queriesthe relevance of these questions, the clinician can truth-fully respond, “I always ask my patients these questions aspart of my initial assessment—it helps me determine thebest way to help. The items may or may not apply to you.”This psychosocial assessment will only be satisfactory ifthe patient is able to speak freely, which requires privacy,a lack of judgment or stigma, and sufficient time. Sensitiveareas of discussion include abuse history, depressedmood, possible suicidal thoughts, and the nature of closerelationships. Sometime these require a second appoint-ment directed toward this area of assessment. In addition,the clinician should provide feedback about the results ofthe entire evaluation and to discuss treatment plans,which can involve both medical and psychosocial treat-ment strategies.

A more detailed psychosocial assessment, preferably bya [health] psychologist, [consultation-liaison] psychiatrist,or specially trained gastroenterologist or other clinician isparticularly useful for severe symptoms, previous treatmentfailure, poor adherence to a treatment regimen, and markeddisability. Our recommended assessment and treatmentflowchart is also included as Supplementary Table 1A(overview) and 1B (detailed steps) and guidelines and flagsfor mental health professional involvement are shown inSupplementary Table 2.

Questionnaires can enhance the information obtainedat the clinical interview, but not replace it. Further,questionnaires only provide meaningful information ifthey are reliable (consistent), valid (measure what theyare supposed to measure), and free of potentialresponse biases. However, although these psychometricproperties have been established in many populationsfor a given questionnaire, they might not have beentested in specific FGID populations. The clinician shouldbe acquainted with the results and interpretation ofsuch questionnaires and a close working relationshipwith a mental health professional is helpful in thisrespect.

Assessment Tools in Adult PatientsAn overview of key areas for psychosocial assessment

in adult patients is given in Supplementary Table 3. Addi-tional standardized self-report questionnaires are listed inSupplementary Table 4.

Assessment Tools in Children and Their ParentsAn overview of key areas for psychosocial assessment in

children and their parents is given in SupplementaryTable 3. Additional standardized self-report questionnairesare listed in Supplementary Table 4.

Structured InterviewsDetails on recommended tools for assessment of the

different psychosocial domains outlined earlier are providedin the Supplementary Material.

TreatmentPsychological Treatments

Rooted in the biopsychosocial model of FGID and itsbiological basis outlined earlier, psychological treatmentshold that biological factors work in concert with psycho-logical and social variables to influence the expression ofsymptoms and their impact on other health outcomes (eg,quality of life and health care use). As such, psychologicaltreatments aim to tackle the environmental and psycho-logical processes that aggravate symptoms. The mostcommonly studied psychological treatments for FGID areCBT, psychodynamic psychotherapy, and hypnosis. A briefoverview is given in Supplementary Table 4.

Cognitive-behavior therapy. CBT refers to a family ofpsychological treatments rather than a specific or uniformset of techniques. The rationale and techniques of CBT drawfrom behavior theories that emphasize learning processesand cognitive theory that emphasizes faulty cognitions orthinking processes. These same learning processes can beused to help patients gain control and reduce symptoms ofFGID.91 Cognitive theory views external events, cognitions,and behavior as interactive and reciprocally related. Assuch, each component is capable of affecting the others, butthe primary emphasis is the way patients process informa-tion about their environment. Cognitive factors, especiallythe way people interpret or think about stressful events, canintensify the impact of events on responses beyond theimpact of events themselves (Figure 3). To the extent thatthinking processes are faulty, exaggerated, and biased, pa-tients’ emotional, physiological, and behavioral responses tolife events will be problematic. Clinically, this means thatmodifying their thinking styles can change the way patientsbehave and feel both emotionally and physically. Thesecognitive changes can occur by teaching patients to sys-tematically identify cognitive errors or faulty logic broughtabout by automatic thinking or providing experientiallearning opportunities that systematically exposes patientsto the situations that cause discomfort.

