Name : Nur Abdi Fadya Hasra Al-Nuranisky

NIM : 105421102519

Correlation Between Major Depression and Irritable Bowel

Syndrome (Brain-Gut) in Biochemistry

Abstract

Mental disorders accompanying digestive system diseases yet

acknowledged both diagnostic and therapeutic problem. Depression is known to

negatively affects patient’s ability to function in a society and a quality of their

lives. For example, as far as children are concerned, the occurrence of digestive

system diseases accompanied by mental disorders, may adversely affect their

further physical and psychological development, which merely results in worse

school performance. All those aspects of mental disorders indicate the desirability

of the psychological care for patients with recognized digestive system disease.

In this essay, I will find out how between mental disorders (such as major

depression and anxiety) and GI disease (such as IBS, colitis, ulcerative) in

Biochemistry are related, by insert some findings by article I read on PubMed,

NCBI, and other research platforms as reference because I have no experience in

doing real research by experiments and why I use this essay as my title.

Keywords : mental disorders; mood disorders; digestive system diseases; irritable

bowel syndrome; depression; gut brain axis depression

Introduction
Review

1. Depression

Depression is a mood disorder that causes a persistent feeling of

sadness and loss of interest.(1) The American Psychiatric Association’s

Diagnostic Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)

classifies the depressive disorders into Disruptive mood dysregulation

disorder; Major depressive disorder; Persistent depressive disorder

(dysthymia); Premenstrual dysphoric disorder; and Depressive disorder due to

another medical condition. The common features of all the depressive

disorders are sadness, emptiness, or irritable mood, accompanied by somatic

and cognitive changes that significantly affect the individual’s capacity to

function.(2)

2. Gastrointestinal tract

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 GI tract contains all the major organs of the digestive system, in

humans and other animals, including the esophagus, stomach, and intestines.

Food taken in through the mouth is digested to extract nutrients and absorb

energy, and the waste expelled at the anus as feces. Gastrointestinal is an

adjective meaning of or pertaining to the stomach and intestines.(3)

3. Biochemistry

Biochemistry is the study of the chemical composition of the living

matter and the biochemical processes that underlie life activities during
growth and maintenance.(4) So, in conclusion Biochemistry is the study of

chemical processes within and relating to living organisms, it’s including

structural biology, enzymology, and metabolism.

4. Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is one of the most commonly

diagnosed gastrointestinal diseases. IBS, in the absence of any other

causative disease, is defined as the presence of abdominal pain or

discomfort with altered bowel habits.(5)

IBS is a chronic and debilitating functional gastrointestinal

disorder that affects 9%-23% of the population across the world.

Classically, IBS presents with abdominal pain or discomfort that is

relieved by defecation or is associated at its onset with a change in stool

frequency (either an increase or decrease) or a change in the appearance of

the stool (to either loose or hard). The absence of red flag (alarm)

symptoms such as gastrointestinal bleeding, weight loss, fever, anemia or

an abdominal mass support such a symptom complex as IBS rather than as

structural disease.(6)

Traditionally, IBS has been conceptualized as a condition of

visceral hypersensitivity (leading to abdominal discomfort or pain) and

gastrointestinal motor disturbances (leading to diarrhea or constipation).

The gastrointestinal motor disturbances identified, including changes in

intestinal transit, do not easily explain mixed or alternating IBS. Some

have suggested that these abnormalities are secondary to psychological

disturbances rather than being of primary relevance. However, not all

 patients with IBS have significant psychological overlay and referral bias

may partly account for the psychological associations. Hints as to why

visceral hypersensitivity and gastrointestinal motor disturbances may arise

are emerging. There is increasing evidence that organic disease of the

gastrointestinal tract can be identified in subsets of patients who fulfill the

Rome criteria for IBS. Evidence for subtle inflammatory bowel disease,

serotonin dysregulation, bacterial overgrowth and central dysregulation

continue to accumulate. The underlying causes of IBS remain to be

adequately identified, but IBS-PI is a clear-cut entity. Furthermore, a

genetic contribution to IBS also seems likely.(7)

How Digestive System Diseases and Biochemistry Related

A. Gut-brain communication

A dysfunction of the gut-brain axis along with genetic factors, food

sensitivity or allergies and infections are postulated as part of the pathophysiology

of IBS and/or depression. (8) It is known that cytokines and inflammatory markers

such as interleukin (IL)-6 and IL-10 are important modulators of the immune

system; these mediators of inflammation are at the forefront of intestinal

inflammation and lead to conditions such as IBS. This inflammation alters gut

microbes and the permeability of the gut mucosa. GIT microbes can produce most

of the neurotransmitters found in the human brain.(9)(10); along with low-grade

inflammation, there is enhanced translocation of the produced neurotransmitters

leading to activation of the hypothalamic-pituitary-adrenal (HPA) axis which is

intrinsic to the pathophysiology of depression(9)(11) and its related comorbidities.

