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20+ IBS Contributing Factors & Genetics

Written by Puya Yazdi, MD | Last updated:
Medically reviewed by
Genius Labs Science Team | Written by Puya Yazdi, MD | Last updated:

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IBS
Irritable Bowel Syndrome is a diagnosis of exclusion, which means that doctors diagnose it after eliminating all the other possibilities. The causes of IBS are still largely unknown, but preliminary research points to different genetic, hormonal & dietary factors that may play a role. Read on to learn the details about each one.

What is Irritable Bowel Syndrome?

The NIH estimates that as many as 20% of Americans may experience signs of IBS, but doctors still don’t know the exact causes behind this syndrome [1].

As you will see, IBS is a complex disease and there are many potential variables in the web of causes.

There are two main types of IBS – one that involves Diarrhea (IBS-D) and one that involves Constipation (IBS-C).

Food goes from stomach -> small intestine -> large intestine.

The large intestine is loaded with bacteria, but the rest of the gastrointestinal tract has relatively few bacteria under normal conditions. When a person has bacteria in the small intestine, unabsorbed carbohydrates are fermented there, producing significant amounts of gas.

This can cause cramping and burning because the gas stretches the small intestine. The gas can also push the intestinal content rapidly toward your large intestine to cause diarrhea. Bacteria generally ferment in the small intestines when gut ‘flow’ (motility/peristalsis) is slowed down in this area [2, 3].

When people have diarrhea, it usually means the flow is quickened in the large intestine.

Gut pain comes from the neurons in the gut being ‘hypersensitive’. When the intestines expand, this is sensed by the neurons in the gut. If neurons are hypersensitive, this distension will feel uncomfortable or hurt.

This post is mainly about IBS, but other gut problems may stem from the same causes.

Potential Contributing Factors

None of the below factors are established causes of IBS. According to preliminary research, they may play a role in this complex syndrome, but the evidence is inconclusive. If you recognize one or more of these factors in your case, it doesn’t mean you have IBS. If you’re experiencing digestive issues, work with your doctor to get adequate diagnosis and treatment.

1) Stress

Chronic stress response activation (HPA) is believed to be a contributing factor of anxiety disorders, bipolar, insomnia, PTSD, borderline personality, ADHD, major depression, burnout, chronic fatigue syndrome, fibromyalgia, IBS, alcoholism, and other diseases [4].

Chronic stress is probably the most common and significant cause of gut flow (motility) changes. Indeed, increased activation of the stress pathway (HPA axis) is associated with IBS [5].

CRH

The effects of stress on the gut mostly have to do with the effects of Corticotropin-Releasing Hormone (CRH), which is released from the hypothalamus when stressed [6].

CRH may play a role in IBS by increasing the flow or motor speed in the colon and decreasing it in the small intestine. When the flow is decreased in the small intestine, bad bacteria overgrow by feeding on carbs and produce gas [7].

This fermentation in the small intestine can increase methane-producing bacteria from carbs, which produces methane gas [8, 9].

People who get IBS are more susceptible to gut dysfunction when CRH is released. In IBS, there are increased HPA axis responses to stressors such as meals, hormones and mental stress compared to controls [7, 10].

Therefore, stress is more harmful to people with IBS with regard to gut function.

CRH also causes the gut to be ‘hypersensitive’ and experience pain more. When given a drug that blocks CRH, some patients experienced pain relief [11].

CRH may also play a role by:

  • Increasing inflammation (Th1 dominance, Nf-kB, IL-1b, IL-6, TNF (13X), MHC-II (HLA-DR), TLR-4 and ICAM-1 expression) [12, 13].
  • Mediating autoimmunity. In rheumatoid arthritis, Hashimoto’s and UC, inflamed tissues contained large amounts of CRH [14]. In a mouse model of arthritis, blocking CRH reduced inflammation and markers of cartilage destruction [15].
  • Activating mast cells and therefore histamine issues, which explains in part why stress induces allergic symptoms [14].

Stress will also cause the release of various neurotransmitters (catecholamines), which decreases intestinal flow [16].

Chronic stress or frequent activation of the HPA axis can cause oxidative stress as well [17].