Rather than focusing on the root causes of a problem,like traditional “talk therapy,” CBT focuses on teaching

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people how to control their current difficulties and what ismaintaining them. Further, because CBT is a more directivetherapy, the therapist plays a more active role. CBT re-quires active participation of the patient both during andbetween sessions, as well as responsibility for learningsymptom self-management skills. In addition, CBT is moreproblem-focused, goal-directed, and time-limited (3�12hourly sessions). In the case of FGID, CBT includes a com-bination of techniques including self-monitoring, cognitiverestructuring, problem solving, exposure, and relaxationmethods.

Self-monitoring. Self-monitoring is the ongoing, real-time recording of problem behaviors. In CBT for IBS, self-monitoring focuses on internal and external triggers, aswell as thoughts, somatic sensations, and feelings thattypically accompany flareups. In addition to providing a richsource of clinically relevant information to structure treat-ment, self-monitoring comprises a useful therapeutic strat-egy because it increases awareness of the determinants of apatient’s problem.

Cognitive strategies. Cognitive strategies are designedto modify thinking errors that bias information processing.Examples include a tendency to overestimate risk and themagnitude of threat, or underestimate one’s own ability tocope with adversity if it were to occur.40 These self-defeating beliefs are clinically important because they arebelieved to moderate excessive stress experiences. Oncethese negative beliefs are identified, the patient works withthe therapist to challenge and dispute them by examiningtheir accuracy in light of available evidence for and againstthem, and replacing these beliefs with those that are morelogical and constructive.

Problem-solving. Problem-solving refers to an ability todefine problems, identify solutions, and verify their effec-tiveness once implemented.92 As an intervention, it is rootedin a problem-solving model of stress93 that emphasizes thecausal relationship between how people problem solvearound stressors and their health. Therapists teach patientshow to effectively apply the steps of problem solving,including identifying problems, generating multiple alter-native solutions (“brainstorming”), selecting the best solu-tion from the alternatives, developing and implementing aplan, and evaluating the efficacy.

Relaxation procedures. Relaxation procedures havelong been a staple of psychological treatments for FGID94

and are designed to directly modify the biological pro-cesses (eg, autonomic arousal) that are believed to aggra-vate GI symptoms.

Progressive muscle relaxation training consists of sys-tematic tensing and relaxing selected muscle groups of thewhole body; it presumably helps patients dampen physio-logical arousal and achieve a sense of mastery of physio-logical self-control over previously uncontrollable andunpredictable symptoms.95

In breathing retraining, the patient is taught to take slowdeep breaths and attend to relaxing sensations duringexhalation. This relaxation procedure is based on theassumption96 that patients with stress-related physical ail-ments develop inefficient respiratory patterns (eg, shallow

chest breathing) which, if chronic, can intensify physiolog-ical arousal that aggravates somatic complaints.

Meditation is a self-directed practice that emphasizesfocused breathing, selective attention to a specially chosenword, set of words, or object, and detachment from thoughtprocesses to achieve a state of calmness, physical relaxation,and psychological balance. One type of meditation featuredin the FGID literature is mindfulness meditation,97 where anindividual disengages him/herself from ruminativethoughts, which are regarded as core aspects of pain andsuffering, by developing a nonreactive, objective, present-focused approach to internal experiences and externalevents as they occur.98

Hypnosis. In hypnosis,99 a therapist typically induces atrance-like state of deep relaxation and/or concentrationusing strategically worded verbal cues suggestive ofchanges in sensations, perceptions, thoughts, or behavior.Most hypnotic suggestions are designed to elicit feelings ofimproved relaxation, calmness, and well-being. In thecontext of IBS, hypnotic suggestions are “gut directed,” thatis, the therapists convey suggestions for imaginative expe-riences incompatible with aversive visceral sensation. Hyp-nosis for a patient with IBS might include a suggestion thatthe patient feel a sense of warmth and comfort spreadingaround the abdominal area.