The bidirectional communication between the brain and the gut mucosa employs

multiple information modalities as depicted in figure 1(8)

Figure 1. Gut-brain communication

Some of the neurotransmitters from the nervous system are released by the

neuroendocrine system, such as the adrenal medulla-produced dopamine.

Similarly, some of the information from the GIT involved in bidirectional

communication includes microbe-derived short-chain fatty acids such as propionic

acid in addition to GIT hormones such as serotonin.(12)

The nervous system plays an important role in homeostasis by monitoring

and coordinating the function of different systems in the body; its action through

the autonomic nervous system and neuroendocrine factors regulate the function of

the GIT (Fig.1). The ability of the nervous system to transform its function,

structure, and connections(13) in response to stressors is termed neuroplasticity.

Any psychosocial disturbances can impact on nervous system neuroplasticity and

this, in turn, will adversely affect downstream systems including the GIT.

B. Biochemistry of Depression
 Depression not only causes great mental anguish, but also intrudes into

biological processes that regulate inflammation, coagulation, metabolism,

autonomic function, neuroendocrine regulation, sleep, and appetite.(14) They are

likely to contribute to the premature coronary artery disease premature

osteoporosis and the doubling of mortality in patients with major depression at

any age independent of suicide, smoking, or significant physical illness.(15)

Depressive illness, like stress system activation, shares a relatively unshifting

effect, a shift from complex modes of thought to those that are relatively well-

rehearsed or reflexive, and a dysregulation of fundamental biological processes

that regulate sleep, appetite, growth, reproduction, and autonomic function.(16)

And, the inflammation, metabolic alterations, and the prothrombotic state that

characterized major depression also occur during the acute stress response.

From the research data, it suggest that it is patients with melancholia

(hyper-depression) who manifest evidence of an activated stress system, with

alterations in a multiplicity of systemic processes affecting inflammation and

metabolism, as well as multiple physiological signs of hyperarousal:

hypercortisolism, suppression of the reproductive and growth hormone axes (the

hypothalamic–pituitary–somatotropic axis (HPS axis), or hypothalamic–

pituitary–somatic axis, also known as the hypothalamic–pituitary–growth axis),

(17) insomnia (most often early morning awakening), loss of appetite, and loss of

interest in sexual activity. Another feature of melancholia is a diurnal variation in

the severity of depressed mood, which is most severe early in the morning.(18)

Depression with significant associated anxiety is often quite resistant to

antidepressant regimens.(19)
1. The Corticotropin Releasing Hormone (CRH) and Locus Ceruleus-

Norepinephrine (LC-NE) Systems during Stress

Corticotropin Releasing Hormone (CRH) or Corticotropin

Releasing Factor (CRF) and its family of related naturally occurring

endogenous peptides and receptors are becoming recognized for their

actions within central (CNS) and peripheral (PNS) nervous systems. It

should be recognized that the term ‘CRH’ has been displaced by ‘CRF’.

(20)

The CRH system contributes to the transduction of many of the

components of the stress response. The intracerebroventricular infusion of

CRH to the rat sets into motion intense arousal, multiple fear-related

behaviors (for example : inhibition of exploration, anxiety), and inhibition

of neurovegetative functions that would be counterproductive during a

threatening situation (sleep, feeding, and reproductive activity).(14)

Two main components of the CRH system are the amygdala and

hypothalamic CRH systems. The amygdala CRH system is largely

responsible for the activation of anxiety and fear related behaviors, and

CRH antagonists given ICV or systemically block fear conditioning. The

amygdala CRH system also contributes to the activation of the

hypothalamic CRH system and the LC-NE system.

The hypothalamic CRH system is responsible for the regulation of

the hypothalamic-pituitary-adrenal axis and contributes to the activation of

the LC-NE system. The hypothalamic CRH systems consist of two

descending pathways. The first is humeral, in which CRH is released into

 the hypophyseal portal system to activate pituitary release of ACTH. A

second pathway descends to the brainstem to areas such as the LC-NE

system.(14)

There is also a peripheral CRH system that consists of CRH

released from sympathetic nerve terminals to locally activate components

of the innate immune system such as resident mast cells. CRH is among

the most potent activators of mast cell degranulation. Administration of

CRH antagonists to experimental animals attenuates experimentally

induced autoimmune disorders such as adjuvant induced arthritis and

myelin basic protein-induced encephalitis.

