The effect of various treatments for juvenile Crohn’s disease on the microbiome

CT scan showing Crohn's disease in the fundus of the stomach

Crohn’s disease is a type of inflammatory bowel disease that is characterized by an autoimmune response in the colon.  It is generally thought that the bacteria in the gut elicit this immune response and cause the disease.  In otherwords, Crohn’s is caused by a shift in the microbiome from a healthy state, to a dysbiotic one, although the ultimate cause of the disease is still unknown.  The standard of care for Crohn’s in adults is combinations of immunosuppressive drugs, although in children this is not normally recommended.  Instead, children take either a prescribed diet, normally something like Soylent that involves only essential nutrients, or antibiotics.  Scientists from UPenn recently monitored the microbiomes of children with Crohn’s that were put on various courses of treatment, as well as the progression of the disease.  They discovered the changes that occurred in the microbiome that yielded a therapeutic response, and many new associations between the microbiome and Crohn’s disease.  They published their results in Cell Host and Microbe.

The scientists measured the microbiomes and inflammatory markers of 90 children before and after entering therapy for Crohn’s: 52 taking anti-TNF (an immunosuppressant), 22 taking the enteral nutrition exclusively (i.e. something like soylent), and 16 taking the enteral nutrition along with any other food they wanted.  The scientists also took samples from 26 healthy children.  They discovered that of the 45 most abundant bacteria in each child, 14 were different between the Crohn’s children and the healthy children.  These included bacteria such as Prevotella and Odoribacter that were largely absent from the Crohn’s group, and Streptococcus, Klebsiella, and Lactobacillus that were in higher abundances in the diseased group.  Overall diversity was also higher in healthy patients compared to those with Crohn’s.  The researchers also discovered that high levels of fungi, such as Saccharomyces cerevisiae, in the stool were high associated with Crohn’s.  When the researchers monitored the response of Crohn’s patients to treatment they saw that in many patients the microbiome shifted rapidly to a healthier state, with less inflammation, within a week of treatment for all three therapies involved.

This study helped further define the dysbiosis that is associated with Crohn’s disease, as well as demonstrate how this dysbiosis is altered using treatment.  It was especially useful that treatment naïve children were used in the study, as many adult studies are unable to remove confounding variables of various previous courses of treatments.  IBD is a difficult disease to study because of its complexity, but this study supports the hypothesis that a dysbiosis is at the root of the problem.

Study finds that C-sections are not a risk factor for IBD

Inflammatory bowel disease (IBD) is a disease of the gut made up primarily of two diseases, primarily Crohn's disease and ulcerative colitis. In IBD, the gut and other parts of the digestive tract are attacked by the body's own immune system.  It is not clear how or why IBD occurs but there is a significant amount of research looking at this. It is known that the human gut microbiome goes through a lot of changes from birth through the first few years of life before stabilizing into the “adult” composition. Therefore, looking at the first years of life could be critical for understanding IBD. Researchers in Canada, in a study published by Clinical Gastroenterology and Hepatology, set out to determine if birth by Cesarean section increases likelihood of IBD.

The logic behind this hypothesis is that birth by vaginal delivery would expose the infant to the mother’s vaginal bacteria, which could possibly be essential in the development of the infant’s own microbiome. To study whether C-sections are a risk factor for IBD, the researchers gathered data from the University of Manitoba IBD Epidemiology Database, which keeps health records of all Manitobans diagnosed with IBD between 1984 and March 2010. These records were matched with birth and maternal health records. 1,671 IBD patients were linkable with mothers and therefore used for analysis. 10,488 matched controls were also used.

Analysis showed that IBD patients were no more likely to be born by C-section than the controls. Additionally, urban rather than rural residence was associated with higher instances of IBD. Within families, the likelihood of IBD was not different between C-section and non-C-section siblings.  

In conclusion, there does not appear to be an increased risk for inflammatory bowel disease if a child is born by C-section. Factors such as breastfeeding, socioeconomics, living environment, pets, etc. are still being analyzed for possible contribution to gut microbiome dysbiosis.

A new way in which some gut bacteria rely on their hosts’ mucous for energy

It is often understood that our gut bacteria live off of the foods we eat.  However, many gut bacteria can actually metabolize the mucous that protects the lining of our gut.  In fact, many bugs have the ability to digest a specific sugar that is attached to our mucins, called sialic acid.  Interestingly, some bacteria have the ability to cleave this sugar from the mucins, others have the ability to consume this sugar once it is released, and others have the ability to perform both of these tasks.  Last week, a new method for how gut bacteria can transform sialic acid was discovered, that some bacteria can actually transform sialic acid before cleaving it, and that this may be clinically relevant for Crohn’s disease and colitis.  The authors published their results in Nature Communications.

The authors were testing a common commensal bacteria, Ruminococcus gnavus, and noted that it had the ability to both cleave and consume sialic acid from gut mucins.  When they identified the metabolites from this process they discovered that the sialic acid was actually being converted to a different form by these bugs.  After further experimentation they realized that a type of enzyme, called an intramolecular trans sialidase, which had never before been observed in gut bacteria, was responsible.  The researchers then compared the genes from R. gnavus to other bugs common in the gut and noted that a full 11% of human gut commensals had this enzyme, and that these bacteria were overrepresented in people with IBD.  The authors think that the bugs who code for this enzyme have an inherent advantage over other gut microbiota because after they transform the sialic acid they can still use it for energy, whereas other bugs cannot, leaving the sugar all to themselves. 

