Functional gastrointestinal disorders (FGID), also known as disorders of gut–brain interaction, include a number of separate

idiopathic An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. For some medical conditions, one or more causes are somewhat understood, but in a certain percentage of people with the condition, the cause ...

disorders which affect different parts of the

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...

and involve

visceral hypersensitivity Visceral pain is defined as pain that results from the activation of nociceptors of the thoracic, pelvic, or abdominal viscera (organs) in the human body. Visceral structures are highly sensitive to distension (stretch), ischemia and inflammation, ...

and

motility Motility is the ability of an organism to move independently using metabolism, metabolic energy. This biological concept encompasses movement at various levels, from whole organisms to cells and subcellular components. Motility is observed in ...

disturbances.

Definition

Using the Delphi method, the Rome Foundation and its board of directors, chairs and co-chairs of the ROME IV committees developed the current definition for disorders of gut-brain interaction. A group of disorders classified by GI symptoms related to any combination of: * Motility disturbance *

Visceral hypersensitivity Visceral pain is defined as pain that results from the activation of nociceptors of the thoracic, pelvic, or abdominal viscera (organs) in the human body. Visceral structures are highly sensitive to distension (stretch), ischemia and inflammation, ...

* Altered mucosal and immune function * Altered

gut microbiota Gut microbiota, gut microbiome, or gut flora are the microorganisms, including bacteria, archaea, fungi, and viruses, that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the g ...

* Altered

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

(CNS) processing

Classification

Terms such as ''functional colonic disease'' (or ''functional bowel disorder'') refer in medicine to a group of

bowel The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. T ...

disorders which are characterized by chronic abdominal complaints without a structural or biochemical cause that could explain symptoms. Other ''functional'' disorders relate to other aspects of the process of

digestion Digestion is the breakdown of large insoluble food compounds into small water-soluble components so that they can be absorbed into the blood plasma. In certain organisms, these smaller substances are absorbed through the small intestine into th ...

. The consensus review process of meetings and publications organised by the Rome Foundation, known as the Rome process, has helped to define the functional gastrointestinal disorders. Successively, the Rome I, Rome II, Rome III and Rome IV proposed consensual classification system and terminology, as recommended by the Rome Coordinating Committee. These now include classifications appropriate for adults, children and neonates/toddlers. The current ROME IV classification, published in 2016, is as follows: A. Esophageal disorders * A1. Functional

chest pain Chest pain is pain or discomfort in the chest, typically the front of the chest. It may be described as sharp, dull, pressure, heaviness or squeezing. Associated symptoms may include pain in the shoulder, arm, upper abdomen, or jaw, along with n ...

* A2. Functional heartburn * A3.

Reflux Reflux is a technique involving the condensation of vapors and the return of this condensate to the system from which it originated. It is used in industrial and laboratory distillations. It is also used in chemistry to supply energy to Chemical ...

hypersensitivity * A4. Globus * A5. Functional

dysphagia Dysphagia is difficulty in swallowing. Although classified under " symptoms and signs" in ICD-10, in some contexts it is classified as a condition in its own right. It may be a sensation that suggests difficulty in the passage of solids or l ...

B. Gastroduodenal disorders * B1. Functional dyspepsia ** B1a. Postprandial distress syndrome (PDS) ** B1b. Epigastric pain syndrome (EPS) * B2. Belching disorders ** B2a. Excessive supragastric belching ** B2b. Excessive gastric belching * B3.

Nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

and

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

disorders ** B3a. Chronic nausea vomiting syndrome (CNVS) ** B3b. Cyclic vomiting syndrome (CVS) ** B3c. Cannabinoid hyperemesis syndrome (CHS) * B4.

Rumination syndrome Rumination syndrome, or merycism, is a chronic motility disorder characterized by effortless regurgitation of most meals following consumption, due to the involuntary contraction of the muscles around the abdomen. There is no retching, nausea, ...

C. Bowel disorders * C1.

Irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating, and changes in the consistency of bowel movements. These symptoms may ...