The LC-NE system is a general alarm system for the brain and

increases the signal-to-noise ratio in key areas that regulate the stress

response. It has many effects similar to those of CRH, such as the intense

arousal, inhibition of neurovegetative functions, and reciprocally activates

the amygdala and hypothalamic CRH systems. NE inhibits key functions

of the prefrontal cortex and enhances the encoding and resistance to

extinction of negatively charged emotional memories.

2. The Amygdala in Major Depression

Patients with major depression show increased cerebral blood

flow and metabolism in the amygdala. Activation in the left amygdala

persisted after recovery from depression. During depression, amygdala

activation correlated positively with depression severity and baseline

plasma cortisol levels. The latter finding is of interest in the light of the

fact that the amygdala activates the HPA axis. Glucocorticoids, in turn,
 accentuate the amygdala CRH system.(21) A recent study found that

neural activity in several 5-HT-related brain areas, for example, dorsal

raphe, habenula, septal region, amygdala, and orbitofrontal cortex,

covaried significantly with plasma levels of tryptophan and ratings of

depressed mood. Antidepressant treated patients who relapsed upon

tryptophan depletion had higher baseline amygdala metabolism that

similar subjects who do not relapse.

3. The hypothalamic-pituitary-adrenal (HPA) axis in depression

Figure 2. The hypothalamic-pituitary-adrenal (HPA) axis in depression

In depression, the hypothalamic-pituitary-adrenal (HPA) axis is

upregulated with a down-regulation of its negative feedback controls.

Corticotropin-releasing factor (CRF) is hypersecreted from the

hypothalamus and induces the release of adrenocorticotropin hormone

(ACTH) from the pituitary. ACTH interacts with receptors on

adrenocortical cells and cortisol is released from the adrenal glands;

adrenal hypertrophy can also occur. Release of cortisol into the circulation
 has a number of effects, including elevation of blood glucose. The

negative feedback of cortisol to the hypothalamus, pituitary and immune

system is impaired. This leads to continual activation of the HPA axis and

excess cortisol release. Cortisol receptors become desensitized leading to

increased activity of the pro-inflammatory immune mediators and

disturbances in neurotransmitter transmission.(22)(23)

C. Impact of corticotropin-releasing hormone (CRH) on gastrointestinal

motility and adrenocorticotropic hormone in normal controls and

patients with Irritable Bowel Syndrome (IBS)

Corticotropin-releasing hormone (CRH) plays a key role in modulating

intestinal motility in stressed animals.(24) Irritable bowel syndrome (IBS) is

presumed to be a disorder of the brain-gut link associated with exaggerated

response to stress. Irritable bowel syndrome (IBS) is characterized by idiopathic,

chronic recurrent abdominal pain associated with altered bowel habits.(25) CRH

is a peptide containing amino acids, distributed in the whole brain with dense

localisation in the paraventricular nucleus of the hypothalamus, and now

considered to be a major mediator of the stress response. Stress releases CRH

from the paraventricular nucleus and CRH stimulates pituitary ACTH secretion.

Growing evidence from animal experiments indicates that endogenous CRH plays

a role in mediating stress induced alteration of gastrointestinal motor function.

Intracerebroventricular administration of CRH mimics the effects of various

stressors in inhibiting small intestinal transit and stimulating colonic motor

function through autonomic pathways in rats. Stress induced alterations in

gastrointestinal motility in animals are abolished by intracerebroventricular

administration of the CRH antagonist, α helical CRH. (24)

A more plausible possibility is that intravenous CRH affects gut motility

through brain CRH receptors at circumventricular organs that are relatively

unprotected by the blood-brain barrier. This hypothesis (by researchers S Fukudo,

T Nomura, and M Hongo) is supported by the report that CRH given

intracerebroventricularly and intravenously was essentially equipotent in

modulating intestinal motility. In vitro effects of CRH on contractions of colonic

smooth muscle cells are not excitatory but inhibitory. In contrast, in vivo effects

of intracerebroventricular CRH on colonic motility is always excitatory.

