Our gut microbiome may be contributing to some forms of blindness

Our eyes are considered ‘immune privileged’, which means that they are generally protected from our own immune system.  The major mechanism for eye immune privilege comes from a tight physical barrier that separates our lymphocytes, such as T cells, from the actual eye.  T cells do have the ability to cross this barrier, but they first must come in contact with, and be activated by eye antigens.  These antigens are sequestered on the opposite side of the barrier, in the eye, so that they are not exposed to the T cells.  There are diseases in which these retinal T cells do mysteriously become activated though, and they cause an inflammatory disease known as uveitis.  Uveitis is responsible for causing blindness and other eye issues in many people, but again the cause for the T cell activation is largely unknown.  Researchers at the NIH recently created a mouse model for uveitis, and were able to test a variety of factors that may be activating the T cells.  To their surprise, the gut microbiota seemed to be activating the T cells.  They published the results of their study last week in the journal Immunity.

The researchers first created a mouse model of uveitis where the retinal T cells spontaneously become activated.  They then noticed that the highest concentration of these T cells were near the gut, suggesting the gut bacteria were playing a role.  The scientists then treated the mice with antibiotics to decrease the gut bacterial concentration.  Although the mice still developed some symptoms of uveitis, the disease was ameliorated greatly in these mice.  As previously discussed, the normal T cell activator antigen is in the and physically separated.  In order to ensure that this antigen wasn’t somehow leaking out of the eye to activate the T cells in their model they created mice that lacked these antigens in their eye.  Still though, the mice presented symptoms of uveitis, meaning that the antigen that is activating the T cells is not from the eye, but rather is being produced somewhere else, such as the gut.  In order to firmly prove the gut bacteria’s role, the scientists showed that T cells could be activated by specific proteins from gut bacteria.  In fact, germ free mice, which otherwise would not have an ocular inflammatory response in their model, showed strong uveitis when they were given just the protein extract from other wild type mice. 

This research is the first to connect the gut microbiome with ocular autoimmune inflammation.  It presents many questions as to how to therapeutically combat this disease, perhaps through monitoring the gut microbiota for presentation of antigens that could activate these retinal T cells.  It also begs to be connected with other sites immune privilege breakdown in the body.  The fetus and placenta in pregnant women, for example, is an immune privileged space.  Immune activation of this site can sometimes lead to miscarriage.  Are gut or vaginal bacteria involved with this response, as we have discussed a few times in this blog?  In time, scientists will know enough to accurately answer this question.

Understanding spatial relations of gut bacteria in ulcerative colitis patients

To sample the microbial communities in the gut, fecal samples are generally collected from an individual and DNA is sequenced to identify bacteria that are present. This is an overall effective method, however, it does not provide information of the specific spatial location of bacteria within the gut. In a study published in the journal Gut, researchers in Ireland looked to determine differences in the bacterial composition of specific regions of the large intestine between patients with ulcerative colitis and control patients.

Four volunteers undergoing routine colonoscopies were recruited to serve as the controls for this study. Five patients with ulcerative colitis (UC), who were undergoing colectomies, or surgical removal of the colon, were also involved in the study. Samples were taken at four locations in the colon in all individuals: the caecum, traverse colon, descending colon, and rectum. The four locations were sampled three times at three different levels: luminal brush, whole mucosal biopsy, and laser captured sample of mucus gel layer. A total of twelve samples were taken per individual.

After analysis of the many samples it was discovered that there was more variability between the bacterial compositions between subjects than there was within the different locations of an individual’s colon. The findings showed a difference between the luminal and mucus gel microbiota in both the controls and the ulcerative colitis subjects. Three bacterial families were common between this difference shared by controls and UC subjects, namely Bifidobacteriaceae, Peptostreptococcaceae, and Enterobacteriaceae being more abundant in UC patients.

This study has its limitations because of the small sample size, however the researchers state that the small sample allowed for extensive analysis of the individual samples. So what do the findings of this study mean for patients with ulcerative colitis? Better understanding of differences in the spatial relations of bacteria could lead to the modulation of microbial communities to help treat ulcerative colitis. 

