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Special Report on Microbiomics: Army of One
January 2019
by Randall C Willis  |  Email the author
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Special Report on Microbiomics
 
Army of One
Finding alliances between microbes and immune cells
 
By Randall C Willis
 
Straight out of Hollywood’s summer line-up, aliens arrive on our shores, in our fields and over our cities.
 
If this was 1950s America, stressed by the ongoing Cold War, the immediate assumption is that these aliens present a threat. By the 2010s, however, people seem to be more open to the possibility that the aliens are transient or might even be benevolent.
 
Healthcare and medicine are undergoing a similar transition in terms of the microbial invaders that have taken residence in the human body, seeing them less as pathogens and maybe more as symbiotes.
 
Increasingly, microbiomics offers researchers and clinicians a more holistic view not just of disease, but also of health. But that expanded vision brings new challenges, layering in complexities never before considered. It takes the Boehringer Mannheim metabolism chart that some might remember from their graduate school days and layers in third (metabolic) and fourth (dynamic) dimensions of these other organisms.
 
“What I have found most impressive about the field is that you see so much interplay between not only the gut, but other systems,” enthuses Alex Maue, director of Microbiome Products and Services at Taconic Biosciences. “The research that has surprised me the most has really been the linkages between the gut bacteria and neurodegenerative diseases.”
 
Perhaps an easier connection to imagine is the one between microbiota and the host immune system, rising as it does from the biological Cold War memories.
 
“It turns out that about 80 percent of the immune cells in the body are in the gut,” offers Bernat Olle, CEO of Vedanta Biosciences, a company working toward using microbial consortia to restore health.
 
“They have to patrol all of the populations of microbes that are sending signals to the body and make sure that they’re behaving themselves properly.”
 
It is this cross-signalling that not only stabilizes the microbial population, but also keeps the immune repertoire in check.
 
“It is well established that the gut microbiota is in close interaction with the intestinal mucosal immune system,” offered Catholic University of the Sacred Heart’s Rossella Cianci and colleagues in a recent commentary. “Indeed, the intestinal mucosa may be considered as an immunological niche, as it hosts a complex immune-functional organ comprised by T cell subpopulations and their related anti- and proinflammatory cytokines, as well as several other mediators of inflammation, in addition to the microbiota.”
 
Any modification to the balance between microbial population and immunological niche, they suggested, could potentially lead to inflammatory, infectious or endocrine disease.
 
Germ-free animals have been instrumental in showing us the power of this interaction, as they allow researchers to start with a clean microbial slate and introduce flora from both healthy and unhealthy individuals to look for large-scale differences.
 
“In IBD and Clostridium difficile-associated colitis patients, fecal microbiota transfer [FMT] was successfully applied to treat disease, establishing a causal relationship between alteration of the microbiota and disease,” wrote Oliver Pabst of Aachen University in a recent review.
 
“Colonization of germ-free mice results in normalization of their immune status, and most of the differences characterizing the deviation from the colonized state disappear in formerly germ-free animals within a few weeks,” he continued. “Thus, immune maturation is clearly driven by and
 
a consequence of the microbiota.”
 
Pabst was quick to note, however, that causality and functionality should not be confused, and that much needed to be understood before microbiome-based diagnostics and therapeutics could become commonplace. Following traditional approaches, a first step is simply identifying the microbial players.
 
Names to faces
“In the past, research on the microbiome was performed through classical microbiology techniques such as culturing,” explains Dev Mittar, head of research and development at ATCC. “Scientists would phenotypically characterize those microorganisms.”
 
Not all microbes were amenable to culturing, however. The advent of new sequencing methodologies such as 16S rRNA profiling and shotgun metagenomic sequencing quickly revolutionized microbial identification, offering a more realistic window onto the microbiomic landscape.
 
“However, these protocols are multistep and very complex,” Mittar continues. “Each step can add significant bias in the methodology, which could then impact the final readout.”
 
Because of this risk for bias in the methodology, he presses, workflow standardization is critical.
 
“One of the primary challenges in standardization was that, for a while, there were no credible reference materials available,” Mittar says. “Microbiomes are complex, comprising thousands of species and strains. There is no way that you can make a perfect standard that could mimic a microbiome specimen and fit all studies.”
 
To address this shortcoming, ATCC has developed two categories of microbiome standards from fully authenticated and sequenced ATCC strains.
 
“One is a mixture of whole cells, where we mix 10 and 20 diverse bacteria on the basis of their Gram stain, GC content, genome size, etc.,” he explains. “The second set is a mixture of genomic DNA prepared from the same set of 10 and 20 different bacteria.”
 