Check out the posts on why stress is bad and all of the triggers of stress response for more details.

Adrenaline

Adrenaline and noradrenaline, through ADRA2A receptors, may inhibit gut flow [18].

In addition, they cause a short-lived increase in blood pressure, but a long term decrease in blood pressure. They also cause sedation and thicker blood (platelet aggregation) [18].

These can be common symptoms in people with IBS-C.

2) Inflammation

In some sense, IBS may be considered IBD-lite, which means it’s like IBD (Crohn’s, colitis), but with lower levels of inflammation. Patients with IBD experience IBS-like symptoms when their IBD cools down [19].

A three-year study found that patients diagnosed with IBS were 16.3 times more likely to be diagnosed with IBD during the study period [19].

The risk of developing IBS increases sixfold after acute gut infection. After salmonella, the risk can increase by 8X. This may be because infections cause inflammation and oxidative stress [20, 21].

Inflammation can affect the gut in many ways. One way is by activating our stress response/HPA axis [22].

People with IBS may have immune reactions to dietary proteins. In one study, food elimination based on IgG antibodies resulted in a significant decrease in symptoms of IBS [23].

Mast cells may increase in intestinal mucosa in patients with IBS, especially by intestinal nerves. According to limited research, they can directly influence gut flow and result in an increase in abdominal pain and discomfort [23].

There’s evidence that anti-inflammatory drugs such as Mesalazine help treat IBS. Mesalazine helps to normalize the gut flora and reduce gut permeability [24].

A wide variety of inflammation types can cause IBS. There’s no one cytokine that’s dominant.

According to some authors, people with IBS are more like to have:

  • Th1 Dominance – people with IBS are more likely to be Th1 dominant (elevated IL-12) [20]. Interferon reduces serotonin in the gut and also increases oxidative stress (by activating IDO) [25]. However, people with Th2 can also have IBS because of Mast cells and other types of inflammation.
  • Th17 Dominance [26]
  • Th2 Dominance [10] – Th2 cytokines quicken gut flow. Stimulated IL-5 and IL-13 are higher in IBS.
  • Higher TNF [27, 28] especially IBS-D [29]
  • Higher IL-1b [27]
  • Higher IL-6 [30, 27] – capable of stimulating gut neurons [10]
  • Higher CRP – People with IBS have an average hs-CRP of 1.17, while healthy controls have a level of 0.72 [31]. Your doctor wouldn’t blink at this difference, but the science begs to differ.
  • Higher IL-8 [29]
  • High Nf-kB Activation [32]
  • Low Tregs (Tregs decrease general inflammation) [33]
  • Low IL-10 (an anti-inflammatory cytokine) [28] – especially in males [34]
  • TGF-b – Intermediate producers [29]
  • Mast Cell Activation and increased Lymphocytes in the mucosa and lamina propria [22, 35]

If you click on the linked articles, you’ll see how each parameter may impact inflammation and get some inflammation-lowering tips.

3) Oxidative Stress

In some people with IBS, markers of oxidative stress were significantly higher – specifically, blood levels of xanthine oxidase (XO), adenosine deaminase (AD), malondialdehyde (MDA) and nitric oxide (NO).

The enzymes that break down oxidants were significantly lower (Superoxide dismutase (SOD), Catalase (CAT), and Glutathione peroxidase (GPx) [36].

4) Bad Diet: Excess Sugar

When bacteria in our gut consume sugar, they stop producing molecules (AhR ligands) that are necessary for our gut protection against pathogens such as candida [25]. These bad pathogens then overgrow.

When sugar is the energy source for our gut microbes, they stop consuming tryptophan and serotonin is reduced. Serotonin is necessary for proper gut function [25].

So stay away from added sugars.

Also, added sugars, sugared drinks, and foods made from flour (bakery products and pasta) are the ones that are most easily fermented by bacteria to cause intestinal gas.

A lack of plants or natural antimicrobials contributes to the bacteria in your gut.

5) Microbial Imbalance and Infections

Individuals with IBS may have decreased diversity and numbers of beneficial microbiota and protective strains such as L. reuteri [37].

