Sialic acid may be key carbohydrate responsible for inflammation and dysbiosis in the gut

A surface mucous cell bordering on the stomach lumen secretes mucus (pink stain).

Our diet is full of various carbohydrates, composed of different monosaccharides and polysaccharides.  Many of these survive our own digestion and make it all the way to the colon where they modulate our microbiome.  Another source of saccharides for our gut bacteria is the mucous that we produce, which can be a rich source of fucose or sialic acid.  Sialic acid has been implicated in many inflammatory diseases, such as bacterial vaginosis.  Last week, researchers from Switzerland showed that sialic acid may play a critical role in colitis, at least in one colitis model commonly used in mice.  They published their results in Nature Communications.

One way to induce intestinal inflammation in mice is to feed them dextran sodium sulfate (DSS).  The reason this molecule causes colitis in this mice is unknown, but it is used in many models of the disease.  In order to understand the possible role of sialic acid in the colitis, scientists created mice that could not produce mucous with sialic acid.  They quickly realized that these mice were not as susceptible to the DSS-induced colitis as their normal counterparts.  After, they tested how various antibiotics affected colitis in the DSS—colitis mice and discovered that Escherichia coli abundance was directly associated with the severity of the disease. Putting these ideas together, they tested and discovered that E. coli used sialic acid as their main carbohydrate source in vitro.

Interestingly, the E. coli cannot actually access the sialic acid from mucins, but instead need other bacteria, such as Bacteroides vulgatus to cleave and release the sialic acid from the mucins in order to access it.  If sialic acid is indeed important to the human form of the disease there may be multiple approaches to combatting the disease.  First, by eliminating E. coli, and second by eliminating the free sialic acid.

Ethnicity and socioeconomic status could have an effect on gut microbiome composition

As many of our readers know, external factors can influence the composition or make up of our gut microbiomes.  It is important to delineate these external factors as we know the gut microbiome composition can have many impacts or consequences on human health.  The extent to which ethnicity and socioeconomic status play a role in microbiome composition has been relatively unexplored, in part because these types of studies are difficult to conduct.  Regardless, this type of research is important for health research and policy on a large scale.  Researchers from Malaysia sought to explore this relationship, as they examined microbiome variation among children of different ethnicities and socioeconomic backgrounds in Southeast Asia. 

Pre-adolescent children were analyzed according to ethnic group and socioeconomic status.  The researchers examined 24 relatively wealthy Malaysian children, 17 relatively wealthy Chinese children (wealthier and described to be more hygienic than the Malaysian group), and 20 Ogran Asli indigenous peoples considered to be economically deprived and rely on subsistence living. 

16s DNA sequencing of fecal samples from the subjects revealed that the Orang Asli children had significantly higher OTUs (operational taxonomic unit – a measurement of species diversity) as compared to both the Chinese and Malaysian groups.  Specifically, the main differences were seen in bacteria in the Aeromonadales order.  Alternatively, the Chinese group displayed the least amount of species diversity.  Expanding upon this, functional diversity was also different between groups.  Metagenomic sampling indicated that the Orang Asli children had enriched pathways relevant to bacterial colonization and chemotaxis.  Functional profiling of the Chinese group showed heightened genetic pathways related to sugar metabolism. 

Understanding these relationships are very important with respect to public health issues, especially since we live in a culturally diverse world concomitant to socioeconomic disparity.  More and more evidence suggests that the gut microbiome composition is a metric to be taken seriously when analyzing global epidemiology data in different populations throughout the world.  

Fecal microbiota transplants for pouchitis not yet effective

Fecal microbiota transplants (FMTs) are generally accepted as an often-effective treatment for Clostridium difficile infection. To date, this is the only accepted use of FMTs however many scientists and clinicians have proposed other uses of FMTs to treat chronic conditions. One such condition is called pouchitis.

Patients with ulcerative colitis or other diseases often need a total proctocolectomy, the surgical removal of their large intestine and rectum, and have their small intestine connected to the anus to create a pouch to eliminate stools. When this “pouch” becomes inflamed or swells after being irritated, pouchitis results. Approximately half of all patients who need this procedure done get pouchitis in their lifetime and many get it every year.

Researchers in the UK hypothesized that FMTs could be used to treat pouchitis because it is thought that these patients have a dysbiosis. They conducted a trial of 8 patients with chronic pouchitis and published the results in Scientific Reports. After administering the FMT through a nasogastric tube, they analyzed clinical outcomes as well as microbiota composition as well as the immune response. Most importantly, they did not see any significant improved clinical outcomes despite some changes to the microbiome composition and in some individuals, the suggestion of a healthier microbiome as a result in changes in proportion of bacterial species abundance.

This negative result (which is always good to see published) leaves the door open for many further questions in regards to the use of FMTs in IBD including what is the proper route of administration, how often, and what interventions should be conducted prior to treatment. These and many more questions remain as clinicians aim to use FMTs in the treatment of IBD. 