And even these mixtures are presented in two ways: evenly proportioned and staggered. In particular, the latter allows researchers to determine limits of detection for their assays.
 
“Now that NGS technology has become mainstream in scientific research, we have embarked upon a huge project that involves sequencing of all of our microorganisms and cell lines, starting with the species that are most pertinent to the scientific communities,” Mittar continues.
 
“Our goal is to provide whole-genome sequencing data in the form of assembled and annotated genomes,” he adds. “This will definitely enhance the authentication of all of our microbial strains and cell lines, which is a key component of our pledge to advance authentication and ensure the scientific community has confidence in their results.”
 
Likewise, Steve Festin, associate director of science and technology at Charles River Laboratories, highlights the enabling technologies that help researchers turn the animal models into useful data, pointing to the sequencing capabilities within Charles River Labs.
 
As an example, he offers his organization’s recent partnership with One Codex, which is providing an interface and database for 16S comparisons.
 
With the new technologies, researchers quickly identified a panoply of microbial species that seemed to vary extensively from study to study and even subject to subject.
 
“The key question, though, is what does this variation really mean?” asks Olle. “Is it meaningful or is it irrelevant?”
 
It may be, he continues, that healthy comes in many flavors.
 
“There are healthy people who are healthy with a gut dominated by Bacteroides,” he explains. “There are healthy people who are healthy with a gut dominated by Firmicutes. And so, health is something that has multiple phases.”
 
Because of this inherent variability, researchers are starting to dig a little deeper, and as Mittar suggests, the field is transitioning from microbial identification to functional profiling.
 
“People are moving from metagenomics to metatranscriptomics and metabolomics to find out what exactly those microorganisms are doing in the human body,” he says.
 
Functions to faces
“One of the things about the microbiome is that it is so dynamic,” Festin offers, pressing on to assert: “People seem to have forgotten what happens after the genes are expressed. It is the enzymes, the metabolism of the bacteria, the metabolites that are then produced, the interaction of the bacteria with the host physiology.”
 
“And then it’s what those bacteria do, how they react, how they metabolize, what would be other factors, that can all directly influence what’s going on,” he says.
 
It comes down to defining the system.
 
“In NMR, a small molecule is what it is,” Festin says. “You put it into a spectrometer, and what you put in is what you get out. In microbiomics, it is the bacteria and all of the other factors involved: the metabolites, the enzymes, the microenvironment; the interplay of the host and the bacteria themselves.”
 
In some ways, he says, it might feel counter-intuitive to researchers, almost like a step backward.
 
“Essentially, what you’re doing is poking the system and seeing what happens, as opposed to being able to analyze and isolate the components of that system in such a way that you can study it directly.”
 
“The field hasn’t really gotten to the point where those factors are easily isolated and measured in some way,” Festin remarks. “You still have to look at it as a whole system, as opposed to being able to take just the individual components and extrapolate that to some biology directly.”
 
That doesn’t mean that people aren’t trying to understand those individual components, however.
 
“In collaboration with Jason Kwan’s lab in University of Wisconsin–Madison School of Pharmacy, we have performed RNA-seq analyses on our whole cell mock communities, where we validate the bioinformatic analysis that we obtained from metagenomics and then correlate it with metatranscriptomics,” Mittar says.
 
ATCC is also interested in exploring metabolomics, again likely with a collaborator.
 
The unique nature of microbes, however, has meant that common transcriptomic techniques may only get you so far.
 
“Classical RNA-seq is a very good technology to identify the expression levels of genes, as well as whether the genes are up- or down-regulated,” explains Laurence Ettwiller, senior scientist at New England Biolabs. “Having said that, you have to fragment the RNA to be compatible with Illumina sequencing, and therefore you lose certain kinds of important information, especially in bacteria.”
 
In particular, she suggests, you will not get a clear picture of the operon structure.
 
“Bacteria are quite compact, there is a lot going on,” she says. “The real estate in bacteria is quite extensive, and therefore everything is sort of compacted. If you look at RNA-seq results, it is really difficult to identify your transcriptional landmarks, such as transcription start and termination sites.”
 
To address this challenge, Ettwiller and colleagues at NEB and Pacific Biosciences developed a technique they call SMRT-Cappable-seq, which allows them to capture the full-length, primary transcriptome.
 
“Knowing where the operons start and end is really key to understanding the metabolic pathways, as well as the genes that are physically linked to a certain metabolic pathway,” she explains.
 
