The term used for describing chronic and recurrent gastrointestinal symptoms and abnormalities is called as Functional Gastrointestinal Disorder (FGID). -It is also known as disorder of gut-brain interaction, include a number of separate idiopathic disorders which affect different parts of gastrointestinal tract and involve visceral hypersensitivity and motility disturbances. FGIDs are the most commonly identified disorders and till date, do not have any gold standard tests or biomarkers available for their diagnosis since their actual pathology is unknown. -FGIDs do not adhere to an elementary pathophysiological model but instead involve a complex interplay between biological, psychological, and social factors.

1. FUNCTIONAL GASTROINTESTINAL DISORDERS (FGIDs)- A SYSTEMIC REVIEW
ON THE ASSOCIATION BETWEEN BRAIN-GUT AXIS
Noida Institute of Engineering And Technology
(Pharmacy Institute)
Greater Noida
UNDER GUIDANCE :
PRESENTED BY:
NASHRA SHAFIQ DR SAUMYA DAS
M.PHARM (PHARMACOLOGY) ASSOCIATE PROFESSOR
NOIDA INSTITUTE OF ENGINEERING AND TECHNOLOGY NIET(PHARMACY INSTITUTE)
(PHARMACY INSTITUTE),GREATER NOIDA (GREATER NOIDA)

2. Functional Gastrointestinal Disorder (FGID)
The term used for describing chronic and recurrent gastrointestinal symptoms and abnormalities is called
as Functional Gastrointestinal Disorder (FGID).
-It is also known as disorder of gut-brain interaction, include a number of separate idiopathic disorders
which affect different parts of gastrointestinal tract and involve visceral hypersensitivity and motility
disturbances. FGIDs are the most commonly identified disorders and till date, do not have any gold
standard tests or biomarkers available for their diagnosis since their actual pathology is unknown.
-FGIDs do not adhere to an elementary pathophysiological model but instead involve a complex interplay
between biological, psychological, and social factors.
Frequent And Relevant Everywhere
No matter which country in the World is evaluated, the prevalence of functional gastrointestinal
disorders (FGID) is very high. In fact, this is the most frequent cause of gastroenterological
consultation.
FGID have a significant impact on patient’s everyday activities and quality of life, inducing
emotional distress because of their chronic symptoms, Moreover, disorders such as functional
dyspepsia (FD) and irritable bowel syndrome (IBS) result in heavy economic burdens through
medical expenses and loss of productivity.

3. Historical Aspects
There have been substantial historical accounts exploring the link between emotional states and
change in GI functions.
In 1833, William Beaumont- The father of gastric physiology, stated that “In a healthy state of the
stomach and an equable frame of mind, bile has seldom been found in the stomach, When so found,
except under peculiar circumstances of diet, it may generally be regarded as an indication of either
mental or corporeal disease, and may be seen as a foreign and offending substance in that organ.
- This quotes is probably the first reference in the literature toward the idea that a disturbance in
gastric function can be the result of central (emotional) mechanisms.
- Beaumont was one of the earliest investigators to demonstrate a relationship between the
psychological factors and the gut functions.
- He observed a patient called Alexis St. Martin who had developed a traumatic gastric fistula from a
gunshot injury and reported that there was a change in emotions.

4. According to the James-Lange Theory- Response to an external stimuli leads to a physiological
response (autonomic arousal) and the interpretation of this response generates emotions.
- This was the first theoretical account for an influence of bodily, especially visceral, signals on
psychological stress such as emotions.
According to Drossman- It noted that the biomedical model, where what could be
considered “organic” and conditions for which a pathological aetiology could not be
found or understood were designated as “functional” problems and that this
distinction still existed in current medical practice.
- The patients with recurrent or chronic GI symptoms for which an underlying
pathology cannot be delinerated are considered as having functional GI disorders.

5. The Rome Process
This history started in Rome 30 years ago when when Aldo Torsoli, Professor of Gastroenterology at the University of Rome,
was active in the creation of working team for the International Gastroenterology Meetings (held in Rome 19880.
- Torsoli has partnered with W.Grant Thomson, MD, of Ottawa, a renowned gastroenterologist, to establish consensus
standards for the treatment of IBS.
Rome I (1994)-
Professor Torsoli, Douglas Drossman has coordinated over 4 years a succession of working teams that have further
evolved these requirements in the 5 anatomical region (esophageal, gastroduodenal, biliary, bowel and anorectal.
- In 1994, their collaborative study was revised and published in The Functional Gastrointestinal Disorders:
Diagnosis, Pathophysiology and Treatment; a multi-national consensus. The research is now known as Rome I.
- It involves the third edition of the Rome IBS criteria.
- From 1988 to 1992, three IBS working teams provided duration parameters, and pain went from being,
unnecessary for the diagnosis of IBS to being a recommended symptom that was eventually required.
Rome II (1999-2000)-
This process involved 4 years of debate by more than 50 investigators from 13 Western countries, distributed into 10
committees. The outcome was the second edition of Gastrointestinal Disorders: Identification, Pathophysiology and
Treatment; a multi-national agreement.