(IBS) ** IBS with predominant constipation (IBS-C) ** IBS with predominant diarrhea (IBS-D) ** IBS with mixed bowel habits (IBS-M) ** IBS unclassified (IBS-U) * C2. Functional

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

* C3. Functional

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

* C4. Functional abdominal

bloating Abdominal bloating (or simply bloating) is a short-term disease that affects the gastrointestinal tract. Bloating is generally characterized by an excess buildup of gas, air or fluids in the stomach. A person may have feelings of tightness, pressu ...

/distension * C5. Unspecified functional bowel disorder * C6. Opioid-induced constipation D. Centrally mediated disorders of gastrointestinal pain * D1. Centrally mediated abdominal pain syndrome (CAPS) * D2. Narcotic bowel syndrome (NBS)/ Opioid-induced GI hyperalgesia E. Gallbladder and sphincter of Oddi disorders * E1. Biliary pain ** E1a. Functional

gallbladder In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow Organ (anatomy), organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath t ...

disorder ** E1b. Functional biliary

sphincter of Oddi The sphincter of Oddi (SO) (also hepatopancreatic sphincter or Glisson's sphincter), is a sphincter, a muscular valve that, in humans and some animals, controls the flow of bile and pancreatic juice out of the gallbladder and pancreas respective ...

disorder * E2. Functional pancreatic sphincter of Oddi disorder F. Anorectal disorders * F1.

Fecal incontinence Fecal incontinence (FI), or in some forms, encopresis, is a lack of control over defecation, leading to involuntary loss of bowel contents—including flatus (gas), liquid stool elements and mucus, or solid feces. FI is a sign or a symptom ...

* F2. Functional anorectal pain ** F2a.

Levator ani The levator ani is a broad, thin muscle group, situated on either side of the pelvis. It is formed from three muscle components: the pubococcygeus, the iliococcygeus, and the puborectalis. It is attached to the inner surface of each side of the ...

syndrome ** F2b. Unspecified functional anorectal pain ** F2c.

Proctalgia fugax Proctalgia fugax, a variant of levator ani syndrome, is a severe, episodic pain in the regions of the rectum and Human anus, anus. It can be caused by cramping of the levator ani muscle, particularly in the pubococcygeus muscle, pubococcygeal part ...

* F3. Functional defecation disorders ** F3a. Inadequate defecatory propulsion ** F3b. Dyssynergic defecation G. Childhood functional GI disorders: Neonate/Toddler * G1. Infant regurgitation * G2. Rumination syndrome * G3. Cyclic vomiting syndrome (CVS) * G4. Infant colic * G5. Functional diarrhea * G6. Infant dyschezia * G7. Functional constipation H. Childhood functional GI disorders: Child/Adolescent * H1. Functional nausea and vomiting disorders ** H1a. Cyclic vomiting syndrome (CVS) ** H1b. Functional nausea and functional vomiting *** H1b1. Functional nausea Digestive system diagram en

H1b2. Functional vomiting ** H1c. Rumination syndrome ** H1d.

Aerophagia Aerophagia (or aerophagy) is a condition of excessive air swallowing, which goes to the stomach instead of the lungs. Aerophagia may also refer to an unusual condition where the primary symptom is excessive flatus (farting), belching (burping) is ...

* H2. Functional abdominal pain disorders ** H2a. Functional dyspepsia *** H2a1. Postprandial distress syndrome *** H2a2. Epigastric pain syndrome ** H2b. Irritable bowel syndrome (IBS) ** H2c. Abdominal migraine ** H2d. Functional abdominal pain ‒ NOS * H3. Functional defecation disorders ** H3a. Functional constipation ** H3b. Nonretentive fecal incontinence

Causes

FGIDs share in common any of several physiological features including increased reactivity of gastrointestinal movement, hypersensitivity, altered immune function, inflammatory function (associated with bacterial

dysbiosis Dysbiosis (also called dysbacteriosis) is characterized by a disruption to the microbiome resulting in an imbalance in the microbiota, changes in their functional composition and metabolic activities, or a shift in their local distribution. For e ...

), and altered central nervous system and

enteric nervous system The enteric nervous system (ENS) is one of the three divisions of the autonomic nervous system (ANS), the others being the sympathetic nervous system (SNS) and parasympathetic nervous system (PSNS). It consists of a mesh-like system of neurons th ...

