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.

Fish oil may be important to altering the microbiome, reducing anxiety

Last week we published a blog on the gut-brain axis, and the various associations between brain health and the gut microbiome.  One of the ailments we discussed was depression, which is often studied in mice by inducing early life stress on the mice.  One way to do this is by separating mice from their mothers for hours at a time at a young age.  The Maternal Separation model, as it is known, causes stress and anxiety in these mice, but more importantly, research has shown that it creates a dysbiosis of their gut microbiomes as well.  Many scientists believe the dysbiosis may be implicated in causing some of the stress phenotypes, and so reversing this dysbiosis could have therapeutic value.  Researchers from the University College Cork, in Cork Ireland, experimented with N-3 polyunsaturated fatty acids (PUFAs), like those found in fish oil, in these maternally separated mice, and found they may be important to preventing the dysbiosis.  They published their findings in the journal PLoS ONE.

In the study, the researchers separated mice into two groups, one underwent maternal separation, and the other had a normal upbringing.  Within each group the mice were separated into two more groups, one that received fish oil supplements and the other that didn’t.  Over the course of 17 weeks each groups’ feces were sampled for their microbiomes.  The Maternal separation tended to decrease the bacteroidetes to firmicutes ratio of the mice’s microbiome, which has previously been linked to depression in humans.  Interestingly, supplementation with the fish oil increased this ratio in those maternally separated mice.  In addition, the fish oil also increased the concentration of bacteria that were higher in non-separated mice, such as populations of Rikenella.  Finally, the fish oil increased the amount of butyrate producing bacteria, and as we have seen many times before, butyrate and other short chained fatty acids (SCFAs) are often associated with health.

Overall this study showed that fish oil shifted stressed mice’s microbiome to a more natural state, presumably helping them in the process.  While the scientists did not directly measure stress levels in these mice to support the microbiome connection, hopefully that will be part of a follow up study.  The scientists noted that fish oil is clinically shown to reduce inflammation, and made it a point to connect the stress in the mice to systemic inflammation.  Systemic inflammation is also mediated by the microbiome.  Indeed, people that have inflammation from IBD, for example, do tend to have more stress and anxiety.  In the end, fish oil could make for an interesting prebiotic to shift the microbiome, counteract inflammation, and improve mental health. 

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.

The gut microbiome shift during pregnancy is related to the mother’s secretor status

Fucose chemical structure

An estimated 20% of women of European descent are not able to produce mucous that have fucose sugars attached to the ends of their mucin molecules.  These women are called ‘non-secretors’, as opposed to ‘secretors’ who can fucosylate their mucins.  This rather peculiar genetic anomaly is not appreciated until it is looked at under the lens of the microbiome.  Many of the microbiota in the gut feed off the host’s mucins for energy, and the lack of fucose is a major factor in dictating which communities can survive in their guts.  During pregnancy the mother’s gut microbiota undergoes a dramatic shift, although what variables are important in determining this shift remain unknown.  Last week though, researchers from Finland showed that secretor status was an important indicator in how a women’s gut microbiome shifts during pregnancy.  They published their results in PLoS ONE.

The researchers sampled the gut microbiome of 71 women throughout their pregnancy, and compared it to the secretor status, as determined by genetic testing.  In the first trimester of pregnancy each women, secretors and non-secretors alike, had similar diversities in their gut microbiota.  However, by the third trimester the non-secretor’s gut microbiomes were much lower than their secretor counterparts.  When the scientists measured specific phyla, they observed an increase in the abundance of Actinobacteria in the secreting women, and an increase In the abundance of Proteobacter in the non-secretors.

The changes in gut microbiota in these women may be very important to the microbiome of the infant that is born to them.  As an infant passes through the birth canal he or she is exposed to the mothers’ vaginal and gut microbiota, and these bacteria serve as the initial populations that seed the infants’ own guts.  In addition, some of these specific bacterial populations, such as Proteobacter, are implicated in diseases like IBD.  If these bacteria persist in the mother after birth they may explain the onset or increased risk of some of these diseases.

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.