6. -George Degnon became Executive Director of the Rome organisation in 1994. Carl
Blackman became the Administrative Steering Committee and the Working Teams.
-In order to ensure that the Rome process remained at arm’s length from the sponsors, the
Industry Research Council (IRC) was formed with Dr. Bill Whitehead as Chair.
-The IRC meets annually to permit members of the Rome Committee, representatives of
sponsoring companies and regulatory authorities to address progress and shared concerns.
-In 1999, the Rome II requirements and thee critical supporting details were published in
the Gut supplement.
ROME III (2006)-
DR. ROBIN SPILLER AND DR. MICHEL DELVAUX JOINED THE SEVEN-MEMBER
COORDINATING COMMITTEE. THE ORGANISATION REGISTERED AS A NON-PROFIT
EDUCATIONAL FOUNDATION AND THE ORGANIZING COMMITTEE BECAME KNOWN AS THE
ROME BOARD OF DIRECTOR. A BROAD VARIETY OF ORGANISATIONAL THEMES, INCLUDING
TIES WITH INDUSTRY: INITIATIVES SUCH AS VALIDATION THAT WENT BEYOND THE
DISCLOSURE OF DIAGNOSTIC CRITERIA; THE PROMOTION OF PROOF AS A BASIS FOR
MODIFYING CRITERIA; AND THE PROMOTION OF “DEVELOPING WORLD” PARTICIPATION.
-IN 14 PANELS, THE BOARD SELECTED 87 MEMBERS FROM 18 NATIONS. MEMBERS HAVE
BEEN INTRODUCED FROM THE CHINA, BRAZIL, CHILE, VENEZUELA, HUNGARY, ROMANIA.
- IN ADDITION, THE MEMBERS OF THE BOARD COMMENTED ON THE ROME III PHASE AT THE
2005 WORLD CONGRESS OF GASTROENTEROLOGY IN MONTREAL AND THE CRITERIA FOR
THE 2006 MEETING OF THE AMERICAN GASTROINTESTINAL ASSOCIATION IN LOS ANGELES.

7. Preservation of Rome III
The Rome III classification works on the principle of symptom-based diagnosis. The classification is based
on the symptoms producing organs and the order of classification is from oesophagus to anus.
The FGID is divided into six major categories for adults-
1. Esophageal (Category A)
2. Gastroduodenal (Category B)
3. Bowel (Category C)
4. Functional abdominal pain syndrome (Category D)
5. Biliary (Category E)
6. Anorectal (Category F)
Every category has some disorders, each with specific clinical features.
The symptoms of FGIDs are derived from some different combinations such which includes-
i. Increased motor reactivity
ii. Enhanced visceral hypersensitivity
iii. Altered mucosal immune and inflammatory function (which consists of changes in bacterial flora)
iv. Altered CNS enteric nervous system (ENS) regulation (regulated by exposures of psychosocial and
sociocultural factors).

8. -The separation 0f functional symptoms into distinct conditions is that they can be diagnosed and treated in an
improvised manner. The Rome III classification system is based on the premise that for each disorder there are
symptom clusters that “breed true” across clinical and population groups.
-This presumption provides a framework for identification of patients for research that is modified as new
scientific data emerges.
- The classification of FGIDs into symptom based subgroups is based on the principle of site specific
differences between symptoms i.e. the fact that symptoms result from multiple influences from
epidemiology data showing similar frequencies of these disorders across cultures and finally out of the
need for diagnostic standards in order to conduct clinical care and research.
What has changed in Rome III-
1.Time frame change for FGIDs: The time taken for the diagnosis of FGIDs (Time Frame) is now six
months preceding the clinical presentation and the diagnosis should meet the criteria for 3 months.
- This current time frame is less confining that that of Rome II (12 weeks of symptoms over 12 months).
This change in classification removes Functional abdominal pain syndrome (FAPs) from functional
bowel disorders (Category C) into its own category (Category D).
2. Changes in classification categories: Nowadays, The Rome II category of Childhood Functional
Disorders is classified as Childhood Functional GI Disorders: Neonate/Toddler (Category C) and
Child/Adolescent (Category H).