L. reuteri switches consumption from sugar to tryptophan and produce the molecules for our gut protection (AhR ligands – 3-IAld).

In one study, L. Reuteri increased gut motility and decreases pain perception [38].

Novel research suggests microbial infections as important contributors to IBS [39, 40].

6) Antibiotic Usage

Antibiotics may disturb the gut microbiome by killing good bacteria; their use is among the potential risk factors for developing IBS [41, 42].

However, some antibiotics like rifaximin may have treatment potential [43].

Further research should cast more light on the connection between the microbiome, antibiotics, and IBS.

7) Intestinal Permeability

Intestinal permeability plays a role in a range of health disorders, including IBS and IBD [44, 5].

Stress can increase gut permeability. In animal models, both acute and chronic stress enhance the ability of bacteria to adhere and penetrate the gut, which causes gut inflammation [5].

Hypersensitivity from stress results from an alteration of colon permeability [5].

According to preliminary research, probiotics such as L. plantarum [45], L. rhamnosus, B. infantis, and S. boulardii may reduce gut permeability and inflammation [5].

Lectins and gluten might also increase gut permeability in sensitive individuals [46, 47]. Elimination diets such as the Lectin Avoidance Diet may help identify food irritants, but their therapeutic value remains unknown.

8) FODMAPs

FODMAPs are types of fiber that result in fermentation and associated gas production, which can cause gut distension and bloating.

Preliminary research shows some IBS improvement when people go on a low FODMAP diet [48].

9) Serotonin

Most of the serotonin in the body (95%) is found in the gut [25].

Serotonin quickens gut flow by speeding up motor neurons and releases chloride. In one study, serotonin cells were significantly higher in IBS-D and lower in IBS-C than in controls [49].

This makes sense. If there’s less serotonin, constipation will occur and if there’s too much, diarrhea will occur.

Serotonin transport is also reduced in some patients with IBS, possibly because of interferon-gamma (Th1) [50].

10) Excess IDO, Low Tryptophan

The enzyme IDO1 degrades tryptophan into kynurenine and is needed to create Tregs (Good) [51].

However, IDO1 may sustain self-attacking antibody production by B cells (Bad), and contribute to chronic inflammation [51].

Some researchers think too much IDO may contribute to IBS. The conversion of tryptophan to kynurenine causes too much oxidative stress in the gut and too little serotonin [25].

High kynurenine and low tryptophan is a potential marker for IBS, but this imbalance is found in other inflammatory conditions, so it’s not specific [25].

Inflammation from interferon gamma (Th1 cytokine) or LPS from bacterial infections will increase IDO [52].

Some studies have found that interferon gamma increases in the small intestine after consuming gluten (by gluten-sensitive patients without celiac disease) [25].

IBS And The Gut Immune System:

AhR is a receptor in gut cells that helps the development of tolerance to proteins and also curbs the growth of bad bacteria (candida) by producing antimicrobial peptides. It regulates the number of Tregs, cytotoxic T cells, B cells and mast cells [53].

Too little activation of this gut immune system may result in autoimmunity and allergies [53].

Good bacteria (LAB such as L Reuteri) eat tryptophan as a source of energy and produce molecules that activate AhR [25]. Kynurenine also activates AhR [54].

This may curb the growth of Candida and boosts the growth of good bacteria (lactic acid bacteria) [25].

Without tryptophan in their ‘diet’, microbes do not produce molecules that activate AhR (IAld). This results in less good bacteria (lactobacilli) and more bad bacteria (Candida), which may be a marker of IBS [25].

However, it’s a double-edged sword because tryptophan metabolism will cause oxidative stress [25].

Cruciferous veggies contain indoles, which activate AhR and may contribute to a favorable microbial environment in the stomach [25].

A variety of herbal extracts such as ginseng, licorice, Gingko Biloba may cause AhR activation, but the clinical significance of this effect is not clear [54].

AhR activation is not always positive, as it can activate mast cells [25].

11) TGR5 and Bile

TGR5 is a receptor that lines our gut and is activated by bile acids and some herbs [55].

It enhances energy expenditure, increases oxygen consumption, prevents obesity, and decreases insulin resistance in a mice model of obesity. In humans, it converts T4 into T3 [55].

