Microbiome Innovation: Roadmap to the Future – Report from the White House

Last week the American Microbiome Institute was invited to the White House to attend the Microbiome Innovation: Roadmap to the Future conference. The conference was hosted by the Office of Science and Technology Policy, which is embracing microbiome science and its promise to revolutionize various fields of research, such as health, medicine, agriculture, ecology, and more.  The purpose of the symposium was to bring together representatives from industry, academia, government, foundations, and non-profits in order to come to a consensus and identify the major roadblocks that are obstructing microbiome science, across all disciplines.

Various agencies from the federal government kicked off the conference by discussing how microbiome science was important to their departments, such as the NSF, USAID, and NIH.  These talks prompted a lively discussion regarding C. difficile treatment and fecal microbiota transplants, and how the FDA should regulate them.  After, working groups were formed to debate and discuss important issues to the field.  For example, groups were tasked with defining a healthy microbiome, but the consensus was that this was difficult because of its dependency on the host.  In addition, groups discussed ways in which interdisciplinary microbiome research could be encouraged.  Two approaches that were recommended to incentivize this were to require grants to include an interdisciplinary component, and to have academic promotion and tenure reward PIs that perform this type of research. 

We at the AMI would like to thank the folks at OSTP for inviting us to the conference.  We actively participated in the discussions to let people know the areas that we have identified as needs, and the things that we are trying to do at the AMI to solve them.  As a non-profit devoted to the microbiome we have a unique perspective on the field, and a mandate to advance it.  

Probiotics and natural herbs may assist in preventing liver disease

Last May we talked about a study that described gut dysbiosis as an underlying cause to the development of steatosis and liver failure.  In brief, the researchers theorized that opportunistic gram negative bacteria can populate the gut as a result of gut dysbiosis.  These bacteria can release lipopolysaccharides into the blood stream, and upon reaching the liver, induce inflammatory toxic damage leading to steatosis. 

Researchers in China have investigated similar theories regarding the microbiome and its role in non-alcoholic fatty liver disease (NAFLD).  NAFLD is a liver malady with an unknown root cause and pathogenesis.  There is no known cure, and unfortunately many patients diagnosed with this condition end up developing non-alcoholic steatohepatitis (NASH) and fibrosis, damaging the liver architecture and presenting potential fatal consequences.  Previous research has shown that lipopolysaccharides from gram-negative bacteria can enter the liver through the portal vein of the liver.  Furthermore, gut dysbiosis can lead to a disproportionate amount of gram-negative bacteria that can produce damaging endotoxins and metabolites.  These investigators address the microbiome concept and examined to see whether a probiotic paired with a natural herb would have any effect or could possibly remedy NAFLD in rats. 

A well-known cholesterol-lowering probiotic was used in addition to a natural herb called Cassia obtusifolia L. (AC).  The molecular components in the AC herb have been shown to have beneficial effects on lower fat and cholesterol, as well as anti-oxidant and neuroprotective properties.  Additionally, the herb has been shown to protect liver function in rats that have experienced liver injury.  The primary hypothesis was that cholesterol-lowering probiotics administered concomitantly with the AC herb could protect rats from NAFLD by way of symbiotic protection of microbial structure and metabolism of the gut microbiome. 

30 rats were divided into 5 groups.  Group 1 was the control, receiving no treatment and a normal chow diet.  Group 2 received a high-fat diet (HFD) and established the NAFLD model.  The remaining 3 groups were all kept on high-fat diets and were distinguished by drug administration: one group received cholesterol-lowering probiotic alone, one received the AC alone, and the final received both the probiotic and the AC herb. 

150 days after diet and drug treatment, the researchers sacrificed that animals and examined lipid parameters, genes related to fat synthesis (in the liver), and species diversity of the gut microbiomes in rats.  Lipid levels in the rats treated with the probiotic and the AC herb were significantly reduced as compared to the HFD group that did not receive any treatment.  Also, reduced levels of hepatic steatosis were observed in the probiotic+AC group.  Furthermore, the probiotic+AC group demonstrated improved mucosal barrier function, as demonstrated by histological analysis showing intact intestinal villi.  Lastly, fecal analysis of the microbiome composition revealed that the microbiome composition in the probiotic+AC combination therapy group were most similar to that of group 1, the normal chow group.  Specifically, this included high populations of Bacteroides and Lactobacillus genus.

