Ulcerative colitis is a chronic disease that results in inflammation of the colon's innermost layer.

15 Proven Facts about IBD (Ulcerative Colitis and Crohn’s)- Genetics, Lifestyle Factors, Gut Flora, and Infections

Ulcerative colitis and Crohn’s are two major types of Inflammatory Bowel Diseases (IBDs), which are chronic inflammatory digestive problems of unknown causes. Read this post to learn more about genetics, lifestyle factors, immune system activation, and infections that contribute to IBDs.

ncpgasthep0528-f1
http://www.nature.com/nrgastro/journal/v3/n7/full/ncpgasthep0528.html

Crohn’s and Ulcerative Colitis Introduction

Crohn’s and Ulcerative Colitis are two of the most frequently diagnosed subtypes of inflammatory bowel diseases (IBD).

IBDs are chronic inflammatory diseases characterized by inflammation and sores in the gut lining, which can result in diarrhea, abdominal pain, fatigue, fever, rectal bleeding, nutritional deficiencies, and weight loss (R).

Both innate and acquired immunity are activated in IBD, although Crohn’s and colitis follow different patterns of T-cell activation.

Characteristics of Crohn’s Disease

Crohn’s may affect any portion of the gastrointestinal tract, but mostly in the ileum (lower portion of the small intestine) (R).

Crohn’s disease mainly involves Th1 and Th17 overactivation (R).

Crohn’s disease involves ulcerations of all cell layers of the gut lining (R).

Characteristics of Ulcerative Colitis

Ulcerative colitis typically affects the colon and rectum (R).

It is mainly a Th2 dominant condition, although in some cases it is not clear (R).

Ulcerative colitis involves the inflammation of the mucosal layer (innermost cell layer) of the gut (R).

Causes and Risks Factors of Crohn’s and Colitis

Genetics

If someone has Crohn’s, their identical twin with the exact same genetics has 50% chance of developing Crohn’s (R).

If someone has ulcerative colitis, their identical twin has 10% chance of developing colitis (R).

Genetics, therefore, contributes to the development of IBD, but is not the sole cause.

Genes that have been associated with Crohn’s and colitis include:

1) CARD15 is Associated with Crohn’s Disease

CARD15 binds to bacterial cell wall, and activates NF-kB, which then stimulates production of proinflammatory signals (R).

CARD15 mutation results in defective innate immune response to gut bacteria, which can cause dysbiosis in IBD (R).

2) OCTN1 and OCTN2 are Associated with Crohn’s Disease

Two genetic mutations that in OCTN1 and OCTN2, SLC22A4 and SLC22A5, respectively, have been associated with Crohn’s disease (R).

These mutated genes are mostly expressed in the gut lining, macrophages, and T cells, and cause decreased carnitine transport (R).

However, there is still no direct evidence other than genetic data that demonstrate that these two genes are directly involved in the development of IBD.

3) DLG5 is Associated with Crohn’s Disease and Ulcerative Colitis

DLG5 helps maintain gut lining integrity.

A mutation (G113A) of DLG5 is associated with CARD15 mutation in Crohn’s disease (R).

4) MDR1 (Multi Drug Resistant 1) is associated with Crohn’s and Colitis

MDR1 transports drugs and foreign substances outside of cells (R).

MDR1 has been associated with Crohn’s and colitis (R, R).

MDR1 is associated with treatment-resistant IBD (R).

Mice without MDR1 spontaneously develop colitis (R).

5) PPAR-gamma is Associated with Crohn’s and Colitis

PPARγ gene has been linked to susceptible of a mouse model of Crohn’s (R).

A rare PPARγ mutation was found to be associated with human Crohn’s disease (R).

PPARγ helps to reduce inflammation by inhibiting NF-kB activity.

Ulcerative colitis patients have decreased PPARγ levels (R).

Treatment with a drug that targets PPARγ is effective against ulcerative colitis in a clinical trial (R).

To learn more about PPARγ and how you can improve PPARγ function, read this post.

Environmental Causes of Leaky Gut

5) NSAIDs can Cause Leaky Gut and IBD

NSAID painkillers can temporarily create inflammation and leaky gut, leading to activation of the gut immune system by components of normal gut bacteria (that wouldn’t otherwise cause a problem).

Leaky gut caused by NSAIDs can stimulate T-cell-mediated intestinal inflammation and cause IBD in genetically susceptible humans (R).

