Soluble protein is a key factor linking early life stress to the development of irritable bowel syndrome (IBS)

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Researchers from the School of Chinese Medicine (SCM) at Hong Kong Baptist University (HKBU) have found that the abnormal rise of a soluble protein called Nerve Growth Factor is a key factor linking early life stress to the development of irritable bowel syndrome (IBS).

The study, which is the first to demonstrate the link between traumatic psychological events occurring in childhood and lifelong health repercussions, could lead to the development of new treatments for gastrointestinal diseases.

IBS is a common functional bowel disorder characterized by stool irregularities, abdominal discomfort and bloating. While evidence increasingly links the impact of early life adversity with the development of IBS later on in life, the underlying mechanisms which translate a psychological event into gastrointestinal disease have remained elusive.

This is especially pertinent since the disease in question, IBS, is widespread globally, including in Hong Kong.

IBS presents a large health burden but there is currently no known cure. As a result, a better understanding of its development may present new ways to treat the disease.

The HKBU research team, which was led by SCM Chair Professor Bian Zhaoxiang and Research Assistant Professor Dr Xavier Wong Hoi-leong, found that Nerve Growth Factor (NGF), a neurotrophic factor essential for neuronal development in the nervous system, was highly elevated in the gut of mice in response to early-life stress induced by neonatal maternal separation (NMS).

This elicited IBS-like-symptoms in the animal model.

Regarding the mechanism, NGF acts on intestinal stem cells (ISCs) directly to promote their growth and proliferation.

The significantly increased number of ISCs in the gut leads to abnormally high numbers of enterochromaffin (EC) cells, a type of intestinal cell responsible for serotonin secretion, which results in aberrantly high serotonin levels. Aberrant serotonin production in the gut is known to cause IBS.

To uncover the mechanism by which early life stress alters intestinal homeostasis, the researchers set up an animal model of early life stress, known as NMS.

They found that mice which experienced early-life stress went on to develop life-long IBS-like symptoms.

In addition, the number of ISCs and EC cells in the gut increased significantly by 50%.

The animal model showed that the elevated secretion of serotonin, which is due to the increase in EC cell density in the gastrointestinal tract, triggered visceral hyperalgesia.

This results in heightened pain in the gastrointestinal tract, which is a hallmark of IBS.

To inhibit the activity of NGF, the team administered a specific NGF-blocking antibody into the animal model.

This did not only reduce ISCs and EC cell numbers but also caused the IBS-like symptoms to completely disappear in the animal model.

Importantly, they analyze HKBU clinical data and found a significant positive correlation between NGF and serotonin in the sera of diarrhea-predominant IBS patients, NGF and serotonin increased by around 30% and 75% respectively in the IBS patients, comparing with healthy one, reinforcing the causal link between NGF and serotonin in the development of IBS.

This shows a man holding his stomach

The researchers concluded that NGF is a key driver of the development of IBS following early-life stress. The image is in the public domain.

The researchers concluded that NGF is a key driver of the development of IBS following early-life stress.

Their work not only highlights the importance of NGF as a novel target in treating IBS, but also demonstrates that early-life adversity, such as a lack of parental care or abuse, may have serious lifelong health consequences.

Their findings, entitled “Early life stress disrupts intestinal homeostasis via NGF-TrkA signaling”, was published in the prestigious international journal Nature Communications (April 2019).

The team plans to continue to investigate the therapeutic potential of NGF-inhibitors as a treatment for IBS, including those found in Chinese medicine, and will strive to uncover the complete chain of events that link childhood stress to the development of IBS in adulthood.


Irritable bowel syndrome is a functional gastrointestinal disorder meaning there are no biochemical or structural abnormalities on investigation.1 However, it is treatable and it is among the most common complaints presenting to GPs2 affecting about 9% of Australians.3

The syndrome is characterised by recurrent abdominal pain, related to defecation, and is associated with a change in stool frequency or form.4 It is subtyped by the predominant stool form as follows:

  • diarrhoea predominant (IBS-D)
  • constipation predominant (IBS-C)
  • mixed subtype (IBS-M).

