A DNA-Binding Immune Receptor’s Link to Crohn’s Disease & IBS (TLR9)

TLR9 codes for toll-like receptor 9, one of a family of toll-like receptors which also includes TLR4. TLR9 senses the presence of bacterial or viral DNA and triggers an immune response to protect the body from invading pathogens [R, R, R, R].

Most of the time, when TLR9 is working correctly, it specifically targets DNA belonging to potentially dangerous invaders. However, excessive activation of TLR9 may result in human DNA being targeted, which in turn may lead to an autoimmune response [R, R].

In the digestive system, TLR9 plays an important role in protecting against changes in the gut flora and metabolism. Mice with very low TLR9 expression also have much more difficulty healing intestinal wounds [R, R].

However, because TLR9 sends inflammatory signals, too much can cause problems. TLR9 activation increases the production of Th17 cells and cytokines, which can lead to chronic inflammation and autoimmunity [R, R].

One potential outcome of this autoimmune response is the development of inflammatory diseases like IBS or Crohn’s disease.

TLR9 differentiates between beneficial and potentially harmful bacteria in the gut and activates the immune response if there is a threat.

What is Crohn’s Disease?

IBD is a group of autoimmune 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. The definition of IBD includes both ulcerative colitis and Crohn’s disease [R].

Crohn’s disease differs from ulcerative colitis in that it is centered higher in the digestive tract (typically in the small intestine, though it can occur anywhere between the mouth and anus) and may damage broader swaths of tissue [R, R].

What is IBS?

Irritable bowel syndrome (IBS) is a gut condition that causes abdominal pain, bloating, and dysregulated bowel movements. 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 [R].

There are two main types of IBS: one that involves diarrhea (IBS-D) and one that involves constipation (IBS-C).

The Role of TLRs in Gut Inflammation

Because of their ability to activate the immune and inflammatory responses, toll-like receptors are under intense investigation as central players in the development of IBS & IBD [R, R].

TLRs sense and regulate the beneficial bacteria that live in our guts and differentiate them from harmful invaders. When they sense a potential threat, they trigger a cascade of inflammation through NF-κB and T cell activation. TLRs are, in turn, suppressed by Tregs, a type of white blood cell that restrains and calms the immune system [R].

People with IBS & IBD tend to have too much inflammation and not enough Tregs, suggesting a potential imbalance of TLRs [R].

What About TLR9?

Researchers disagree about the precise role of TLR9 in Crohn’s disease and other inflammatory diseases of the gut. Some studies seem to suggest that it is protective; however, genetic studies have found lower rates of IBD in people with lower TLR9 expression. Furthermore, a study of IBD patients found increased TLR9 expression linked to increased disease severity [R, R].

Despite the disagreements, most of the evidence suggests that high TLR9 is linked to worse IBD [R, R].

If TLR9 is activated when there is no bacterial threat, it may cause harmful inflammation. Many studies have linked excessive TLR9 to Crohn’s disease and other inflammatory diseases.

Crohn’s Disease

Multiple studies have found potential links between TLR9 genetic variants and Crohn’s disease. The most significant associations have been in three SNPs: rs352139, rs352140, and rs574383 [R, R, R].

Of these, rs352139 has been studied the most. Researchers have produced differing results when associating this SNP with IBD, but the ‘T’ allele is generally considered protective. The ‘T’ allele also decreases expression of TLR9, supporting the idea that excess TLR9 may contribute to IBD [R, R].

Other SNPs that have been linked with Crohn’s disease include rs5743836-G and rs352140-T, though these have not been studied as well, and they are also not available on most commercial DNA chips [R, R, R].

IBS

Some studies have also found links between TLR9 variants and IBS, a less severe disorder likewise caused by gut inflammation. Generally speaking, the same alleles associated with IBD are also associated with IBS [R, R].

TLR9 variants that increase expression, such as rs352139-T, have been associated with increased rates and severity of Crohn’s disease and IBS.

SNP Summary and Table

TLR9 rs352139

• ‘C’ = Relatively higher TLR9 expression, not protective against IBD or IBS
• ‘T’ = Relatively lower TLR9 expression, protective against IBD & IBS

TLR9 rs352140

• ‘C’ = Not associated with IBD & IBS
• ‘T’ = Associated with IBD & IBS

TLR9 rs5743836

• ‘A’ = Not associated with IBD & IBS
• ‘G’ = Associated with IBD & IBS, even in the presence of protective variants in other genes (IL23R & NOD2)