The paper did not discuss specific mechanisms as to why these bugs may be overrepresented in Crohn’s and colitis.  They did however test a few molecules that inhibited the activity of the enzymes.  Perhaps if these enzymes or the responsible bugs are the cause of IBD, than these inhibitors could be used as therapeutics to combat the disease. 

Cigarette smoke changes the gut microbiome

When we talk about smoking cigarettes, we usually discuss the harmful effects that it has on our lungs, mouth, skin, and other parts of the body. However, we don't often talk about the gut even though cigarette smoke is the best-known environmental risk factor for Inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis.  While the exact mechanism for why people get these diseases is not yet known, it is recognized that a dysbiosis of the gut plays a contributing role to the onset of these conditions. A research team in Germany investigated the effects that cigarette smoke exposure had on the mucus layer and the microbes in the gut.

The scientists exposed mice to cigarette smoke or air for a period of 24 weeks. They found there was a shift in the microbial community in the caecum and distal colon after exposure to smoke. Specifically, there was an increase in Lachnospiraceae in the colon however it remained the same in the ileum, the last part of the small intestine.

They also found that smoke exposure led to changes in mucin exposure. Mucin is a type of protein that is known for producing gels that act to lubricate and protect parts of the body, both internal and external. The most common mucins are Muc2, Muc3, and Muc4. Muc2 for example is a protein that is secreted onto the mucosal surfaces of the large intestine and serves as a protective barrier for the epithelium. In this study, they found that Muc2, Muc3, and Muc4 gene expression was altered after cigarette smoke exposure.

The authors hypothesize that cigarette smoke affects the immune system in the ileum and may lead to the inflammation associated with Crohn’s disease. Overall, this study found that exposure to cigarette smoke had a profound effect on the gut bacteria and mucin composition in the mouse. While this was not done in humans, the same effects would likely be seen.

Immune cells are educated in the gut to not attack beneficial bacteria

The gastrointestinal tract is made up of trillions of bacteria that are largely ignored by the body’s immune system.  Why is it that the body’s immune system knows to ignore these beneficial bacteria that are so important for our ability to live a healthy life? The answer to this question could play an important role in understanding how to maintain a healthy gut and how to treat diseases. Scientists led by Gregory Sonnenberg at Weill Cornell Medical College may have answered this question in a study published last week in Science.

The researchers studied T cells, cells that are made in the thymus and are trained there to kill-off foreign microbes and other intruders that make their way into the human body. But why don’t these T cells attack helpful bacteria in the GI tract? They found that the T cells are again educated in the gut to not attack beneficial bacteria but when this education is disrupted, it can lead to disease.  For example, inflammatory bowel diseases like Crohn’s disease and ulcerative colitis occur when the immune system attacks the GI tract and bacteria in the GI tract.

In the thymus, T cells that could attack the body are destroyed before they are released into circulation. In the gut, a type of cell called innate lymphoid cells (ILCs) educate the T cells to not attack beneficial bacteria. These ILCs had previously been found to make a physical barrier between the bacteria in the gut and the immune system.

In mice, they found that ILCs attacked T cells that were destroying beneficial bacteria and when they prevented this attack by ILCs on the T cells, severe intestinal inflammation resulted. They also looked at intestinal biopsies of young patients with Crohn’s disease. In the biopsies they found that the ILCs lacked specific molecules that are important for educating the T cells not to attack the bacteria in the gut. They found that a decrease in this molecule correlated with an increase in pro-inflammatory cells in children with Crohn’s disease.

The authors state that it may be possible to get rid of these T cells that are causing the inflammation and by doing so you may be able to help treat the disease.  By restoring this molecule (Major Histocompatibility Complex class II) that is preventing the education of the T cells, pro-inflammatory T cells may be reduced resulting in reduced intestinal inflammation.

Fecal microbiota transplant as a potential therapy for Crohn's disease

Seattle Children's Hospital

Clinicians at Seattle Children’s Hospital have found that fecal microbiota transplants (FMTs) may be a therapeutic option for patients with Crohn’s disease. Crohn’s disease (CD) is an inflammatory disease of the GI tract that is marked by an immune attack on a person’s own body, specifically in the gut.  The microbiome of CD patients is altered compared to healthy indivduals, but it is not clear if this is a cause or effect of the immune attack.  The group at Seattle Children’s Hospital hypothesized that if they could alter the microbiome of these patients that they would promote less inflammation resulting in fewer symptoms. 

The successful results were published in the journal Inflammatory Bowel Disease. They conducted fecal microbiota transplants in 9 individuals with pediatric Crohn’s disease between the ages of 12 and 19.  Patients received transplants from their parents, 7 from their mother and 2 from their father.  After two weeks, 7 of the 9 patients were in remission and at weeks six and twelve, 5 of the 9 patients were still in remission.  While the patients did have some side effects, almost all of them were mild.

The investigators looked at the differences in the microbiome between donor and recipient and what impact this had on disease.  They found that the individual who received the transplant of a microbiome that was most similar resulted in the smallest change of clinical course and the FMT recipient whose microbiome was the most different resulted in the greatest change in clinical course. They also found that increased levels of Escherichia coli correlated with increased clinical symptoms and inflammatory markers.  While it is not likely that E. coli is the cause of CD, it is an interesting observation that could be investigated to better understand what impact it has on disease progression.

This study provided evidence that the microbiome plays and important role in Crohn’s disease.  The results of this small study were promising and show that fecal microbiota transplants were generally safe and should be further investigated as a potential therapeutic option for individuals with this inflammatory disease. Further longitudinal studies are important to understand the entire impact that the FMT has on an individual.  As we have seen in previous blog posts, while it may cure the disease it is aiming to treat, there can also be other unintended consequences.