9. -This change in classification removes Functional abdominal pain syndrome (FAPs) from Functional
bowel disorders (Category C) into its own category (Category D).
3. Criteria changes: Due to its symptom of heterogeneity, Functional dyspepsia in Rome III is
apathized as an entry for research, Therefore another term “dyspepsia symptom complex” has been
recommend by gastroduodenal committee which is subdivided into two conditions that may overlap
i. Postprandial Distress Syndrome
ii. Epigastric Pain Syndrome
Rome III suggests much strict analysis of Functional biliary tract, these disorders are of low existence
as compared to other FGIDs, but they are analysed with invasive and risky studies, such as
Endoscopic Retrograde Pancreatography (ERCP) or sphincter of Oddi manometry.
Rome IV- After 2006, the Rome Foundation became increasingly recognized as an authoritative
body developing diagnostic criteria for research and also for providing education about the FGIDs to
clinicians, trainees, and investigators worldwide.
- However, to meet their goal to advance the field of FGIDs, the foundation had to address the
following limitations:
i. The term Functional GI disorders, although entrenched in the literature, was imprecise and to
some degree stigmatizing.

10. ii. The diagnostic criteria were cumbersome in clinical practice.
iii. The criteria oversimplified the full dimension of the patients illness experience and were not
precise enough to identify meaningful physiological subgroups or biomarkers that might lead to
more targeted treatment.
iv. The criteria did not specify the investigative pathway to use before applying the criteria.
V. The foundation traditionally approached knowledge acquisition from a western base of
knowledge and this was a limitation to other countries and cultures.
- Rome IV provides a foundation for future changes that will be made in our understanding of these
disorders.
Changes For Rome IV
Rome IV changes are as follows-
1. The Addition of new diagnoses with known eotiologies. Narcotic bowel syndrome (opioid-
induced gastrointestinal hyperalgesia) has been added to the centrally mediated disorders of
gastrointestinal pain article, opioid-induced constipation has been added to the bowel article, and
cannabinoid hyperemesis syndrome has been added to the gastroduodenal article.

11. - These diagnoses differ from other FGIDs by having substances ( opioids and cannabinoids) that
produce the symptoms, and their avoidance may lead to recovery because these diagnoses result
from known etiologies.
- They are not truly functional, but we include them in Rome IV because they fit the new
definition: disorders of gut-brain interaction characterized by altered function of the CNS or
enteric nervous system, their clinical presentations are similar to FGIDs and thus need to be
distinguished from them; and they have not yet been well characterized or reached a level of
acceptance in the field to be considered separate disorders ( such as lactose intolerance,
microscopic colitis ).
2. Removal of functional terminology when possible. The debate to retain or change the term
functional has existed for decades, however, the word “Functional” has limitations by being non-
specific and potentially stigmizing.
- Therefore, we provide an improved definition of FGIDs (i.e. disorders of gut-brain interaction) to
help clarify its meaning.
- In addition, we have removed the word functional from article titles (e.g. esophageal disorders
rather than functional esophageal disorders) and from certain diagnoses (e.g. Fecal incontinence
instead of functional fecal incontinence) as occurred in Rome III.
- In addition, Functional Abdominal Pain Syndrome has been changed to centrally mediated
abdominal pain syndrome to more appropriately address the disorder’s pathogenesis, minimize the

12. Stigma of the term functional, and reverberate with the new brain-gut information that is
emerging.
However, some clinical disorders (e.g. Functional Diarrhea, Functional Heartburn) have retained the term
to distinguish them from disorders having similar symptoms but with clear structural etiologies.
3. Article additions and modifications. A new article entitled micro-environmemt and the Functional
Gastrointestinal Disorders combines knowledge of the microbiome, food and nutrition to improve
understanding of the luminal aspects of GI function.
- Pharmacological and Pharmacokinetic aspects of Functional Gastrointestinal Disorders to include the
role of genetics in the clinical response to pharmaceutical treatments, gender, age, society, culture and
the patient’s perspective from Rome III has split into 2 articles to reflect the rapid growth of
knowledge in these areas of age, gender, women’s health and the patient and multi-cultural aspects of
functional gastrointestinal disorders.
- Psychosocial aspects of functional gastrointestinal disorders has been changed to Biopsychosocial
aspects of functional gastrointestinal disorders to reflect the multi-determined nature of
biopsychosocial processes.
- The Rome II article functional abdominal pain syndrome is changed to centrally mediated disorder of
gastrointestinal pain to reflect the predominant CNS contribution to the symptoms.