These findings demonstrate an interesting association, and among other things point to the potential value of Eastern medicine.  Many more studies, conducted at a larger scale, should be carried out in the future as NAFLD is an ailment with an unmet medical need.  

Elective vs. acute c-section deliveries: does it make a difference?

Caesarean sections are often needed when there are complications during a pregnancy or a woman often will elect to undergo a c-section due to a variety of reasons. In some nations, c-section delivery rates are incredibly high and there are attempts to lower these numbers. In Brazil for example, 85% of births in private hospitals are c-section deliveries. Babies born via C-section have been shown to have an increased risk of disease related to immune function. Previous studies had not discriminated against elective or acute c-sections and scientists in Denmark set out to do just that.

Conducting a population based study of 750,569 children born between January 1997 and December 2012, they analyzed children born via elective c-section, acute c-section, and those born vaginally as the reference. They found that the children born by either elective or acute c-section had a higher risk of asthma, laryngitis, and gastroenteritis though electively born c-section babies had a more pronounced risk than acute c-section babies. Those born via elective c-section had an increased risk of lower respiratory tract infection and juvenile idiopathic arthritis. Babies born by acute c-section had an increased risk of ulcerative colitis and celiac disease.

There were other factors not taken into account such as if the children were breastfed or if the mothers had asthma. While not everything was able to be taken into account, with such a large sample size, it is likely that the results from this study would not have been significantly affected by other factors. Most of the effects were seen in diseases that involved the mucosal immune system. The authors believe that the reason for the differences is a result of disturbed immune function as a result of differing microbial colonization in c-section babies.  

Can hookworms fight against celiac disease?

Helminths, or gut worms, are native inhabitants of our microbiome that are known to have substantial immunosuppressive effects.  Some scientists believe they are a keystone species in the microbiome and that their absence in people following a Western lifestyle may be contributing to the rise in autoimmune diseases, such as celiac disease.  In fact, scientists have recently shown that hookworm infection leads to higher gluten tolerance in individuals with celiac disease.  The cause of hookworm’s broad immunosuppression is unknown, but those same scientists investigated the possibility that it may be caused by the worms’ ability to modulate the bacteria in the gut.  The researchers recently tested this hypothesis and published their results in Nature Scientific Reports.

First, the researchers measured the fecal microbiota of eight human subjects with celiac disease, all of whom had followed a gluten free diet for at least five years prior to the trial.  Compared to a control group that hadn’t followed a gluten free diet, the trial subjects had a greater abundance of Bacteroidetes, while the control group showed greater abundance of Firmicutes.  Next, the subjects were successfully infected with hookworm and gluten was slowly reintroduced into their diets over a period of 44 weeks. The scientists measured the subjects gut microbiota at different time points and discovered that the hookworms, in conjunction with the gluten introduction, restored levels of Firmicutes in the celiac disease patients.  By the end of the study all of the remaining participants had rich abundances of both Bacteroidetes and Firmicutes.

It should be noted, and the authors admit, that the study is limited by its small sample size.  Still though, the results lead one to believe that helminths are modulating the microbiome, and that this may contribute to the overall immunosuppressive effects of these worms.  People have been known to practice helminth therapy to achieve immunosuppression in the gut, however this is dangerous for a number of reasons.  Instead researchers, such as the ones that performed this study, are in search of the mechanism for this immunosuppression.  There is certainly some very interesting biology that occurs during a helminth infection, and hopefully sometime soon scientists can turn these helminths into therapies.

A brief summary of a recent review of the gut-brain axis

Comparison of a normal aged brain (left) and the brain of a person with Alzheimer's (right). 