(CNS-ENS) regulation. The pathophysiology of FGID has been best conceptualized using

biopsychosocial model Biopsychosocial models (BPSM) are a class of trans-disciplinary models which look at the interconnection between biology, psychology, and socio- environmental factors. These models specifically examine how these aspects play a role in a range o ...

help to explain the relationships between an individual factors in their early life that in turn can influence their psychosocial factor and physiological functioning. This model also shows the complex interactions between these factors through the brain-gut axis.Drossman DA. The Rome IV Committees, editor. Functional Gastrointestinal Disorders and the Rome IV process. In: Drossman DA, Chang L, Chey WD, Kellow J, Tack J, Whitehead WE, editors. Rome IV functional gastrointestinal disorders: disorders of gut-brain interaction.I. Raleigh, NC: The Rome Foundation; 2016. pp 1–32. These factors affect how FGID manifest in terms of symptoms but also affect the clinical outcome. These factors are interconnected and the influences on these factors are bidirectional and mutually interactive.

Early life factors

Early life factors include genetic factors, psychophysiological and sociocultural factors, and environmental exposures. * Genetics – Several polymorphisms and candidate genes may predispose individuals to develop FGID. These include alpha-2 adrenergic and

5-HT receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the Central nervous system, central and peripheral nervous systems ...

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

and

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

transporters (SERT, NET); inflammatory markers interleukin-(IL)10, tumor necrosis factor-(TNF) alpha, and TNF super family member 15 (TNF-SF15); intracellular cell signaling (

G protein G proteins, also known as guanine nucleotide-binding proteins, are a Protein family, family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell (biology), ...

s); and ion channels (SCN5A). However, the expression of a FGID requires the influence of additional environmental exposures such as infection, illness modeling and other factors. * Psychophysiological factors may affect the expression of these genes, thus leading to symptoms production associated with FGID. * Sociocultural factors and family interactions have been shown to shape later reporting of symptoms, the development of FGIDs, and health care seeking. The expression of pain varies across cultures as well including denial of symptoms to dramatic expression. * Environmental exposures – Prior studies have shown the effect of environmental exposures in relation to the development of FGIDs. Environmental exposures such as childhood salmonella infection can be a risk factor for IBS in adulthood.

Psychosocial factors

There is a strong link between FGIDs and psychosocial factors. Psychosocial factors influence the functioning of the GI tract through the brain-gut axis, including the GI tract's motility, sensitivity, and barrier function. Psychosocial factors also affect experience and behavior, treatment selection, and clinical outcome. Psychological stress or one's emotional response to stress exacerbates gastrointestinal symptoms and may contribute to FGID development and maintenance. Specifically in children and adolescents, anxiety and depression may present as FGID-associated somatic complaints, such as

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

, and

abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...

. Similarly,

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

in individuals with FGIDs is linked to greater pain severity, frequency, duration, chronicity, and disabling effects. This is because psychological stress can impact the gut's mucosal barrier functions, allowing bacteria and bacterial products to migrate and cause pain, diarrhea, and other GI symptoms. Conversely, since the brain-gut axis is bidirectional, GI inflammation and injury can amplify pain signals to the brain and contribute to worsened mental status, including

and depression symptoms. Individuals with FGIDs may also experience poor socialization. Due to the nature of the disease, individuals with an FGID may have difficulty with regular school or work attendance and participation in extracurricular activities, leading to isolation and a lack of peer support. This lack of peer support may lead to depression and loneliness, conditions which exacerbate FGIDs symptoms. In addition, children with FGIDs are more likely to experience bullying. As such, stressful situations which influence socialization (seen as either a lack thereof or negative experiences) may lead to an impaired functioning in patients with FGIDs. Family interactions may also play a role in the development of FGIDs through their effects on the physical and psychosocial functioning of an individual. Family factors which may influence the development of an FGID include child attachment style, maladaptive parenting behaviors (paternal rejection and hostility), and even the parents' health status, as children of chronically ill parents experience increased somatic symptoms, insecure attachment, and worsened biopsychosocial functioning. Each of these factors leads to the accumulation of stressors, which can ultimately lead to the development of an FGID. In addition, family units which have a member with an FGIDs diagnosis are more likely to face family functioning difficulties, including challenges to familial roles, communication, affective involvement, organization, and cohesion. These challenges arise due to the nature of the disease, and ultimately worsen symptoms for the FGID patient.

