Genetics and Inflammatory Bowel Disease

 

Inflammatory bowel disease has two different types of diseases which is ulcerative colitis and Crohn's disease. The NOD2 gene is an IBD risk gene which was observed in 2001. There have been 163 risk genes or loci that have been identified and are associated with both Crohn's disease and ulcerative colitis. After the second World War, the rates have increased with IBD in northern Europe and North America. The risk of IBD in an offspring increases dramatically if both parents have IBD. For the population, there are different percentages of who gets it which is shown in the image above. The symptoms of IBD include abdominal pain, diarrhea, loss of appetite, etc. 

Crohn's Disease Triggered by Bacteria Genetic Changes

A new study by Weill Cornell Medicine and New York-Presbyterian investigators found that certain changes in a gene can allow harmful bacteria in the stomach to cause inflammation that drives Crohn's disease. The host gene, AGR2, encodes part of a cell's machinery that helps prepare newly made proteins to properly repel "bad" bacteria. When the process is disrupted, protein production gets backed up and causes the cell to become stressed. The cell's stress response plays a central role in the development of Crohn's disease. Crohn's disease is a type of inflammatory bowel disease (IBD), which causes inflammation in the digestive tract. This may cause abdominal pain, severe diarrhea, fatigue, weight loss, and malnutrition.

In a different study, researchers were able to genetically engineer mice to prevent the expression of the AGR2 gene and discovered that they developed Crohn's-like inflammation. This caused them to link the inflammation in that study to adherent-invasive E. coli, or AIEC, which were found to be bacteria implicated in Crohn's disease. In this study, they were able to connect that changes in the AGR2 activity levels with increases in the bacteria group that AEIC belongs to. They ended up discovering that the inflammation that was kicked off by the interaction was linked to the production of IL-23, an immune signal that is an important driver of inflammatory bowel disease (IBD) and colorectal cancer tumorigenesis and is also an important therapy target.

In my opinion, I find this research interesting in how this research could affect treatment and medication for this type of disease. If Crohn's disease is triggered by AEIC, I wonder if other digestive and bowel diseases could be caused by similar bacteria found in the digestive tract and if this research can be used to do similar experiments on other gut bacteria and digestive diseases.

Do Genetics Play a Role in Ulcerative Colitis?

 

Ulcerative Colitis is an autoimmune disease that attacks the digestive system, leaving the intestines, the colon, and the rectum inflamed. This illness falls under the category of Irritable Bowel Disease, also known as IBD. The other disease that shares similar symptoms is Crohn's disease. Many researchers have wondered how this disease is triggered, as studies have shown there is not one definitive answer. However, an article from Medical News Today shows that there are specific genetic factors that come into play as research develops.

The article features several studies that were conducted in order to support the role genetics has in Ulcerative Colitis. One study was done in 2018 in focusing on heredity and the likelihood of the disease running in your family. It discussed how having an immediate family member who has the disease makes it more likely for you to be diagnosed with it as well. Children where both parents have the disease are more likely to be at risk as well, and identical twins are more likely to develop Crohn's disease than Ulcerative Colitis.

Genetic testing is also a question when looking into Ulcerative Colitis. Currently, genetic testing is not really used to look into the chances of developing the disease. Gene variations occur with this disease and there are many genes that determine the likelihood of the disease. At the same time, environmental factors like stress and diet have had links to those who live with the illness. However, new research is progressing. A study done in 2019 using thiopurines, medications used to help manage the symptoms of IBD, were connected with genetic variants in IBD patients. One of the side effects of the drug is myelosuppression, which decreases bone marrow in patients. By looking at patients who were and were not affected by this effect, they found that there were 3 coding variants of the NUDT15 gene, and that included a deletion of a 6 base-pairs. This confirmed that these variants were linked to the side effect produced by the thiopurines, a big development in IBD research.

As someone who has Ulcerative Colitis, I find this extremely interesting. I am currently the only one in my family with the disease, but autoimmune diseases run on both sides of my family. I have never done a genetic test or looked into my ancestry to identify if there were any genes or if I possessed any variants that affected my risk of developing the disease. I also took a thiopurine for 4 years and have never heard of the induced myelosuppression, so this really intrigued me. I look forward to more research regarding genetics and IBD because I do think it plays a role in developing and working towards further treatment or even a cure for the disease.