TGR5 and its activation by bile acids speed up the gut flow [55].

Mice without TGR5 have leaky gut [55].

Therefore, a deficiency of bile could lead to IBS-C and too much bile could lead to IBS-D. (See below for variations in the TGR5 receptor) [55].

Indeed, up to 30% of people with IBS-D have bile acid malabsorption (which is a different condition, but the results are similar: diarrhea). Some of them do well with bile acid sequestrants [56].

Still, the science behind this connection is young and requires further confirmation.

12) Low Stomach Acidity

Stomach acidity prevents the growth of bacteria. If the stomach isn’t acidic enough, more bacteria will reach the small intestine.

A meta-analysis found that proton pump inhibitors, which suppress stomach acid, can contribute to small intestinal bacterial overgrowth (SIBO) [57].

IBS and Hormones

The section below discusses possible connections between different hormones and IBS, based on preliminary research. None of these hormones are established diagnostic criteria. If your lab results for any hormone are irregular, make sure to discuss them with your doctor.

13) Excess CCK

CCK may contribute to gas production after meals. This might be because of activation of the vagus nerve or because CCK directly interacts with the hypothalamus to stimulate the colon [58].

14) Excess Cortisol

Cortisol is unusually high in some women with IBS [59].

CRH may cause significantly more ACTH and cortisol to be released in people with IBS when compared to people without IBS [7].

When researchers evaluated the psychological stress in one study, they found that higher cortisol levels in IBS could not be explained by differences in psychological stress [60].

15) Sex Hormones: Testosterone, Estrogen, Progesterone

According to limited clinical evidence, low estrogen and progesterone may play a role in IBS. Their receptors are found in the gut [60].

Some women are more likely to experience symptoms such as stomach pain, diarrhea, nausea, and bloating when estrogen and progesterone drop down to the lowest levels in the body (during the menses) [60].

During the low estrogen and progesterone phase (menses), some women with IBS are more sensitive to gut pain. Bloating also seems to be worse during the phase associated with higher progesterone (the luteal phase) [60].

16) Decreased Motilin

Motilin is a hormone that stimulates the gut flow and is normally decreased after meals but increased in between meals or fasting. Insulin inhibits motilin [61].

Some IBS patients have decreased motilin response to both a meal and water. However, they show an increase in motilin in response to mental stress and this causes abnormally increased gut activity [60].

17) Excess VIP

VIP stimulates the intestines. It stimulates the secretion of water and electrolytes, bicarbonate and pepsin (an enzyme) and inhibits gastric acid secretion [62].

Thus, it may contribute to cramps and watery diarrhea when highly concentrated in the gut [59].

In two studies, VIP was twice as concentrated in IBS patients compared to control subjects [60].

In another study, VIP was only high in women with IBS-D [35].

18) Low PYY

PYY stimulates the absorption of water and electrolytes and inhibits PGE2 and VIP, which stimulates intestinal fluid secretion [49].

It acts to slow down the small intestines. According to preliminary research, PYY cells are reduced in both IBS-D and IBS-C [49].

19) Ghrelin

In one trial, ghrelin cell density was significantly higher in IBS-D and lower in IBS-C than in the controls [63].

20) Secretin, GIP

In some IBS-diarrhea patients, there are fewer cells that release CCK, secretin, GIP, and somatostatin [64].

These hormones stimulate bicarbonate, enzyme secretion, and gall bladder contraction (CCK) [64].

21) Other

According to limited clinical evidence, irregular levels of the following hormones may also be found in IBS patients:

  • Oxyntomodulin [65]
  • Somatostatin [63]
  • Substance P [35]
  • TRH [66]

Once again, the role of the above hormones in IBS is not well established. The findings presented here should drive further research but shouldn’t be used to make any health recommendations.

IBS and Other Factors

22) Defective Mucus Layer

The gut mucus layer is an important barrier to keep out the microbes. If it’s not functioning properly (not enough mucin), bacteria may cross over, cause inflammation and disturb the gut microbiota. These changes are common in IBS patients [67, 68].