Bacterium identified that may be associated with cervicitis

Cervicitis is an inflammation of the uterine cervix of women. This condition is known to be associated with many different infections, such as Chlamydia trachomatis or Neisseria gonorrhoeae, however the true cause of the inflammation is still unclear. Researchers in Seattle, Washington performed a study, recently published by the journal Sexually Transmitted Diseases, to determine whether it is an imbalance of the vaginal and/or cervical microbiome that is at the root of the problem. The study’s aim was to look at the associations of bacteria with cervicitis in two different groups of women, to see if the results of each group agree.

At a clinic in Seattle, vaginal and cervical samples were collected from a group of predominantly young white women that agreed to the study. Of the 210 women from the clinic, only 14 were identified as having cervicitis based on certain identification criteria. A parallel control study was performed in Mombasa, Kenya with the hopes that the gathered information would either refute or confirm the results of the Seattle group. The Seattle results showed that women with cervicitis were more likely to have Mageeibacillus indolicus in the cervix and vagina than women without the condition. The bacteria Lactobacillus jensenii was the only species that was more present in women without than with cervicitis.

The Kenyan study did not show that M. indolicus was more present in women with cervicitis. In fact, the bacterium was more common in women without the condition. While the results of this study are confusing, because the Kenyan study seems to disprove the results of the Seattle study, it important to keep in mind the flaws of this study as a whole. There were many factors not taken into consideration during analysis, such as birth control intake and viral infections. Additionally, the criteria of cervicitis diagnosis were most-likely different in Seattle and Kenya, and there were very few women in the study that even had the condition. Regardless of the flaws, this study still gave good results which could lead scientists too look further into M. indolicus and L. jensenii for their contribution to cervical health. 

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.

Vaginal microbiome once again tied to preterm birth

Preterm birth is major global health challenge.  Today, around 11% of all babies are born prior to 37 weeks, and are considered preterm.  Many of the causes of these preterm births are still unknown, but it is thought that around 25% of them may be related to a bacterial infection that comes from somewhere in the mother’s own body, i.e. her microbiome.  Many studies are now linking specific vaginal bacteria to risk of preterm birth, and other studies have even shown a connection between other microbiome sites, such as the gut and oral microbiome.  Unfortunately, studies on the microbiome and preterm birth are extremely difficult to conduct, so there are just not enough to have any sort of scientific consensus on the topic.  Last week though, a very rigorous study out f Stanford University was published in the Proceedings of the National Academy of Sciences that monitored expectant mothers vagina, gut, and oral microbiome throughout the course of her pregnancy and then for one year after.  Among many interesting findings, which are discussed below, the most important one was yet another connection between bacterial vaginosis and preterm birth.

The researchers monitored the vaginal, distal gut, salivary, and tooth/gum microbiomes of 49 women, 15 of which ended up delivering preterm, over the course of their pregnancy and for one year after.  Interestingly, the non-vaginal sites’ microbiomes remained relatively stable over the duration of the pregnancy, and even for the one year after.  The vaginal microbiome, however, did show some differences during and after pregnancy.

As many of our readers already know, a healthy vaginal flora is dominated by Lactobacilli, but around 20% of American women are dominated by other species, such as Gardnerella vaginalis, and have an overall increased vaginal diversity.  These women have what is known as community state type four, or CST4, and these women could be diagnosed with bacterial vaginosis (BV), though the clinical diagnosis is not so specific.  The other community state types, CST1, 2, 3, and 5, are dominated by different strains of Lactobacilli, and are generally regarded as healthy.  This current research showed that many of the women’s vaginal microbiomes actually shifted between various CST’s during pregnancy, most often shifting to and from CST4.  These transitions had no association with preterm birth, though.  After giving birth the vaginal microbiome became more diverse, and had greater abundances in anaerobic bacteria, such as Peptoniphilus, Prevotella, and Anaerococcus.  In addition, this usually coincided with a decrease in Lactobacilli.  Surprisingly, these changes did not seem to relate to mode of delivery (C-section of vaginal).

CST4 has been linked to preterm birth before, and this was reinforced in this study.  The scientists found that the longer a women’s vaginal microbiome was within CST4, the greater risk she had for preterm birth.  In addition, the abundance of Gardnerella and Ureaplasma, specifically, were linked to preterm birth.

This study reinforces what many microbiome scientists already suspect, and that is the importance of the vaginal flora in preterm birth.  It is unclear at this point if manipulating the vaginal flora prior to, or during pregnancy would help prevent preterm birth, but it is certainly worthy of discussion and clinical testing.  If you are reading this and wondering what your vaginal microbiome is, then we recommend you participate in the citizen science project, YourPrivateBiome, to find out.  You can learn more about it by following this link on our site, or just click the link above.