Mice lacking IL-10 taking an NSAID develop colitis within 2 weeks (R).

6) Diet can Contribute to IBD

Dietary components that cause cause leaky gut, such as lectins and gluten can contribute to the development of IBD (R).

Food additives that can stimulate the immune system and bacterial virulence such as aluminum and iron may also contribute to the development of IBD (R).

7) Smoking and IBD

Active smoking is a risk factor for Crohn’s disease, but does not affect the outcome or needs for treatment (R).

Interestingly, smoking is associated with better outcomes for ulcerative colitis, as indicated by reduced needs for treatments and surgery. In addition, quitting smoking is associated with worsened outcome for ulcerative colitis (R).

Interactions between Gut Bacteria and the Gut Immune System

In IBD, gut bacteria interact with receptors on the surface of gut lining and gut immune cells (TLR and NOD2 receptors) thus activating NF-kB signaling and causing inflammation (R).

8) Normal Gut Bacteria Causes Inflammation Only in Crohn’s and Colitis

In mice lacking IL-10, native (commensal) bacterial species like Enteroccocus faecalis and E. coli increases gut inflammation. These two bacterial strains don’t cause increased inflammation in mice that have normal IL-10 (R).

9) Introducing Beneficial Strains Alleviates IBD

Supplementation of probiotic VSL#3 is more effective than placebo at reducing inflammatory bowel disease score in ulcerative colitis patients (R).

In rats, Lactobacillus rhamnosus GG does not prevent colitis, but is superior to Lactobacillus plantarum 299v in preventing recurrent colitis (R).

In another study, L. plantarum 299V helps with immune-mediated colitis in mice (R).

Protective species include (R):

  • Lactobacillus
  • Bifidobacteria
  • specific beneficial E. coli strains
  • Streptobacillus salivaris
  • Saccharomyces boulardii
  • Clostridium butyricum

10) Some Strains of E. coli Infection May Contribute to UC

E. coli is a normal part of the gut flora. However, certain strains of E. coli grow rapidly in inflammatory environments produce alpha-hemolysin (a toxin) that causes leaky gut, inflammation, and bleeding characteristic of ulcerative colitis (R).

However, it’s possible that E. coli is the consequence of increased inflammation rather than the cause (R).

In fact, the presence and action of E. coli bacteria may actually lower free radical formation by preventing the Fenton reaction, and thereby induce remission (R).

A strain of E. coli, called Nissle 1917, is actually considered the equivalent of mesalazine, generally the drug of choice for treating Ulcerative Colitis (R).

E. coli Nissle 1917 (EcN) is the active ingredient of the microbial drug (pharmaceutical-grade probiotic), Mutaflor® (R).

Pathogenic bacteria and viruses

11) Mycobacterium avium paratuberculosis (MAP) is Associated with IBD

One of the most studied infections associated with both Crohn’s Disease and Ulcerative Colitis (UC) is called Mycobacterium avium paratuberculosis (MAP) (R).

It is thought that besides genetic predisposition, other factors that determine whether MAP manifests as Crohn’s Disease or Ulcerative Colitis is the sex of the individual, his or her age, the route of infection, and the dose (R).

A higher exposure to MAP is associated with Crohn’s while a lower exposure is associated with UC (R).

This infection is passed from ruminant animals (those that chew their cud) to humans via consumption of MAP-contaminated meat or secretions (milk) (R).

It may also be passed to humans (or between animals) through MAP-contaminated water (R).

Ruminant animals include cattle, bison, sheep, goats, deer, elk, and the like. Therefore, consumption of beef, lamb, dairy (cow, sheep, and goat), venison and other ruminant wild game carries the risk of MAP infection.

 

One of the arguments for the MAP – IBD connection is a number of instances where not only did a number of family members receive a diagnosis of IBD, but couples or groups of friends living together had co-diagnoses of IBD –indicating an environmental factor in addition to genetic predisposition. In some families, couples, or housemates, some individuals were diagnosed with Crohn’s Disease and others with Ulcerative Colitis (R).

However, a more recent (2016) study found that while MAP was significantly higher in patients with Crohn’s (29%) than controls (0%), no significant difference was found in the prevalence of MAP in patients with UC compared to controls (R).

Another earlier study found no correlation between MAP infection and either Crohn’s or Ulcerative Colitis (R).