23) Guanylate cyclase 2C

Guanylate cyclase 2C is a receptor in your gut cells that influences gut flow. When it’s activated, it speeds up the flow.

A drug called Linaclotide uses this mechanism (FDA approved in 2012 for IBS-C). It reduces the activation of sensory neurons in the colon, potentially reducing pain. At the same time, it activates colonic motor neurons, which increases gut flow and thus promotes bowel movements [69].

24) Nutrient Deficiencies

Vitamin D deficiency may contribute to IBS and some case reports show improvement in symptoms [70].

A low intake of vitamin B6 may correlate with worse symptoms of IBS [71].

The research is far from conclusive. Well-designed clinical trials should investigate the connection between these nutrients and IBS.

Soluble fiber supplementation (e.g., psyllium husk) appears to be safe effective for IBS symptoms [72].

IBS Genetics

It’s important to note that just because certain genotypes are associated with a condition or irregular lab marker, it doesn’t necessarily mean that everyone with that genotype will actually develop the condition! Many different factors, including other genetic and environmental factors, can influence the risk of IBS.

Inflammation

IBS/IBD individuals are less often HLA-DQ 2/8 positive than healthy controls, according to one study [73].

People with a genetic predisposition to produce higher TNF are more likely to have IBS and IBD. The (A) allele of TNF-308 (rs1800629) is associated with higher levels of TNF. 41% of people with one A allele had IBS vs 26% of the people with no A alleles [28].

Transit

A variant in the FGF4 gene (rs351855 – TT) may be associated with slower gut transit [74].

Bile

A gene variation of TGR5 (rs11554825), a bile acid receptor, was associated with a quicker gut flow. The TC/CC group had an average 50% faster gut flow compared with the TT group in one trial [75].

Oxidative stress

The Glycine transporter (GLYT1) is essential for the protection of gut cells against oxidative damage. This is controlled by the SLC6A9 gene (rs3791124).

Excluding Other Conditions

Conditions with IBS-like symptoms include parasitic infections, lactose intolerance, SIBO, and celiac disease. However, SIBO goes hand and hand with most cases of IBS, so they might not even be separate diseases.

The following investigations should be performed to exclude other conditions [40]:

  • Stool microscopy and culture (to exclude infectious conditions)
  • Blood tests: Full blood examination, liver function tests, erythrocyte sedimentation rate, and serological testing for coeliac disease
  • Abdominal ultrasound (to exclude gallstones and other biliary tract diseases)
  • Endoscopy and biopsies (to exclude peptic ulcer disease, coeliac disease, inflammatory bowel disease, and malignancies)
  • Hydrogen breath testing (to exclude fructose and lactose malabsorption)

Associated Conditions

Several medical conditions may appear with greater frequency in patients diagnosed with IBS [76]:

  • Up to 94% of IBS patients have psychiatric disorders – most commonly anxiety and depressive disorders
  • IBS occurs in 51% of chronic fatigue syndrome patients and 49% of fibromyalgia patients
  • IBS occurs commonly with migraines and headaches

About the Author

Puya Yazdi

Puya Yazdi

MD
Dr. Puya Yazdi is a physician-scientist with 14+ years of experience in clinical medicine, life sciences, biotechnology, and nutraceuticals.
As a physician-scientist with expertise in genomics, biotechnology, and nutraceuticals, he has made it his mission to bring precision medicine to the bedside and help transform healthcare in the 21st century.He received his undergraduate education at the University of California at Irvine, a Medical Doctorate from the University of Southern California, and was a Resident Physician at Stanford University. He then proceeded to serve as a Clinical Fellow of The California Institute of Regenerative Medicine at The University of California at Irvine, where he conducted research of stem cells, epigenetics, and genomics. He was also a Medical Director for Cyvex Nutrition before serving as president of Systomic Health, a biotechnology consulting agency, where he served as an expert on genomics and other high-throughput technologies. His previous clients include Allergan, Caladrius Biosciences, and Omega Protein. He has a history of peer-reviewed publications, intellectual property discoveries (patents, etc.), clinical trial design, and a thorough knowledge of the regulatory landscape in biotechnology.He is leading our entire scientific and medical team in order to ensure accuracy and scientific validity of our content and products.

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