Exposure. Exposure treatments are designed toreduce catastrophic beliefs about IBS symptoms, hyper-vigilance to IBS symptoms, fear of IBS symptoms, andexcessive avoidance of unpleasant visceral sensations orsituations100 by helping patients confront them in a sys-tematic manner. Exposure can include interoceptive cueexposure in which the patient repeatedly provokes un-pleasant sensations, or situational or in vivo exposure inwhich feared situations or activities are confronted. Thebasic idea behind exposure interventions is that the mosteffective way to overcome a fear is by facing it head on sothat the natural conditioning (learning) processesinvolved in fear reduction (habituation and extinction) canoccur. Without therapeutic assistance, the individualwithdraws from fear-inducing situations, thereby inad-vertently reinforcing avoidance. Through exposure treat-ments, patients learn that the stimuli that are a source offear and avoidance are neither dangerous nor intolerableand that fear will subside without resorting to avoidance,a behavior that reinforces fear and hypervigilance in thelong-term.101

Efficacy of psychological treatments. Two meta-analyses102,103 have concluded that psychological therapies,as a class of treatments, are at least moderately effective forrelieving symptoms of IBS when compared with a pooledgroup of control conditions. One measure of clinical efficacyis the numbers needed to treat, referring to the number ofpatients needed to be treated to achieve a specific outcome,such as a 50% reduction in GI symptoms. Numbers neededto treat of 2 and 4 were found in both meta-analyses.Ljótsson and colleagues104 have used the Internet as aplatform for delivering treatment to a larger proportion ofFGID patients than would have had access to clinic-basedtreatments.

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Is the Patient a Good Candidate forPsychological Treatments?

Characteristics to guide decision making about whichpatients are likely to benefit from psychological treatmentsare provided in the Supplementary Material.

Pharmacological Treatment. We recognize and haveacknowledged that there is limited evidence from random-ized controlled trials in gastroenterology for some of theagents discussed here. However, we have relied onevidence-based data from other related pain disorders, aswell as on the consensus of experts in this field to providetheir best current recommendations for practice.

Mechanism of action of centrally acting agents infunctional gastrointestinal disorder. There are several(not mutually exclusive) putative mechanisms of actionexplaining the therapeutic effects of antidepressants andother centrally acting agents in the treatment of FGID inadults, including effects on gut and/or ANS physiology, andcentral analgesic effects, which may or may not be inde-pendent of anxiolytic and antidepressant effects.

Further details on the mechanisms of action of psycho-tropic drugs in FGID are also described elsewhere in this issue.

Clinical considerations for the use of psychotro-pic medications in functional gastrointestinal dis-orders. Although antidepressants are used extensively,they are still considered “off label” for their use in FGID. Theaccumulated clinical experience, lack of other effectivetreatment options, and evidence from other FSS, such asfibromyalgia, make them viable options for treating painand improving quality of life in FGID. In general, they shouldbe reserved for patients with moderate to severe diseaseseverity, with significant impairment of quality of life, andwhere other first-line treatments have not been sufficientlyeffective.

Choice of agent. Choice of agent is determined by thepatient’s predominant symptoms, disease severity, presenceof comorbid anxiety or depression, prior experience withmedications in the same class, and patient and prescriberpreference.

In general, tricyclic antidepressants (TCAs) are the firstchoice for pain in nonconstipated IBS patients due to theirdual mechanism of action (serotonin and noradrenalinreuptake inhibition). Nortriptyline or desipramine isgenerally better tolerated than amitriptyline or imipraminedue to less anti-histaminergic and anti-cholinergic effects.The usual starting dose is 25�50 mg at night and can betitrated up as needed up to about 150 mg/d, while care-fully monitoring side effects and/or blood levels, althoughtypically lower doses than the full antidepressant dose areeffective for visceral pain if no psychiatric comorbidity ispresent. Because selective serotonin reuptake inhibitorsare less effective for pain, they are not commonly used asmonotherapy. Rather, selective serotonin reuptake in-hibitors are a useful augmentation agent in combinationwith other drugs, such as serotonin noradrenalin reuptakeinhibitors (SNRIs) or TCAs, or when the patient has a highlevel of anxiety that is contributing directly to their clinicalpresentation. The selective serotonin reuptake inhibitorsand SNRIs have a more narrow therapeutic range and