13. -.
4. Addition of reflux hypersensitivity diagnosis. In Rome III, Functional Heartburn defined heartburn
symptoms in the absence of evidence that the heartburn is associated with gastroesophageal reflux.
- However, there also are patients who have normal acid reflux levels, but they sensitive to the
physiological reflux and so develop heartburn.
- For Rome IV, A3 Reflux Hypersensitivity characterizes this situation and is to be differentiated
from A2 Functional Heartburn or even nonerosive reflux disease by their greater association of
symptoms with reflux, albeit physiological.
5. Revision of SOD (Sphincter of Oddi) disorder criteria. Recommendations to perform biliary
sphincterotomy based on clinical criteria (biliary dilatation and increased liver chemistries or
increased pancreatic enzyme levels). For presumed sphincter of Oddi pain has not had convincing
supportive evidence.
- Thus, balancing the benefits of symptomatic relief with the potential risks ok pancreatitis,
bleeding and perforation has been challenging and Rome III criteria for these disorders were not
particularly helpful in providing proper guidelines
- Now, driven by evidence that debunks the value of sphincterotomy for type III SOD, the
Gallbladder and Sphincter of Oddi Disorders chapter committee has reclassified these disorders, and
they provide a more rational algorithm for treatment.

14. 6. Functional bowel disorders now exist on a spectrum of symptom presentation. The
predominant bowel diagnosis of IBS with subtypes of constipation, diarrhea, mixed and
unclassified, are no longer considered distinct disorders.
- Instead they exist on a spectrum with linked pathophysiological features that are variably
expressed clinically by patient-specific differences in the quantity, intensity , and severity of
symptoms.
- This overlap of clinical features is well observed for IBS with predominant constipation and
chronic constipation in which categories may switch depending on the degree of pain and across
the subcategories of IBS related to changes in stool habit over time.
- This also can occur with functional dyspepsia or functional constipation with pelvic floor
dyssynergia. For clinical trials, specific diagnostic criteria are necessary to assess the targeted
effects of the drugs, however, in clinical care, patients may transition from one diagnosis to
another or have combinations of diagnoses that may require overarching management (e.g. anti-
depressants for pain across multiple diagnoses.
7. Change in identification of subtypes. The Rome III classification for IBS subtypes required that
the proportion of total stools using the Bristol Stool Form Scale be used to classify IBS with
predominant diarrhea (>25% loose/watery, <25%hard/lumpy), IBS with predominant constipation
(>25%hard/lumpy, <25% loose/watery), mixed-type IBS (>25% loose/watery, <25% hard/lumpy).

15. - Based on this observation and the result of a Rome Foundation Normative Symptoms Study, the criteria for
subtypes of IBS have been changed and relate to the proportion of symptomatic stools (ie, loose/watery and
hard/lumpy) rather than all stools (including normal ones). As a result, the unclassified group is reduced.
8. Removal the term discomfort from IBS criteria, The Rome III criteria for IBS resymptoms.quired
abdominal pain or discomfort, presuming that these terms exist on a continuum from more severe (pain) to
less sever (discomfort) . However, more recent data have indicated that patients consider the two terms as
qualitatively different and discomfort can incorporate a variety of symptoms.
- In addition, the term discomfort has different meanings and is reported with different frequencies
across cultures. Therefore, to avoid symptom-related and cultural heterogenicity, only with the term
pain is used as the key diagnostic criterion for IBS.
9. Combined nausea and vomiting disorder. For Rome IV the new diagnosis B3a. Chronic Nausea
Vomiting Syndrome combines the previous Rome III entities Chronic Idiopathic Nausea and Functional
Vomiting .
- This is owing to a lack of evidence delinerating different diagnostic approaches and management of
nausea compared with vomiting and the clinical observation that these 2 symptoms commonly are
associated .
- Although we recognize that patients may present only with nausea, the clinical approach to diagnosis and
management is still the same.

16. Scientific observations on FGIDs
Genetic predispositions- Genetic factors may predispose some individuals to develop FGIDs. These factors play an
important role in several pathways such as- Lower levels of IL-10 is an anti-inflammatory cytokine in patients with
IBS that affects the gut mucosal neural sensitivity, serotonin reuptake transporter polymorphisms that affect the levels
of 5-HT neurotransmitter or blocking the response of 5-Hydroxytryptamine agents (5-HT).
- G-protein polymorphism can affect both the CNS and gut-related actions, while α-2 adrenoreceptor polymorphism
affect motility only.
Psychosocial factors-Research on the psychosocial aspects of patients with FGIDs contain three observations.
i. Psychological stress affects the GI function and produces symptoms in healthy subjects, but mot in patients with
FGIDs.
ii. It modifies the illness behaviours and the illness experiences. The patients suffering from FGIDs have more
profound psychological disturbances as compared to the healthy patients.
iii. There are psychosocial disturbances effects of FGIDs on general well-being, daily function, sense of control over
the symptoms. This is understood in terms of health- related quality of life.
Abnormal motility- Environmental stress and strong emotion in healthy patient can ameliorate motility in
the esophagus, stomach, small intestine and colon. These responses are related to bowel symptoms
particularly vomiting, diarrhoea and constipation, but these are not sufficient to explain reports of chronic
or recurrent abdominal pain.