It’s also been suggested that while MAP is a fairly common infection, it tends to colonize intestines that are inflamed due to an already active disease process (R).

And so the jury is still out on MAP and IBD.

12) Salmonella or Campylobacter Infections May Contribute to UC.

Salmonella or Campylobacter infection resulted in an 8 to 10 times increased risk for that person developing UC within 1 year following the infection (R).

While the risk for developing UC decreased over time, there was still a heightened risk 10 years post infection (R).

One surprisingly high-risk food for both Salmonella and Campylobacter infections is poultry.

In 2011, tests conducted by the National Antimicrobial Resistance Monitoring System (NARMS) found Campylobacter in nearly half (47%) of all the raw chicken they tested at grocery stores (R).

A Salmonella infection may also be derived from raw poultry during food preparation (R). The risk for Salmonella infection is also increased by the presence of live chickens. So, raising your own chickens for meat or eggs does carry risk of infection (R, R2).

13) Clostridium difficile Worsens Outcomes for Those with UC

IBD patients with C. Difficile infection have twice the risk of having a colectomy and 4-6 times the risk of dying (R).

14) Infections of Serpulina, Fusobacterium, Enterobacteriaceae, and/or Gardnerella May Leading to UC

Bacteria that infect the gut, including Serpulina, Fusobacterium, and Enterobacteriaceae can create biofilms on the surface of the gut wall, making it easier for normal gut bacteria to get into the mucosa, where they don’t belong (R).

Fusobacterium varium is significantly higher in the mucosa of patients with ulcerative colitis (84%) than in those with Crohn’s Disease (16%) or other controls (3-13%) (R).

A follow up study found that a combination antibiotic therapy against Fusobacterium was effective for patients with Ulcerative Colitis (R).

Aggressive/detrimental strains include (R):

  • Enterococcus faecalis
  • invasive and toxic E. coli strains
  • Eubacterium
  • Peptostreptococcus species
  • Fusobacterium varium
  • Helicobacter species (such as H. pylori) 

Viral Infections

15) Cytomegalovirus Infection May Contribute to UC

Inflammatory cytokines from inflamed colon, in particular TNF-alpha, can activate dormant cytomegalovirus and cause it to replicate quickly (R).

Additionally, when immune system is compromised, such as in the case of immune therapy for UC (steroids), Cytomegalovirus can become activated and make the inflammation worse, causing a vicious cycle (R).

Probiotic Products that Contain Beneficial Strains

VSL#3

Metagenics Ultra Flora Intensive Care contains L. plantarum 299v

Culturelle contains L. rhamnosus GG

Technicals

Cytokines Associated with Inflammatory Bowel Disease

(source: http://www.nature.com/nrgastro/journal/v3/n7/fig_tab/ncpgasthep0528_T2.html)

Cytokine Crohn’s disease Ulcerative colitis

aRepresentative of a large number of chemokines. Abbreviations: arrow indicates increase; IL, interleukin; N, normal.

Innate immune response
IL-1beta up arrow up arrow
TNF up arrowup arrow up arrow
IL-6 up arrow up arrow
IL-8a up arrow up arrow
IL-12 up arrow N
IL-18 up arrow up arrow
IL-23 up arrow N
IL-27 up arrow N
T-cell response
IFN-gamma up arrow N
IL-5 N up arrow
IL-13 N up arrow
IL-17 up arrow N
IL-21 up arrow N
nature06005-f3-2
How IBD susceptibility gene products modulate host cells function response to microbial flora. source: doi:10.1038/nature06005
http://www.nature.com/nrgastro/journal/v3/n7/full/ncpgasthep0528.html
Receptor activation in IBD http://www.nature.com/nrgastro/journal/v3/n7/full/ncpgasthep0528.html

Comments

  1. Mike

    Outstanding compilation. I have been trying to pull together data on this since being diagnosed with UC in 1985. It is great having all this in one place with citations, etc. Glad to see you included the work of Ellen S Pierce I am a fan of her theories. Hope to invest in a genetic decode / consult this year.

  2. Mito

    Is it possible to control the expression of the genes that correspond to Crohn’s? You stated that in identical twins where one has Crohn’s the other only has a 50% chance of Crohn’s rather than 100%. So specific genes make it more likely to develop Crohn’s, but it is still environmental factors that cause the gene expression and therefore disease. Do we have any idea what they are for Crohn’s?

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