Related articles:

Specific Genes linked to Ulcerative Colitis Activity

The Process of Genetic Testing with IBD

Parasitic Worms May Prevent Crohn's Disease by Altering Bacterial Balance

The thought of parasitic worms swimming around in some people's intestines may be revolting, but they seem to forestall Crohn's disease and other various types of inflammatory bowel disease (IBD). A new study may explain how this works, which will reveal how worms enable microbes in the intestines to fight bacteria that promote inflammation.

In people with IBD, inflammation in the digestive tract usually results in bleeding and diarrhea which can sometimes lead to intestinal obstructions or other severe complications. Because parasitic worms can be harmful, they are unlikely allies against these diseases. IBD is rare in parts of the world where parasitic worms are prevalent. But, in more developed parts of the world where less people carry these parasites in their intestines, IBD is much more common.

To determine the "frenemy" relationship between our intestines and these parasites, immunologist Ken Cadwell and colleagues tested mice with the same genetic defect found in many humans with Crohn's disease. Mucus-secreting cells in the intestines malfunction in these animals, which reduces the amount of mucus secreted to protect the lining of the gut from harmful bacteria. Researchers also found a change in the rodents' microbiome. The abundance of a microbe, an inflammation-inducing bacterium found in the Bacteroides, soars in the mice with genetic effect. 

The researchers found that feeding the rodents one type of intestinal worm restored their mucus-producing cells to normal. At the same time, the levels of two different indicators declined in the animals' intestines. In addition, the bacterial lineup in the rodents' guts shifted. Bacteroids's numbers plunged, yet the prevalence of the Clostridiales, a species in a different microbial group, increased. A second species of worm also triggers similar changes in the mice's intestines. 

To check if these parasites cause the same effect in humans, the scientists compared two populations in Malaysia. One group consisted of urbanites living in Kuala Lumpur, who have few intestinal parasites. The second group consisted of an indigenous group, the Orang Asli, who live in a rural area where the parasites are widespread. A type of Bacteroides, the pro inflammatory microbes, predominated in the people of Kuala Lumpur. It was more rare among the Orang Asli, where Clostridiales was common. Treating the Orang Asli with drugs to kill their intestinal worms reversed this pattern, favoring Bacteroides species over Clostridiales species. The team analyzed two sets of data on the frequencies of different intestinal microbes, which included U.S. residents who were healthy, and children in North America who have IBD. They saw the same inverse relationship, where Clostridiales species are up and Bacteroides are down, and vice versa. 

The study's findings suggest that parasitic worms deliver their benefits through their impact on the microbial mixture in the intestines. But, the researchers caution that direct evidence is still warranted to show that Bacteroides species are responsible for Crohn's disease. Also, turning the results into clinical treatment may be difficult, because recent clinical trials were disappointing. The researchers indicated that worm therapy might only work on roughly 30% of people suffering from Crohn's disease, who have the same genetic flaw as the mice tested. 

I think this data is very interesting, and the correlation seems promising, but this treatment may not be realistic for many with Crohn's disease because people may not agree to this treatment. On paper this sounds like a great, natural treatment, but there also may be complications of these parasites inside the body that have not been researched or tested. I cannot imagine that the majority of Crohn's patients would choose to have these worms inside of them, over taking other medications to control their symptoms. Again, I believe these various studies are promising and do show correlation, but more research is definitely warranted, and may not be clinically realistic. 

Could having worms be beneficial for Crohn's patients?

A recent study suggest that parasitic worms could lead to new drug development for people with Crohn's disease and other bowel related diseases.  Mice with a mutation in the Nod2 gene were used in the experiment because its similar to the gene in humans that is associated with Crohn's.  The introduction of parasites caused the mice to have more mucus in their intestines than uninfected mice, as well as more bacteria from the Clostridiules family and less B. vulgatus bacteria.  This shift in the bacteria populations and increase of mucus in the intestines was shown to calm inflammation in the bowels.

Studies showed that chemicals from T helper cells, interleukin-4 and interleukin-13, are triggered by the worms which stimulate mucus production.  The Clostridiales bacteria feed on the mucus which allows them to outcompete the bacteria from the Bateriodales family.  When the interleukin-13 was blocked, mucus production was prevented and there was no shift in the bacteria populations.  Scientists believe that giving interleukin-4 and interleukin-13 to uninfected mice could alter the production of mucus and balance of bacteria without the introduction of parasites to the organism.