Physiology

The physiology of FGID is characterized by abnormal motility, visceral hypersensitivity as well as dysregulation of the

immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

and barrier function of the GI tract as well as inflammatory changes. * Abnormal motility
Studies have shown altered muscle contractility and tone, bowel compliance, and transit may contribute to many of the gastrointestinal symptoms of FGID which may include

, and

. * Visceral hypersensitivity
In FGID there is poor association of pain with GI motility in many functional GI disorders. These patient often have a lower pain threshold with balloon distension of the bowel (visceral

hyperalgesia Hyperalgesia ( or ; ''hyper'' from Greek ὑπέρ (''huper'') 'over' + ''-algesia'' from Greek ἄλγος (algos) 'pain') is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and ...

), or they have increased sensitivity even to normal intestinal function; Visceral hypersensitivity may be amplified in patients with FGIDs. * Immune dysregulation, inflammation, and barrier dysfunction
Studies on postinfectious IBS have shown that factors such as mucosal membrane permeability, the intestinal flora, and altered mucosal immune function. Ultimately leading to visceral hypersensitivity. Factors contributing to this occurrence include genetics, psychological stress, and altered receptor sensitivity at the gut mucosa and myenteric plexus, which are enabled by mucosal immune dysfunction. * Microbiome
There has been increased attention to the role of bacteria and the microbiome in overall health and disease. There is evidence for a group of microorganisms which play a role in the brain-gut axis. Studies have revealed that the bacterial composition of the gastrointestinal tract in IBS patient differs from healthy individuals (e.g., increased Firmicutes and reduced Bacteroidetes and Bifidobacteria) However, further research is needed to determine the role of the microbiome in FGIDs. * Food and diet
The types of food consumed and diet consumed plays a role in the manifestation of FGID and also their relationship to intestinal microbiota. Studies have shown that specific changes in diet (e.g., low FODMAP—fermentable oligo-, di-, and monosaccharides and polyols, or gluten restriction in some patients) may help and reduce the symptom burden in FGID. However, no one diet has been shown to be recommended for all people.

Brain-gut axis

The brain-gut axis is a bidirectional mechanism in which psychosocial factors influence the GI tract and vice versa. Specifically, the emotional and cognitive centers of the brain influence GI activity and immune cell function, and the microbes within the gut regulate mood, cognition, and mental health. These two systems interact through several mechanisms. There are direct, physical connections between the central nervous system and nerve plexuses to the visceral muscles. In addition, neurotransmitters send signals related to thoughts, feelings, and pain regulation from the brain to the GI tract. The brain-gut axis influences the entire body through a variety of pathways; it regulates sensory, motor, endocrine, autonomic, immune, and inflammatory reactions. Within the physical and psychological interactions of FGIDs specifically, psychiatric disorders such as anxiety, depression, and even autism are well-linked to GI dysfunction. Conversely, functional GI diseases are linked to several comorbid psychiatric diseases. Negative emotions such as fear, anxiety, anger, stress, and pain may delay gastric emptying, decrease intestinal and colonic transit time, and induce defecation and diarrhea.

Treatments

Psychotherapeutic treatments

Because FGIDs are known to be multifactorial with external stressors and environmental factors playing a role in their development, current research demonstrates that psychological treatments may be effective in relieving some symptoms of the disease. Interventions such as

cognitive behavioral therapy Cognitive behavioral therapy (CBT) is a form of psychotherapy that aims to reduce symptoms of various mental health conditions, primarily depression, PTSD, and anxiety disorders. Cognitive behavioral therapy focuses on challenging and chang ...

(CBT),

hypnotherapy Hypnotherapy, also known as hypnotic medicine, is the use of hypnosis in psychotherapy. Hypnotherapy is generally not considered to be based on scientific evidence, and is rarely recommended in clinical practice guidelines. However, several p ...

