Reflecting on the microbiome during National Breast Cancer Awareness Month

As you watched the future Hall of Fame quarterback Eli Manning over the past two weeks, you probably noticed NFL players wearing pink for National Breast Cancer Awareness Month. Before this month comes to a close we want to bring your attention to one of our previous posts about the microbiome and breast cancer.  The study showed that post-menopausal women who had a more diverse gut microbiome had a lower risk of getting breast cancer. You can read more about it here.  

We also want to take this time to encourage natural breast feeding, whenever possible, for all new mothers.  A new review article published in Nature Pediatric Research describes the importance of breast milk in creating a healthy infant microbiome.  Breast milk is a complex food that contains bacteria and also supports the growth of bacteria.  The review highlights that when compared to formula, breast feeding leads to more infant gut colonization of Bifidobacterium, Lactobacillus, and Clostridia, and these bacterial strains are linked to the development of a healthy gut and a healthy immune system.  In addition, breast milk leads to a lower infant gut pH, compared to formula, and infant gut pH affects further species colonization.  Breast milk has evolved to support both us and our microbiomes, and no simple formula can substitute for the real thing.  

Every week there are new studies connecting the microbiome to public health and disease areas that may not seem as obvious as others. We know that the microbiome influences diseases and conditions like obesity, inflammatory bowel disease (IBD), diabetes, and necrotizing enterocolitis (NEC), but we are now learning that the microbiome is also connected to diseases and conditions like breast cancer, alcoholism, autism, and depression. While it is important to keep our excitement about the microbiome in check, the AMI is building new resources for the microbiome field because we believe our impact can be vast.  Advancing the field of research as a whole can influence the development of new treatments and therapies for a wide range of diseases. 

The microbiome may affect vaccination efficacy

We know that vaccines are often not as effective in developing nations as they are in industrialized nations and a recent study published in September in Immunity may provide insight into why this discrepancy exists.  Researchers in the US and Brazil examined a possible link between the microbiome and the effectiveness of vaccines. 

Previous research had shown that expression of TLR5, a cell-surface receptor for bacterial flagellum, correlates with TIV (a popular flu vaccine) vaccination antibody response in humans. In this study, researchers observed this correlation between TLR5 expression and the immune response from the TIV vaccine through a series of experiments.

First, researchers found evidence to suggest that the correlation between TLR5 and antibody response is not because of any kind of contamination in the vaccine. They also saw a significant decrease in antibody response in mice with a mutated TLR5 gene, when they were given the TIV vaccine, even though they showed no prior immunodeficiency. Other evidence was found to suggest that the gut microbiome is necessary for a rapid antibody response after vaccination, because the response of antibody secreting cells depends on the microbiome. Research also suggested that multiple types of bacterial communities are necessary, and not just a few specific species, for gut bacteria to mediate immune responses. 

These findings of the microbiome’s role on the effectiveness of a vaccine in inducing an immune response could impact future vaccine development. Further research may be done to better understand the role that diet, health, and other factors that affect the human microbiome play in vaccine response. Microbiome differences between individuals in developing nations and those in industrialized nations could play a significant role in the efficacy of existing and future vaccines.  

Obesity, mental illness, and the microbiome

A study published by Biological Psychiatry studied the neurological effects of gut bacteria typically part of the obese microbiome, because obesity, depression, and the microbiome have each been associated with one another.  To do this, 8-week-old male mice were fed either a regular chow diet or a high-fat diet. The microbiomes of these mice were then transplanted into 3-month-old male mice that were on a regular chow diet and antibiotics (the antibiotics were used in place of germ free mice to keep their gut populations low).  16S sequencing eventually showed successful transplantation of the donor microbiome to the recipient mice.

The recipient mice were subjected to anxiety, exploratory, stereotypical behavioral testing, as well as memory testing, all of which are common techniques that test for anxiety and depression in mice. In addition, the mice’s microbiomes and blood were sampled, and the mice’s guts and brains were investigated post-mortem.

Results of the experiment showed that the recipient mice, which were raised conventionally, showed significant disruption of mental behavior after harboring the gut microbiome of obese mice that eat a high-fat diet.  Furthermore, these mice had lower microbiome diversity, higher gut permeability (i.e. leaky guts), and higher levels of overall inflammation and brain inflammation than mice with the normal chow transplants.  It is not understood exactly how gut bacteria affect behavior, but it is further evidence of the importance of the gut-brain axis and the potential value of prebiotic and probiotic therapeutics for mental health.  