17. Visceral hypersensitivity- Visceral hypersensitivity explains the unsatisfactory association of pain
with GI motility with several functional GI disorders (For e.g. functional chest pain [A1], epigastric
pain syndrome [Bb1] and Irritable Bowel Syndrome [C1}.
-Perhaps visceral hypersensitivity is enhanced in patients with FGIDs and the process is called as
sensitization or stimulus hyperalgesia. It may happens through adjusted receptor affectability at the gut
mucosa and myenteric plexis, which might be empowered by mucosal inflammation.
Inflammation- Increased inflammation in the enteric mucosa or neural plexis may lead to the
development of symptoms, researchers have proposed.
- Nearly half of IBS patients showed increased activation of inflammatory mucosal cells. Approximately
one third of patients with IBS or dyspepsia report that their symptoms started after an acute enteric
infection and upto 25% of patients with an acute enteric infection will continue to experience IBS- like
or dyspeptic symptoms, usually with increased inflammatory cells and inflammatory cytokine
expression in the mucosa of these individuals.
Brain-Gut peptide- The Brain gut axis links the various centre of the brain (emotional and cognitive
centres) to the peripheral GI and vice-versa . Thus the brain gut axis allows bi-directional input. Therefore,
the enteroceptive and the extrinsic factors have the potential to alter the GI motility, inflammation ,
secretion and sensation. Also, the visceral afferent communication to the brain inversely alters the central
pain perceptions mood and behaviour.
Brain imaging- Brain imaging with positron emission tomography, functional magnetic resonance
imaging or other modalities offers an opportunity to evaluate brain activity in response to visceral stimulus
among healthy subjects and patients with FGIDs.

18. -There is a correlation of anterior cingulate cortex (ACC) activation to rectal distension in IBS
associated with controls. Studies using both functional magnetic resonance imaging and positron
emission tomography indicate changes in ACC activity relative to controls. Activation to rectal
distension correlates with anxiety, traumatic life activities, ill-adapted coping, and history of
violence.
Brain-Gut Peptides- A therapeutic strategy which is consistent with the idea of brain-gut
dysfunction includes the neuropeptide and receptors of the enteric and central nervous system. These
neuropeptides have interspersed or combined activities on GI function and human behaviour based
on their location.
- The current Phase II and III pharmacological treatment studies using active agents at these
receptor sites resolve diverse but interlinked symptoms of pain, bowel impairment and
psychosocial distress. So, it is generally associated with FGIDs.

19. The Microbiota-Gut-Brain Axis
The Role of CNS in Functional Gastrointestinal Disorders- Psychological and psychosocial
factors are important for understanding the pathophysiology of FGIDs. Psychiatric conditions such
as- anxiety, depressive disorders and neurotic disorders are common comorbidities in patients with
FGIDs.
-A recent 12-year prospective study aimed at determining the role of the brain-gut system in IBS and
FD , concluded that both brain-gut dysfunction occur in FGIDs. FGID patients are also characterized
by defects in the autonomic nervous system, neuroendocrine and immune function, which are
impaired by psychological distress.
- In the Emotional Motor System (EMS) model, which responds to interoceptive and exteroceptive
stress. Specific brain structures involved in the EMS, including the anterior cingulate cortex
(ACC), amygdala, hippocampus, hypothalamus and periaqueductal grey, interact with the
gastrointestinal tract through the hypothalamus-pituitary-adrenal (HPA) axis, the autonomic
nervous system, the endogenous pain control system and the ascending aminergic pathways.
- Corticotropin-releasing hormone (CRH) found in the effector neurons of the paraventricular
nucleus (PVN) of the hypothalamus, amygdala, and locus coeruleus complexes that activate both the
autonomic nervous system and the HPA axis are important players in the EMS.