Can gut microbes be used to diagnose and treat malnutrition?

Credit: Tanya Yatsunenko

When people think about malnutrition, they often think that not eating enough food leads to stunted growth, neurocognitive issues, weakened immune systems, and other health problems associated with malnutrition. While this is largely true, food scarcity and insecurity does lead to undernutrition, it is not the sole contributing factor to this pervasive global health problem.  Jeffrey Gordon and his group at Washington University School of Medicine in St. Louis have shown once again that gut microbes play an important role in undernutrition in a paper in Science Translational Medicine. 

To show the importance of the microbiome in undernutrition, Gordon’s team studied children in Malawi who were undernourished and others that were not. Specifically, they studied individuals with kwashiorkor, a form of severe undernutrition that occurs in children who often eat similar diets as other healthy children. They studied identical twins, one with the disease and one without the disease and sampled their gut microbes.  They transplanted the bacteria from the sick child into germ-free mice to see what effects the bacteria would have. When transplanted into the mice, the bacteria were very harmful causing weight loss as well as severe damage to the lining of the intestines and colon.

The scientists looked for bacteria that were targeted by an important molecule of the immune system called immunoglobin A (IgA). IgA is prevalent throughout the body and specifically in the gut. It plays an important role in preventing the bacteria in the gut from interacting with the human cells that line our intestines. As we saw in the paper on the blog on Monday about emulsifiers in our food, when gut bacteria in the gut interacts with the epithelial cells of the gut lining, severe health problems can arise. The scientists found that IgA and the immune system largely targeted Enterobacteriaceae, a large family of bacteria found in the gut that includes E. coli, Salmonella, and many others. The scientists were able to prevent weight loss in the mice by transplanting two strains of IgA targeted bacteria from the guts of healthy children into the mice, before they were exposed to the bacteria from the undernourished child.

This is an important study as it not only shows the significant role that gut bacteria have on malnutrition, but it shows that it may be possible to use the microbiome as a diagnostic tool to identify which children are at risk for undernutrition, and it may also be a therapeutic target for intervention. The scientists also studied 19 other groups of twins and found that higher levels of Enterobacteriaceae led to a greater risk of kwashiorkor. By sampling children at a very early age for gut bacteria, it could be possible to identify which children were at greater risk of becoming malnourished and intervening with probiotics or other therapeutic foods to alter the microbiome.

Gut bacteria may prevent kidney injury

Scientists have found that short chain fatty acids (SCFAs), a product of gut bacteria, may protect the kidneys from acute kidney injury (AKI), a condition with high mortality rates that can also lead to other very serious kidney diseases. AKI is often caused by something called ischemia reperfusion injury, an injury resulting from a loss of oxygen to the tissue (ischemia) and a rush of blood back to the site (reperfusion). This instigates a cascade of events resulting in several immune cell populations accumulating at the site of the injury, causing inflammation and kidney damage.

Because AKI is a result of inflammation and because SCFAs are known to have anti-inflammatory effects, scientists in Brazil hypothesized that treatment with SCFAs could ameliorate kidney function. The results published in the Journal of the American Society of Nephrology were the first to show the protective role of SCFAs in kidney ischemia reperfusion injury (IRI). They found that when the three main SCFAs (acetate, propionate, and butyrate) were administered to mice undergoing this IRI injury, they protected the kidney from undergoing AKI.  As suspected, the SCFAs prevented an autoimmune response which resulted in less inflammation and apoptosis (cell death).

Acetate was the SCFA that was most protective to the kidney, so in another experiment the scientists administered acetate-producing bacteria to the mice.  Bifidobacterium adolescentis and Bifidobacterium longum were administered separately and each did produce acetate, as evidenced by increased acetate levels in the mice's feces. They found that these mice were protected from kidney IRI and therefore the bacteria were effective. They did note, though,  that it is unlikely the bacteria colonized the gut, so further investigation is needed.  