, and biofeedback-assisted relaxation training (BART) each show promise in symptom reduction. Each of these therapies aims to alter an individual's thought patterns and behaviors while improving self-efficacy, which all work together to improve health outcomes. Cognitive behavioral therapy is a treatment based on the theory that thinking affects one's feelings and behaviors. As such, alterations in one's thought process can have a positive or negative effect on actions and perceptions. Through the lens of FGIDs, a negative thought pattern may be associated with a negative physical experience of abdominal pain, discomfort, and general sickness. In theory, retraining the patient's thought patterns can alleviate these symptoms and improve quality of life. In patients with FGIDs, CBT is an effective treatment option; one study found 87.5% of participants to be completely pain-free following treatment. Internet-based CBT (iCBT) is similarly effective, and may be a good treatment option for individuals who either cannot afford or otherwise lack access to traditional CBT. Virtual CBT for FGIDs has become a growing area of interest. In addition to patients being unable to afford or arrange transportation for in-office CBT, patients also face limited availability of providers trained in GI-specific psychotherapy. Part of the interest in virtual CBT for functional gastrointestinal disorders is due to the effectiveness initial studies have reported. When compared to in-office CBT treatment, both telephone-based CBT treatment and web-based CBT treatment show statistically significant improvements in patient symptoms. Additionally, virtual CBT may allow for better adherence to treatment. Currently, Regulora is the only smartphone app that is approved by the FDA for virtual treatment of FGIDs in adults. Regulora was approved for use as a digital therapeutic that is available by prescription only. Although a relatively newer treatment option, initial evidence from app users suggests statistically significant reductions in abdominal pain for some participants. Hypnotherapy, another method for reducing symptoms of FGIDs, teaches users how to alter their perception of uncomfortable sensations in the body. Gut-directed hypnotherapy specifically gives greater improvements in symptoms than standard treatment of the disease. Research demonstrates directed hypnotherapy to be an effective mechanism of reducing visceral hypersensitivity (a low pain threshold of the internal organs) and sympathetic activity, due to the reduced activity of the anterior cingulated cortex and state of relaxation achieved during hypnosis. For patients with irritable bowel syndrome (IBS) and functional abdominal pain (FAP), hypnotherapy reduces pain intensity and frequency. BART therapies monitor the physiological changes occurring with thoughts, feelings, and emotions. These therapies aim to teach patients how to visualize the effects of the interventions they are undergoing. BART is used to improve mood and somatic responses to anxiety disorders, which may relieve some of the psychological and physiological symptoms of FGIDs. The visual, real-time feedback given through BART empowers the patient to see the difference that the therapy is making, thus giving the patient control over the physiological components of the disease. This allows the patient to maximize their mind-body connection and eventually optimize symptom management and quality of life. BART allows the patient to break the positive feedback loop of anxiety and pain, thus reducing disease exacerbations.

Pharmaceutical treatments

Antidepressants have been thoroughly studied as a potential treatment for FGIDs. Tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and selective norepinephrine reuptake inhibitors (SNRIs) show the most promise in treating some of the symptoms of FGIDs. TCAs, specifically amitriptyline, show promising results when examining common FGIDs symptoms such as pain and poor quality of life. SNRIs also demonstrate pain-relieving qualities. SSRIs are less effective in pain management, but may reduce symptoms of anxiety and depression, which would, in turn, reduce some FGIDs symptoms.

Pediatric implications

FGIDs are common in children and adolescents, with a prevalence of 23.1%. The most common functional gastrointestinal disorders affecting children are functional abdominal pain and functional defecation disorders. Despite most children with DBGIs having no clear underlying pathology, these disorders can have profound effects on day-to-day life. As mentioned above, family dynamics may influence the development of FGIDs. Children with at least one parent with a mental health condition are more likely to develop a FGID by age 6. Treatment for these disorders is currently in accordance with treatment for adults. This includes CBT, hypnotherapy, and distraction techniques. Overall, prognosis of FGIDs in children is good. Children have better outcomes when there is family support and acceptance of the child's disorder.

Epidemiology

Functional gastrointestinal disorders are very common. Globally, irritable bowel syndrome and functional dyspepsia alone may affect 16–26% of the population.

Research

There is considerable research into the causes, diagnosis and treatments for FGIDs. Diet, microbiome, genetics, neuromuscular function and immunological response all interact. A role for mast cell activation has been proposed as one of the factors.

References

External links

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