20. -Patients with FGID demonstrate the dysregulation of the HPA-axis response to stress and changes in
free cortisol secretion that correlate with gastrointestinal symptoms.
- Early life stress can permanently impair the development of the HPA (Hypothalamus-pituitary-
adrenal) axis, lead to altered visual pain regulation and behavioural changes associated with
stress-related disorders.
- Corticotropin-releasing factor (CRF) has therefore been suggested as a potential mediator in IBS,
as central CRF administration mimics acute stress- induced colonic reactions and improve
colorectal distension –induced visceral pain, while peripheral CRF alters neuromotor intestinal
function.
- Neuroimaging research has enabled the investigation of underlying mechanisms of altered
visceral perception in patients with IBS.
- Abnormal brain activity in response to visceral stimuli and CNS dysregulation was observed in
patients with FGID relative to healthy controls. However, it is not clear if the recorded abdominal
pain represents irregular afferent brain input, or central alteration of the intestinal signals or both.

21. Gut Microbiota and Functional Gastrointestinal Disease- Alterations in the composition of
intestinal microbiota have been well defined in many functional gastrointestinal disorders and are
discussed in depth in a recent study by the Rome Working Group.
- Recent studies have confirmed that IBS is associated with a decrease in intestinal microbiota
stability and biodiversity. There is however, no strong consensus about what constitutes a
balanced microbiota.
- Post-Infection (PI) FGID care is a type of the general FGID classification . The underlying
mechanisms involved in PI-FGIDs are yet to be completely clarified.
- Although several studies have shown signs of low-grade “immune activation” in IBS patients. It
has been suggested that temporary inflammation can lead to mild but permanent changes in the
structure and function of the digestive system, such as lymphocytes, mast cells, enterochromaffin
cells (EC), and enteric nerves, which in addition, cause illness.
Microbiota-Gut-Brain Interaction in FGIDs- The gut brain axis (GABA) comprises of the brain,
the enteric nervous system (ENS), the vagal branches, and the spinal nerves, including the somatic
and autonomic connections of the enteric intestine. The relation between the CNS and the ENS is
established by the intestinal microbiota, which causes neural, immune, humoral and endocrine
changes.

22. Complex Pathophysiology
- FGID pathophysiology is extremely complex with digestive, neural, and microbiota interplays.
Several mechanisms are involved including intestinal dysmotility, increased visceral sensitivity,
disturbed intestinal reflexes (intrinsic and extrinsic), psychological disorders, and dysbiosis ( See in
below Fig).
Fig- Functional gastrointestinal disorders pathophysiology is extremely complex, with digestive,
neural, and microbiota interplays.
- The predominance and combination of these mechanisms are most probably responsible for the
different manifestations of Functional Dyspepsia and Irritable Bowel syndrome.

23. - Therefore Rome IV defines FGID as disorders of the gut-brain interaction, being symptoms related
to any combination of the following: motility disturbance, visceral hypersensitivity, altered mucosal
and immune function, altered gut microbiota, and altered central nervous system (CNS) processing.
- This multifactorial origin of symptoms can only be (Partially) explained under the biopsychosocial
model: early life, genetics, sociocultural influences, and environmental factors may affect one’s
psychosocial development in terms of personality traits, susceptibility to life stresses, psychosocial state, and cognitive and
coping skills.
-These factors also influence the susceptibility to gut dysfunction (abnormal motility or sensitivity, altered mucosal immune
dysfunction or inflammation),and the microbial environment, as well as the effect of food and nutritional substances,
-Furthermore, these brain-gut variables reciprocally influence the CNS expression.
- The close relationship between the CNS and the enteric nervous system (the so-called brain-gut), or even more, the
bidirectional correlation among the CNS, the enteric nervous system, and the microbiota (the brain-gut-microbiota axis),
is the basis of most of the actual research on FD (Functional Dyspepsia) and IBS (Irritable Bowel Syndrome), not only
concerning pathophysiology but also treatment.
- It is conceivable that in the near future better umderstanding of IBS pathophysiology will help us to tailor treatment for
different FGID patients.

24. - At the moment, subclassification of the diverse patterns of symptomatology allows adjustment of
new treatments for FGID according to the clinical symptom predominance for each patient only.
- The knowledge of motor and sensory response to different stimuli in IBS patients, and the
pathways to the CNS is an important source of information for the development of new molecules.
- However, it is not likely that one single treatment will help every patient with FD or IBS, and
many of them will need a more complex approach with a multidisciplinary therapy (diet,
psychotherapy, medications).
- On the contrary, medications with just a single mechanism of action will help only a subset of
patients (suffering this specific pathophysiology abnormality ).
- Prokinetics, antispasmodics, antinociceptives, selective antibiotics, and probiotics, among others,
are used in patients with FGID, each being effective is some cases.
- Nevertheless, very frequently, they have to be used in combination to get a more pronounced and
general effect.