Although it seems like it could be a good idea, the article states that some individuals that took a deworming drug experienced negative consequences.  For these individuals, they had less Clostridiales and more Bacteriodales bacteria populations in their gut due to a significant drop in Trischuris trichiura whipworm eggs.  Evidently, more research needs to be done.

CPAG: software for leveraging pleiotropy in GWAS to reveal similarity between human traits links plasma fatty acids and intestinal inflammation

Apparently, Crohn's disease and plasma palmitoleric acid have an association. Using a new technology, CPAG or Cross-Phenotype Analysis of GWAS, scientists were able to perform meta-analyses of genome-wide association studies (GWAS) and search for similarities between over 600 traits. Using GWAS is particularly helpful being that Crohn's disease is associated with a genetic variant. Pleiotropic SNPs (single polynucleotide polymorphisms) are common within the human genome, which means one genetic locus affects multiple phenotypes. The significance of cross-phenotype associations lies in the fact that they may represent pleiotropy, and it has been discovered that the PTPN22 gene is associated with many conditions, such as Crohn's disease, rheumatoid arthritis, type 1 diabetes, and more. It was found that 7% of SNPs are associated with more than one raw trait. In addition, by identifying traits associated with particular genetic variants and clustering the traits in order to visualize associations, clusters of known cholesterol-related traits, such as type 2 diabetes, obesity, and autoimmunity, were easy to see and represented known relationships. 

The results were compared using a Chao-Sorensen model, the first use of a model usually used for ecology research, to study genetics. The model assessed heterogeneity, or the discordance of observed disease groups with already defined disease group. Many traits were had a high correspondence, which can be explained by reasons such as a similar risk factor, consequence of a disease, a similar gene affecting different pathways. Crohn's disease and psoriasis only overlap with two SNPs but were found to have genes in the interleukin (IL)-23 pathway, suggesting that the risk of both conditions could be related to signaling. Researchers went on to test whether increased plasma fatty acid would induce intestinal inflammation in zebrafish to find that plasma fatty acids have an effect on intestinal inflammation. It is known that countries with high fat diets have a stronger correlation with Crohn's disease. Three different fatty acids were injected into zebrafish larvae. Palmitic acid induced a greater increase in inflammation compared to TNBS-exposed and BSA-injected. Linoileic acid was suggestive of having an anti-inflammatory effect. 

I found this study to be of great interest, as it supports that environment can have a direct effect on the expression of certain diseases. The consumption of too much unnecessary fat could lead to the expression of Crohn's disease. 

Over 200 Genes can be Attributed to Crohn’s Disease

Scientists at the University College of London have created a new method to identify and map gene locations for complex inherited diseases by utilizing detailed maps of the human genome. Their study specifically highlighted Crohn’s disease, which they found has over 200 genes involved in the complex disease. The number of gene locations for Crohn’s disease is more than have been found for any other disease. The article explains that there are only 66 known gene regions for type two diabetes. With the new method of identifying and mapping gene locations, it is possible that there are many more genetic regions that attribute to such diseases. By narrowing down the genetic component to many diseases, it will be easier for those scientists in the medical field to improve treatment for painful symptoms. In addition to creating better treatments, studying the genetic component of such diseases can provide better understanding as to how they are inherited. 

Crohn's disease is a chronic inflammation that may affect any part of the digestive tract

Crohn’s disease is just the stepping stone into detailed genetic studies of diseases. In the article, a senior author from the University College of London, Dr. Nikolas Maniatis, was interviewed as saying: “The discovery of so many gene locations for Crohn's Disease is an important step forward in understanding the disease, which has a very complicated genetic basis. We hope that the method we have used here can be used to identify the genes involved in other diseases which are similarly complex, for example different cancers and diabetes.” The additional genes attributed to Crohn’s disease were found through the use of incredibly detailed maps of the human genome as well as through the subdivision of patients based on the disease present. This study is incredibly exciting and will lead to great strides in better diagnosis of disease and more personalized treatment plans for those who are suffering from disease. It is especially fascinating that such complex diseases are effectively being broken down and the specific genes that cause such complex illnesses are correctly being identified. 

Crohn's disease is incredibly complex