This study provides another example of probiotics preventing conditions that may have resulted in serious injury and even death. The bacteria in this study are already used in probiotics to treat other diseases, and so repurposing them for kidney disease should be possible.  The study also describes the anti-inflammatory effects of SCFAs, which we have written extensively about in this blog. 

Viruses in the gut connected to inflammatory bowel disease

Drawing of a bacteriophage

A new study has shown that the composition of viruses in the gut may play an important role in inflammatory bowel diseases (IBD).  If you’ve been reading the blog for a while, you’ve seen us write about something called the virome. The virome is the collection of viruses in the body and similarly to the microbiome, it may have profound affects on human health. This study led by scientists at Washington University in St. Louis and published in Cell is the first to correlate a disease with changes in a person’s virome.

IBD, specifically Crohn’s disease and ulcerative colitis (UC), are diseases that have been characterized by decreased bacterial diversity in the gut.  However in this study, the scientists found that patients with Crohn’s and UC showed greater diversity of viruses than healthy individuals.  This suggested that viruses played a role in the disease.

The team of scientists studied individuals in Boston, Chicago, and the United Kingdom with the disease. They took stool samples from patients with UC and Crohn’s and sequenced their viral DNA. They compared this to the viruses in stool samples from healthy individuals living in the same areas and households. Patients with the disease had a higher number of viruses than those without IBD. Specifically, they found that Crohn’s and UC patients had higher levels of Caudovirales bacteriophages (viruses that infect bacteria) that were specific to each disease.

Further research is needed to better understand the relationship between the virome and the microbiome but as we see from the increase in bacteriophages, there is certainly a relationship between these two systems. While the authors state that it does not look as if changes in the virome were secondary to changes in bacterial populations, it is not yet clear if changes in the virome are the result of bacterial alterations in the gut or if it may lead to microbiome changes - or a combination of the two.  This study is the first of its kind to show a connection between disease and the virome and I think we are going to see several more studies in the coming years showing this type of correlation with disease.  While we generally think of viruses as causing infections like influenza, their impact on chronic disease may be vast.  

Diet plays a more important role than genetics in shaping the microbiome in mice

Today is December 31st which means it’s time to make our New Years Resolutions! Luckily for all of us, a new paper by Peter Turnbaugh’s laboratory gives us good reason to make improving our diet an important goal for the New Year. Dr. Turnbaugh and colleagues at Harvard University and University of California, San Francisco have shown that diet plays the dominant role over genetics in shaping the gut microbiome in mammals. 

Published in Cell Host and Microbe, the team of scientists used several strains of mice to investigate whether diet or the genetics of the mice played a more important role in what bacteria colonized the gut.  They exposed the mice to a low-fat, plant-based (LFPP) diet and a high-fat, high-sugar (HFHS) diet. When mice were given the HFHS, an increase in Firmicutes bacteria and a decrease in Bacteroidetes bacteria was seen, regardless as to what their genetic background was.  When the LFPP diet was given, the shift went in the other direction.  Further investigation needs to be done to better understand whether diet plays a direct role in shaping the bacterial communities in the gut or if it is due to an indirect role that the food has on the entire body of the host.

Another important takeaway from the study was that most changes to the microbiome are reversible. This means that once you shift to a new diet, the microbiome changes with the new diet and the new microbial communities are established within 3 days of exposure to the new diet.  However, the microbiome does remember past dietary patterns.  They leave an imprint on the microbial communities in the gut and some bacterial species are dependent on prior consumption.  

Dr. Turnbaugh suggests that in the future it may be possible to design diets that shape the microbiome in ways that are therapeutically beneficial.  He also states that due to this finding that diet plays a more important role than genetics on establishing gut bacteria, diets won’t need to be tailored to every individual person and specific diets may be useful for most people. 

So while you make your New Years Resolution to eat better and have a healthier diet, know that you are not only impacting your nutritional intake but you are also shaping your microbiome.

We wish all of our readers a happy and healthy New Year. This has been a particularly exciting first year for us and we look forward to another great year ahead.