25. Treatment of FGIDs
Functional Gastrointestinal Disorders (FGIDs) remain a prevalent concern in the paediatric age group.
These conditions were first recognised by Apley in 19583. when he coined the later term recurrent pain
(RAP) for a group of children with recurrent or persistent abdominal pain that associated with daily
functioning and had no apparent organic aetiology.
Accupuncture As Alternative Treatment-
Accupuncture has been used for many centuries in the treatment of FD in Eastern countries. The practice
of acupuncture consists of inserting fine solid needles (32 to 36 gauge) into selected locations of the body
(acupoints).
- The central concepts of traditional Chinese medicine are that both health and disease derive from the
imbalance of yin ( the feminine component of life) and yang (its male counterpart).
- Movement between these opposite powers, called Qi, is considered to be an integral part of the healing
mechanism.
- In western countries, accupunture is increasingly recognised as an alternative therapy for FGIDs.
- Recently, Zeng et al have been researching brain reaction to acupuncture in FD.
- Seventy-two FD patients were randomized to undergo either sham or classical acupuncture on four
particular acupoints; ST34 (Liangqiu), ST36 (Zusanli), ST40 (Fenglong) and ST42 (Chongyang).

26. Fig- A Schematic representation of the four classic acupuncture points for gastric disorders:
ST3A (Liangqiu), ST36 (Zusanli), ST40 (Fenglong) and ST42 (Chongyang).

27. Ten patients in each category were randomly chosen for fluorine-18 fluoro-deoxyglucose positron
emission tomography (PET-CT) scans to identify changes in cerebral glycometabolism.
- Neuroimaging revealed that the acupuncture commonly displayed extensive deactivation of cortical
function relative to the placebo acupuncture group.
-This description was correlated with symptom relief, implying the possible efficacy of acupuncture
at particular FD points.
- This statement was partly backed by a recent PET-CT scan study exploring similarities and
discrepancies in clinical and cerebral responses at various acupoints in 20 FD patients.
- The author hypothesised that the effect on sensory transduction regions and visceral modulation
regions may be a common mechanism for a different acupoint therapy
- More recently, the meta-analysis, covering almost the same research as the Cochrane review, draw
opposite conclusions claiming that “Accupunture appears to be effective in alleviating symptoms
of FD and improving quality of life.”
Treatment by Diet-
A.1 Low-lactose Diet- Dearlove et al offered a lactose-free diet to 21 children for 2 weeks. During
the next 2-week cycle, either lactose solution or placebo were administered in a double-blind
crossover study.

28. - No variations in signs of pain were found in either group. In 21 of 69 children with RAP
(Symptoms of cramps, discomfort, bloating, gas, diarrhea, or loose stools).
- Lebenthal et al found an irregular oral (2g/kg) lactose tolerance test recorded a blunt
increase in blood glucose of <20mg/ml).
- In three consecutive 6-week blinded trials (Cow-milk formula containing lactose, soy protein-
based non-lactose formula and regular diet and milk consumption), the level of pain increased by
10/21 for lactose-free formula and 7/21 for lactose-free soy.
- These two studies indicate that lactose intolerance can play a role in symptom development in
some but not some children with RAP.
A.2 Dietary Fiber- Christensen et al analysed 40 children between 3 and 15 years of age randomised
to obtain either a cracker with a psyllium fibre content of 2 % (placebo) or 66% (treatment) and did
not find any differences between groups in the mean number of episodes of suffering.
- Humphreys et al randomised 64 children with RAP (Recurrent Abdominal Pain) to receive fibre
treatment on their own, fibre in addition with biofeedback, biofeedback fibre and cognitive
behavioural interventions, or fibre and family help.
- All groups improved their effects, although it is unclear if the result in the fibre group alone may
have been due to a placebo stool.

29. - Fiber can have potential benefits on GI motility and sensitivity in addition to acting as a stool
softner and bulking agent to minimise some of the suspected RAP (Recurrent Abdominal Pain)
contributing factors, including constipation.
- While other studies have already shown significant benefits of supplemental fibre in adults with
IBS, further studies are required to determine its beneficial role, if any in the treatment of RAP
(Recurrent Abdominal Pain) in children.
- It is doubtful that soluble fibre will exacerbate symptoms and can provide relief to symptoms in
some children.
A.3 Low-Fructose Diet- Fructose, particularly in the form of high-fructose corn syrup, was believed
to cause chronic abdominal pain. Fructose, like lactose, when malabsorbed by a small intestinal
lumen, can induce osmotic diarrhea and may also act as a substrate for colonic bacterial fermentation,
resulting in gas production and abdominal pain.
B. Treatment by Medications-
B.1Anti-depressant- Drugs used to treat depression, anxiety and seizures have become progressively
desirable agents for use in FGIDs because they work on the central and peripheral nervous system to
modulate mood, visceral and neuropathic pain as well as autonomic control, in part through
anticholinergic impact.