therefore the doses used for the treatment of pain arecloser to the doses used to treat mood and anxiety disor-ders.105 Starting doses are usually within the lower rangeof the psychiatric dose (eg, citalopram 20 mg or duloxetine30 mg) and titrated up as needed. For SNRIs, especiallyvenlafaxine, the analgesic effect usually requires higherdoses (�225 mg) because the noradrenergic mechanism ofaction only kicks in at these doses. If nausea and weightloss are of concern, the addition of a low dose (15�30 mg)of mirtazapine can be helpful. Atypical antipsychotics, suchas quetiapine, are only recommended for patients withsevere, refractory IBS, especially if severe anxiety andsleep disturbances are also present and patients havefailed to respond to other centrally acting agents. A lowstarting dose of 25�50 mg is recommended and can betitrated up as required.106,107

Augmentation. Augmentation, that is, the use of acombination of drugs from different classes in submaximaldoses instead of one drug at a maximal dose, is common inpsychiatry and increasingly used in FGID. Examples ofaugmentation include adding buspirone to an selective se-rotonin reuptake inhibitor, TCA, or SNRI to enhance theirtherapeutic effect, or adding a low-dose antipsychotic (eg,quetiapine) to a TCA or SNRI to reduce pain and anxiety andimprove sleep.106 If there is a component of abdominal wallpain associated with the GI pain, pregabalin or gabapentincan be added to a TCA or SNRI.106

Adherence. Careful patient selection, initiation at a lowdose with gradual escalation, monitoring for side effects,and a good patient�doctor relationship are important formedication adherence and, therefore, therapeutic response.In particular, eliciting and addressing any potential con-cerns/barriers to taking psychotropic medications for FGID,discussing potential side effects, setting realistic expecta-tions, and involving the patient in decision making result inimproved adherence.107

Centrally acting agents and psychological treat-ments. Centrally acting agents and psychological treat-ments are often used together for their complementary andsynergistic effects; such combination is recommended whenthe FGID is severe and associated with anxiety or depres-sion comorbidity.106

Although drugs work faster and are readily available,psychological treatments have several advantages: they aresafe, effective, their effects persist beyond the duration ofthe treatment, and they may be more cost-effective.108

Limitations of using psychological treatments are longertreatment duration and need for patient motivation, as wellas availability and access to a mental health professionaltrained in FGID treatment.

ConclusionsIn this article, we provided a comprehensive overview of

recent research to improve understanding of the complexinteractive biopsychosocial processes that constitute thepathophysiology of FGID. In addition, we outlined the clin-ical tools and practices health care practitioners can utilizeto improve assessment and treatment of these disorders.

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Further research is needed to expand this knowledge base,which will foster the development of novel, more efficacioustreatments that are more efficiently delivered as well asbetter tailored to individual patients.

Supplementary MaterialNote: The first 50 references associated with this article areavailable below in print. The remaining references accom-panying this article are available online only with the elec-tronic version of the article. To access the supplementarymaterial accompanying this article, visit the online versionof Gastroenterology at www.gastrojournal.org, and at http://dx.doi.org/10.1053/j.gastro.2016.02.027.

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Reprint requestsAddress requests for reprints to: Rona L. Levy, MSW, PhD, MPH, BehavioralMedicine Research Group, University of Washington, Mailstop 354900, 410115th Ave NE, Seattle, Washington 98195. e-mail: rlevy@u.washington.edu;fax: (425) 488-3616.

AcknowledgmentsThe authors would like to thank Jerry Schoendorf for his help with making andadapting the figures.

Conflicts of interestThese authors disclose the following: Albena Halpert is on the advisory boardof Allergan; Michael Crowell is a consultant for Medtronic-Covidien and Salix.The remaining authors disclose no conflicts.

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