The diagnostic criteria, referred to as the Rome criteria, are based on an expert consensus governed by the Rome Foundation (see Box 1).5

Box 1

The Rome IV diagnostic criteria* for irritable bowel syndrome

Recurrent abdominal pain, on average, at least one day per week in the last three months associated with two or more of the following criteria: 
1. Related to defecation 
2. Associated with a change in the frequency of stool 
3. Associated with a change in the form (appearance) of stool
     * Criteria fulfilled for the last three months with symptom onset at least six months before diagnosis.
     Source: reference 5

Given the broad definition of irritable bowel syndrome, it is likely to represent multiple different conditions, each developing from unique pathophysiological mechanisms.6 These include intolerance to particular foods, hypersensitivity to pain and psychosomatic manifestations of anxiety or stress. Other associated mechanisms include low-grade inflammation, altered microbiota, genetic factors and altered 5-HT (5-hydroxytryptamine) metabolism.

Irritable bowel syndrome can result in significant disability, reduced quality of life and impaired workforce productivity.7 Fortunately, it is not directly associated with mortality8 or an increased risk of gastrointestinal malignancies.9Go to:

Diagnosis

Irritable bowel syndrome is not a diagnosis of exclusion. A positive diagnosis should be based on the presence of characteristic symptoms4 (Box 1), and the absence of red flags. Patients with red flags should be referred for further investigation, including imaging or specialist review (Box 2).6 A significant proportion of patients with irritable bowel syndrome may have symptoms that overlap with another functional gut disorder.

Box 2

Red flags that require further testing or specialist assessment

Age over 50 years, no previous colon cancer screening and presence of symptoms 
Recent change in bowel habit in people over 50 years of age 
Evidence of overt gastrointestinal bleeding (i.e. melaena or haematochezia) 
Nocturnal pain or passage of stools 
Unintentional weight loss 
Family history of colorectal cancer or inflammatory bowel disease 
Palpable abdominal mass or lymphadenopathy 
Evidence of iron deficiency anaemia on blood testing 
Positive test for faecal occult blood
     Adapted from reference 6

Initial testing should be minimally invasive. Full blood counts, urea and electrolytes, C-reactive protein and liver function tests would constitute reasonable initial investigations.

Coeliac serology should be considered as there is a significantly increased risk of coeliac disease among patients with symptoms that fit the Rome criteria for irritable bowel syndrome.10 

Genetic testing for coeliac disease is not recommended – it is unlikely to discriminate between irritable bowel syndrome and coeliac disease because more than 30% of the population share the HLA-DQ2/8 gene.11

The symptoms of irritable bowel syndrome share similarities with inflammatory bowel disease and gastrointestinal malignancies.

The concern of organic gastrointestinal pathology, even in the absence of red flags, may prompt many clinicians to recommend an endoscopic assessment.

There is no role for a faecal occult blood test to exclude gastrointestinal malignancy in patients with symptoms of irritable bowel syndrome.12 

A normal faecal calprotectin test result, which measures intestinal inflammation, reduces the need for endoscopy to rule out inflammatory bowel disease.13

Understandably, many clinicians are not confident to make a diagnosis of irritable bowel syndrome without specialist assessment.

However, clinicians should be reassured that patients presenting with symptoms of irritable bowel syndrome in the absence of red flags are extremely unlikely to be affected by serious organic illness.14Go to:

Treatment

The treatment for irritable bowel syndrome should involve addressing the patient’s concerns, and prescribing treatments that tackle the mechanisms underpinning their symptoms.

The consultation

An appropriately conducted consultation can be therapeutic for a patient with irritable bowel syndrome. However, only a minority of patients consult their GP, and an even smaller proportion seek specialist care.15 

Clinicians should therefore recognise that patients who present with irritable bowel syndrome require a holistic consultation.

A positive diagnosis and reassuring explanation of irritable bowel syndrome should be delivered in an empathetic manner, while allowing time for the patient to discuss their concerns.

randomised controlled trial showed patients who were given sham acupuncture were less likely to have adequate relief of irritable bowel syndrome symptoms compared with patients who received sham acupuncture combined with a ‘warm empathetic’ consultation (44% vs 62%, p<0.001).2

Diet

Many patients with irritable bowel syndrome report aggravated gastrointestinal symptoms related to specific foods.16 

This perception lends itself well to a therapeutic manipulation of diet. However, clinicians should be mindful of overly restrictive eating patterns,17 and dietary manipulation should be supervised by a dietitian.