Too much jetlag may contribute to obesity

A study published last week in Cell explores the microbiome of the gut in both mice and humans, and it’s responses to changes in its biological rhythm. Researchers performed many experiments that were comprised of altering the dark-light conditions in which mice were kept, as well as the feeding times of mice.

Many important results were found from the multiple variations in experimental conditions to which the researchers subjected the mice. First, researchers uncovered that the microbiome has time-of-day- specific differences in function and composition. Evidence suggests that feeding patterns dictate this fluctuation. After mimicking jet-lag in mice, compared to a control group, these mice exhibited imbalances in their gut microbiome. It was later found that this imbalance could be transferable from jet-lagged mice to mice raised germ-free, through the fecal transfer of the gut microbiome. An experiment was also done in which jet-lagged and control group mice were fed high fat diets. The jet-lagged mice exhibited enhanced weight gain and glucose intolerance. Antibiotic treatment showed a decrease in these symptoms. Lastly, a study was done in humans who were subjected to jet-lag, which suggested that the microbiome of humans also undergoes daily oscillations, and that disruption of this rhythm can lead to imbalances in the microbiome and in human metabolism. The human study was only done with two individuals and fortunately, their microbiomes returned to normal after just two weeks though still raising questions about the impact that too much travel and jet-lag could have on health.

The experiments done in this study opens the door for further research on the microbiome’s sensitivity to changes in a human’s biological clock, as well as the impacted microbiome’s influence on the metabolism of its host.  

More evidence that probiotics help to prevent necrotizing enterocolitis

In an article published by Nature Pediatric Research, researchers investigated the effectiveness of the bacteria Bifidobacterious longum subsp. infantis as a probiotic used to decrease the risk of necrotizing enterocolitis (NEC). NEC, as we have discussed previously in this blog, is a type of bacterial infection in premature babies, which can often be fatal. To study the effectiveness of B. infantis, researchers assigned 50 rat pups into three groups, which were delivered one day premature of term, to be fed by their mothers, fed with formula, or fed with formula supplemented with B. infantis. The pups were also exposed to hypoxia and cold stress. Intestinal tissue was tested for response.

The results of this experiment reinforced the importance of maternal milk, and showed the importance of a probiotic, B. infantis, if formula must be used.  None of the mother fed mice were diagnosed with NEC, while ~80% of formula fed pups were.  By supplementing the probiotic though, less than 40% of the rat pups were diagnosed with NEC, and the severity of NEC was lower in these instances.  Results also suggested that the probiotic decreased the inflammatory immune response of the underdeveloped intestinal mucus layer. The second part of the experiment, involving putting stress on the rat to observe responses, resulted in data that was inconclusive but suggested that stresses such as hypoxia and cold may not significantly alter the microbiome of the intestines.

While the results of the above experiment did not conclude whether outside stress effects the response of the microbiome in premature rat pups, they still show that certain bacteria such as B. infantis can be useful as a probiotic in preventing NEC.

The virome

Bacteriophages (bacterial viruses) attached to a bacterial cell wall.

A review in the journal Cell written by Herbert Virgin describes the exploration of the virome, a part of the overall microbiome which includes viruses, as an emerging study of importance in relation to human health. The size of the mammalian virome –viruses that infect mammals- is still unknown, but it is believed by scientists that, in the human body, viruses may outnumber the bacterial microbiome by at least 10x, making the virome out number human cells by 100 times or more. 

The human virome includes all the viruses that affect human cells, along with those that affect our bacterial, archaeal, and fungal microbiome, in addition to other viral derived genetic material.  Viruses have already been studied as important pathogens for each of these hosts, but their mutualistic and beneficial interactions are only beginning to be explored.  This is similar to the story of bacteria, which are only now being recognized for their importance in humans.  In addition, it appears there are many important, complex interactions within the microbiome that include the virome.  For example, it is likely that viruses that attack bacteria are embedded in the gut mucous and attack and destroy bacteria before the bacteria can reach the gut lining, providing host immunity.

Investigation into the viral microbiome is still at its beginning. Discovery of new viruses and their interactions with humans is likely to continue and perhaps increase with the increase in availability of viral genome information.  We encourage everyone to read the linked article.  The virome is a fascinating subject which we hope to explore in future blog posts.