30. Antidepressants drugs such as tricyclic antidepressants (TCAs), serotonin reuptake inhibhitors
(SSRIs) and monoamine uptake inhibitors boost IBS symptoms in adults. TCAs (through an
anticholinergic effect) and SSRIs strengthen diarrhea by delaying transit and constipation,
respectively, by accelerating transit time.
Compared to SSRIs, TCAs have shown a more significant reduction in chronic neuropathic pain in
animal models and are considered to be more successful in central than peripheral nervous system.
- Their side effects, more often seen in tertiary TCAs (amitriptyline, imipramine) than in secondary
amines (desipramine, nortriptyline), include sedation, anticholinergic effects (constipation and
urinary retention) and central nervous system effects (insomnia and agitation).
- SSRIs bock the reuptake of 5-hydroxytryptamine (5-HT) and enhance its concentration at
presynaptic nerve ends.
- While SSRIs have also been shown to alleviate neuropathic pain correlated with back pain and
migraines, the impact on GI-related pain in adults is less visible
- However the tendency of SSRIs to induce diarrhea makes it a possible treatment for constipation
related IBS.

31. B.2 Prokinetics- Agents that function to increase motility (prokinetic) reduce acid
development, minimise visceral pain due to gastric distension, or enhance postprandial
gastric accommodation have been successful in adults with FD (Functional Dyspepsia)
and have been used off-label to treat the same symptoms in paediatric patients.
- Prokinetic agent are widely used in adults to treat FD in order to improve
symptomatology of delayed gastric emptying.
- Dopamine (D2) receptor anatgonists such as metoclopramide and domperidone
(Canada) boost gastric motility but are restricted by their side effects, including
extrapyramidal reactions, somnolence, agitation, irritability, weakness and dystonic
reactions.
- Motilin agonists (e.g. erythromycin) have significant properties in the stomach, but
also minimize sleeping habits (gastric relaxation in response to food).
- However, at a lower but not higher dose ( 1 to 2 mg/kg/dose), erythromycin improve
gastric motility without loss of accommodation. As far as we know, there are no
monitored data on the use of any prokinetic drugs in children with FD (Functional
Dyspepsia).
B.3 Anti-histamine- Cyproheptadine, a 5-HT receptor antagonist can be used off-label for
many purposes and is a potentially effective treatment for FGIDs.

32. - Its potency has been documented in children with FAP (Functional Abdominal Pain) in a
double-blind, placebo-controlled study as well as in retrorespective trials for the treatment
of FAP (Functional Abdominal Pain), FD (Functional Dyspepsia), IBS (Irritable Bowel
Syndrome) and AM (Abdominal Migraine).
-5-HT is a polyfunctional signaling molecule that function as a paracrine factor, endocrine
hormone, neurotransmitter, and growth factor.
- Numerous 5-HT receptor subtype control intestinal motility, secretion, and visceral
sensitivity, intraluminal pressure increases, electric stimulation, vagal stimulation.
- Ingestion of a meal or the involvement of acid, amino acids, or hypo-orhyperosmotic
solutions in the duodenum induces the release of 5-HT.
B.4 Herbal Medication- Herbal medications have a long history of use in the diagnosis
of functional disorders. Their mode of action is well understood, but it has been known for
centuries that they contain, for example, essential oil known for their spasmolytic,
carminative and local anaesthetic,
- In the past, least attention is being paid to the evaluation of herbal remedies in the care
of FGID patients.
- The herbal medicinal product STW 5 (Iberogast, Steigerwald, Darmstad, Germany) is
a fixed

33. mixture of nine different herbal extracts, each containing a very low concentration relative to doses
used in a single drug therapy.
-The extract have various proven pharmacological effects on different regions of the gastrointestinal
tract and thus resolve the entire symptom complex of FD (Functional Dyspepsia ) and IBS (Irritable
Bowel Syndrome).
- In vitro gastric motility studies have shown that the STW 5 ethanol-free lyophilisates exert
pleiotropic effects on the muscles of various gastric region.
- Specific components generate different effects on the myogenic activity of the proximal and distal
stomach, i.e. the calcium-mediated behaviour of the constituents can be proximal stomach and
improving antral motility.
- An addition effect of STW 5 can result from the regulation of visceral nociception resulting from
the antinociceptive effect of STW5 on both mechanical and chemical stimuli.
- In addition, therapeutic advantages may be linked to its anti-inflammatory properties, as shown in
animals using TNBS (Trinitrobenzene Sulfonic Acid) and DSS (Dextran Sodium Sulfate) colitis-
induced models.

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37. THANK YOU