The gut-brain axis refers to the interplay between the gut microbiome and our behavior.  There are a few mechanisms by which the gut microbiome can affect the brain, such as by directly communicating with it via the vagus nerve, by producing hormones or other metabolites that influence brain function, and by eliciting a systemic inflammatory response.  This past month researchers Timothy G. Dignan and John F. Cryan, both of the University College Cork, in Cork, Ireland, published a review of the recent advances in the gut-brain axis literature.  Many exciting scientific developments have occurred in the past few years, including new advances that connect the microbiome with depression, autism, Alzheimer’s disease, and schizophrenia.  Here, we discuss some of those studies and summarizing the review.

Depression: Studies have shown a possible association between the microbiome and feelings of depression.  It is not clear, however, if these changes are due to drugs that are being taken.  Other studies have shown that probiotics can reduce thoughts of depression, and a separate study showed that eating yogurt improved the moods of oil workers.

Autism:  Again, research has shown a correlation between the microbiome and autism, but not any sort of cause or relation with symptoms.  Multiple studies in mice have shown that a dysbiotic microbiome can lead to autism like symptoms, and that altering the microbiome can alleviate them.  Again, however, there are few mechanistic links between the microbiome and the disease.

Alzheimer’s disease:  Very few studies have linked Alzheimer’s and the microbiome.  Some studies have seen a broad decline in microbiome diversity amongst Alzheimer’s patients, but decreased diversity is known to be associated with many other phenotypes.  Smaller studies on mice have shown some symptoms of Alzheimer’s, such as memory loss, can be somewhat reversed using probiotics, but the results are hardly robust and do not necessarily imply a link with Alzheimer’s.

Schizophrenia:  Like Alzheimer’s, very few studies have linked the microbiome and schizophrenia.  Like all of the above, various associations have been made between the disease and the microbiome, but no strong correlations have been measured.  In mouse models of schizophrenia, antibiotics can alleviate symptoms of the disease.  In addition, there is evidence that antibiotics can also improve the mental state of humans. 

Taken collectively, there is a compelling reason to believe that the microbiome is important to each of these indications, and that it is critical to a healthy mind.  It is still early days though, and much more research is needed to prove mechanisms and pathways.  

The oral microbiome can predict childhood caries

Early childhood caries is an oral disease common in young children.  The infection leads to sustained demineralization of tooth enamel and dentin and can also spread to gums and surrounding areas.  Unfortunately, the damage from this disease is irreversible and can put a child at risk for tooth loss for the rest of his or her life.  In an effort to explore different ways to prevent childhood caries, researchers from China sought to investigate whether or not changes in the oral microbiomes of children could serve as a predictive measurement for development of caries.  

In a longitudinal cross sectional study conducted over 2 years, the researchers examined spatial and temporal variations in the microbiomes of 50 4-year old preschoolers.  The researchers took microbiota samples from saliva and plaque at four different time points.  Based on clinical monitoring among this cohort, the children were further segmented into 3 groups based on diagnosis: 1) healthy, which constituted 17 children, 2) caries onset, which constituted 21 children, or 3) caries progression, which represented 12 in the group. 

It was found that the caries onset group experienced delayed microbiota development, adjusted for age (which has shown to be a significant confounder as microbiota composition changes significantly during development).  Furthermore, changes in microbiota composition were more associated with ECC in onset children as opposed to progression, thus lending to the possibility of using the microbiome composition as a predictive tool.  In this light, the researchers developed a model termed Microbial Indicators of Caries (MiC) and successfully diagnosed ECC saliva/plaque samples from healthy samples with 70% accuracy, while predicting ECC onset in children with 80% accuracy.  The MiC model derived a readout based on an identified “intermediate” state of microbiota that represents a compositional shift. 

We’ve discussed in the past how microbiome composition and metabolites could be indicators of disease.  These findings point to another potential tool that can use features of the microbiome as a diagnostic method.  More research and further understanding of our microbiome can introduce a new field with the potential to provide immense health benefits.