General dietary advice

The UK’s National Institute of Health and Care Excellence (NICE) recommends eating smaller frequent meals, avoiding trigger foods, and avoiding excess alcohol and caffeine. This diet has been found to be as effective as a low-FODMAP diet (low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols) for the diarrhoea-predominant irritable bowel syndrome.16

Fibre

Insoluble fibres are more likely to worsen abdominal pain and bloating in patients with irritable bowel syndrome.6 However, soluble fibres such as psyllium improve symptoms, especially in patients with the constipation subtype.18

Low-FODMAP diet

Foods containing FODMAPs (which are short-chained carbohydrates) are poorly absorbed by the small intestine.

This leads to an osmotic effect in the colon and excess gas production causing pain and diarrhoea.

A low-FODMAP diet has been proven to significantly reduce symptoms related to irritable bowel syndrome compared to a regular Australian diet.19 

Patients with irritable bowel syndrome, especially those with the diarrhoea subtype, should consider a low-FODMAP diet as their initial therapy. Individual symptoms of pain and bloating seem to respond to this diet.

A dietitian-supervised low-FODMAP diet involves an exclusion phase where patients reduce FODMAP-containing foods over six weeks.

If the patient reports a significant reduction in symptoms, FODMAP-containing foods can be carefully re-introduced over subsequent weeks. Remaining on an exclusively low-FODMAP diet in the long term has been shown to transform the intestinal microbiota to a potentially negative profile,19 and therefore is not recommended.

General lifestyle advice

Symptoms of irritable bowel syndrome can be mitigated by regular exercise20 which should be recommended in conjunction with dietary advice. The importance of sleep should also be discussed as improved quality of sleep has been found to control symptoms.21

Medicines

Drugs exclusively developed for irritable bowel syndrome are not available in Australia, unlike the USA and Europe. Most of the drugs used here were designed for other indications.

Mebeverine and hyoscine

Antispasmodic drugs have only modest effects in irritable bowel syndrome and have a limited role.22 Although hyoscine has greater evidence for symptom relief,23 it is associated with significant adverse effects including constipation and dry mouth.

Peppermint oil

Peppermint oil acts as an antispasmodic through smooth muscle calcium channel antagonism.24 A systematic review found that it significantly reduces symptoms compared with placebo.25

Antidepressants

Antidepressants can significantly reduce symptoms of irritable bowel syndrome.26 They are purported to work by manipulating visceral hypersensitivity and abnormal central pain sensitisation.24 Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) have both demonstrated benefit.26 Tricyclics are ostensibly used for the diarrhoea subtype due to their known adverse effect of constipation. Similarly, SSRIs may be better used for the constipation subtype due to their adverse effect of diarrhoea. Although SSRIs have been shown to be of benefit,26 the exact dose and their use are not universally accepted for the treatment of irritable bowel syndrome.

It is important to advise patients that antidepressants are used for their neuropathic-pain-modulating effect, rather than for an antidepressant effect. Patients should take a low dose of the antidepressant every day for 4–6 weeks before assessing efficacy.

Rifaximin

Rifaximin has a limited role in irritable bowel syndrome and it is not subsidised by the Pharmaceutical Benefits Scheme for this indication. It is a non-absorbed antibiotic that modestly reduces symptoms of non-constipating irritable bowel syndrome compared to placebo.27 Despite theoretical concerns of developing persistent bacteria that are resistant to rifaximin, studies have not demonstrated this to be the case.

Probiotics

Probiotics possibly have a role in irritable bowel syndrome but the dose and strain needed for benefit is not clear. Of the products available in Australia, the strains and doses are too varied to provide a meaningful recommendation based on evidence.28


Source:
Hong Kong Baptist University
Media Contacts: 
Mavis Wong – Hong Kong Baptist University
Image Source:
The image is in the public domain.

Original Research: Open access
“Early life stress disrupts intestinal homeostasis via NGF-TrkA signaling”. Hoi Leong Xavier Wong, Hong-yan Qin, Siu Wai Tsang, Xiao Zuo, Sijia Che, Chi Fung Willis Chow, Xi Li, Hai-tao Xiao, Ling Zhao, Tao Huang, Cheng Yuan Lin, Hiu Yee Kwan, Tao Yang, Frank M. Longo, Aiping Lyu & Zhao-xiang Bian.
Nature Communications. doi:10.1038/s41467-019-09744-3

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