Therefore, altered gastrointestinal motility in the research results is probably not

mediated by peripheral receptors, but by central CRH receptors in the

circumventricular organs. Administration of a specific antagonist would determine

the precise sites and effects of intravenous CRH on gut motility. In the study by S

Fukudo and his research team, they found that colonic motor function, of the

descending colon in particular, was stimulated by CRH. The mechanism by

which intracerebroventricular CRH influences colonic motility involves peripheral

cholinergic neurotransmission. This neurotransmission is probably mediated

through the sacral parasympathetic pathways. By replicating previous reports,

there is no significant difference in basal colonic motility between IBS patients

and healthy control subjects in this study. In contrast, provocation tests such as

loading psychological stress or injection of neostigmine are reported to induce

colonic dysmotility in IBS patients. These observations and their current data

suggest that the colon of IBS patients is hypersensitive to acetylcholine and

CRH which are presumably released by stress. Duodenal contraction was also

induced by intravenous CRH in humans for a short duration. A significantly

greater incidence of phase III within 15 minutes after CRH injection than that

within 15 minutes of the start of baseline suggested that this is not incidental.

Exogenous CRH induces a faster rhythm of the MMC period in the proximal

jejunum in dogs and increases post-prandial motor activities in humans,

suggesting its stimulatory action on motility of the small intestine in certain

species. Prolonged ambulatory recording of duodenal motility showed that most

IBS patients show increased incidence of clustered contractions under alert

conditions. In this study, administration of CRH in IBS patients induced duodenal

dysmotility with abdominal pain. These observations suggest that not only the

colon but also the small intestine is sensitive to the centrally derived stimuli in

IBS patients. They found an increased ACTH response to CRH in IBS

patients. Psychosocial stress onset and/or exaggeration of gastrointestinal

symptoms in the majority of IBS patients. The responses of the

hypothalamopituitary-adrenal axis during chronic stress in rats are characterised

by increased hypothalamic CRH mRNA and immunoreactive CRH, decreased

pituitary CRH receptors, higher pituitary content of ACTH, normal or slightly

elevated plasma ACTH, and hypersecretion of the ACTH responses to a novel

stress (new/different stress). Another study in this research showed that

pretreatment with short inescapable stress induced exaggerated ACTH secretion to

a novel stress, whereas cortisol secretion did not differ between previously

stressed and control rats. These results from stressed animals resemble their

human data. Stress experience may account for a sensitized ACTH response in the
pituitary gland and a desensitised adrenocortex of IBS patients. Furthermore, α2

adrenergic antagonists potentiate exogenous CRH induced ACTH secretion in

rats. A blunted growth hormone response to desipramine in IBS patients, which

suggests impaired α2 adrenergic function, was also reported. Therefore,

exogenous CRH induced ACTH hypersecretion in IBS patients may be due to α2

blockade in the brain. It is also possible that decreased levels of CRH binding

protein, which inhibits the ACTH releasing properties of CRH, may play a role in

ACTH hypersecretion in IBS patients.(24)

Patients with depression have CRH hypersecretion in the brain,

especially the paraventricular nucleus. Neuronal circuits relay visceral information

to these nuclei. Distension of the distal colon increases the firing rate of the locus

caeruleus. As the majority of IBS patients have a decreased visceral threshold to

colonic distension, increased visceral information to the locus caeruleus may

cause more activation of CRH neurones in the paraventricular nucleus. Exogenous

CRH decreases the visceral threshold to rectal distension in humans and this

mechanism probably relates to CRH induced abdominal symptoms in IBS patients

as well as motility change. Furthermore, intravenous administration of CRH

decreases slow wave sleep in humans and the proportion of rapid eye movement

(REM) sleep is notably increased in IBS patients.(26) They previously reported

the stress induced increase in electroencephalographic beta power in IBS patients.

These findings support their hypothesis that CRH is increased in the brain of IBS

patients.

The conclusion in the study, intravenous administration of CRH partially

mimicked the stress response of the gastrointestinal motility and neuroendocrine

response in humans. These responses were exaggerated in IBS patients. Their

present study suggests that CRH plays an important role in modulating brain-gut

functions under stress in humans, and that this neuropeptide relates to the

pathophysiology of IBS.(24)

Conclusion

In conclusion, patients with Major depression (clinical depression) may

affect gastrointestinal disease such as Irritable Bowel Syndrome because of

overstimulating-stress that caused by some hormone especially CRH system that

has big role in contribution for the transduction of many of the components of the

stress response in the brain.

Also, patient with Major depression has risk of weaken immune system,

for example, it is now apparent that, in major depression, there is a relationship

between the severity and duration of the disorder and the increased frequency of

heart disease, type-2 diabetes, various autoimmune diseases, arthritis and cancer.

(27)

In summary, there is correlation between Irritable Bowel Syndrome and

depression. However, this association is multifactorial, and there is a need for

more research to further elucidate the association and to propose therapeutic and

preventative approaches to IBS and depression.

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Picture :

1. Figure.1 : Mudyanadzo TA, Hauzaree C, Yerokhina O, Architha NN,

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axis in depression [Internet]. Lundbeck Institute Campus. Lundbeck

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