Working solely with E. coli under rich and minimal growth conditions, the researchers were surprised to discover operon variants, where specific subsets of genes were expressed in the long transcripts under specific circumstances, hearkening back to alternative splice variants found in eukaryotic systems.
 
“It is a little less complex because we don’t have introns and exons,” Ettwiller says, but the number of alternative transcription start sites as well as read-through of termination sites offers unanticipated combinatorial possibilities in gene expression and therefore metabolism.
 
A key next step for the group is to apply the technology to microbiota collections, such as clinical samples. This might involve the addition of single-cell platforms to correlate cell identity with metatranscriptomic profile, but Ettwiller is not sure this is necessary.
 
“The other way of thinking about it is not to think so much about the species, but more about what are the genes that are globally expressed, the pathways that are globally expressed in the microbiome, regardless of where it comes from,” she notes. “After all, the small molecules are secreted by the microbiome, so it doesn’t really matter if it is made by this or that bacterium, as long as you can see the RNA and even better if you can see the proteins.”
 
Taconic’s Maue echoes her sentiment, suggesting that there is likely to be extensive functional redundancy within the microbiota network, so multiple functions can be carried out by divergent groups of bacteria.
 
“You’re layering levels of complexity,” he remarks, which can make it difficult to proceed with a reductionist approach to understanding what is happening.
 
According to Bo Yan, Ettwiller’s colleague and technical lead on SMRT-Cappable-seq development, the platform is based on sequencing of the cDNA from RNA, which also includes PCR amplification steps. This, she says, may introduce some bias toward small fragments, adding that “By moving to direct RNA sequencing, this problem could be solved and give us more accurate computation of the expression levels.”
 
Even this deeper molecular dive has two edges, according to Catherine Lozupone at University of Colorado.
 
“Use of integrated omic technologies, including shotgun metagenomics, metatranscriptomics, and metabolomics—to more deeply characterize phenotypes of both the microbiome and the host—has the potential to generate hypotheses regarding novel mechanisms of immune modulation of importance in disease contexts,” she wrote last spring. “Integrated multi-omic analysis, though promising, is only the first step toward mechanistic understanding. Functional exploration with in-vitro assays, animal models and genetic manipulation of bacteria is key for validating results.”
 
Her lab studies microbial polysaccharides that appear to suppress inflammation by stimulating CD4+ T cells to differentiate to anti-inflammatory regulatory T cells (Treg).
 
“We verified that predicted ZPS [zwitterionic polysaccharide] producers had anti-inflammatory properties by comparing the abilities of phylogenetically integrated ZPS producers versus non-ZPS producers to induce IL-10 and Tregs in in-vitro assays with peripheral blood mononuclear cells, and also by evaluating protection in a mouse model of inflammatory disease,” Lozupone recounted. “We further confirmed ZPS to be a driving factor of Treg and IL-10 induction in in-vitro assays performed with Bacteroides cellulosilyticus by genetically disrupting ZPS operons.”
 
“We are continuing to work in mouse models of inflammatory disease and in in-vitro systems to establish whether any of these novel ZPS molecules or the microbes that produce them have therapeutic potential for diseases of chronic inflammation, including HIV infection.”
 
Thus, the field is rapidly moving from academic to translational research.
 
Beyond the gut
“Knowing that 70 percent of microbiota reside in the colon of the human, perhaps it is no surprise that a lot of the research has been to date focused on the gut,” Maue says.
But what starts in the gut doesn’t always stay in the gut, as exemplified by recent work of New York University’s Smruti Pushalkar and colleagues, who showed that fluorescently tagged bacteria given orally to germ-free mice relocate to the pancreas.
 
More specifically, the group characterized the microbiome of pancreatic ductal adenocarcinoma (PDA), starting with a germ-free version of a PDA mouse model.
 
They noted that germ-free status conferred protection from disease progression, and that microbial ablation with antibiotics in wild-type mice bearing tumor cells cut tumor burden by 50 percent. This protection could be reversed, however, if the germ-free mice were given fecal transplant from PDA-bearing mice, but not from cancer-free mice.
 
The researchers then looked deeper, characterizing the immune response to antibiotic treatment.
 
“Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting Th1 differentiation of CD4+ T cells and CD8+ T-cell activation,” the authors noted. “Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression.”
 
Alone, anti-PD-1 treatment was not sufficient to reduce tumor progression, and yet, when combined with antibiotic treatment, the checkpoint inhibitor reduced tumor growth at levels surpassing antibiotic treatment alone.
 
Extending further from the gut, Chinese Academy of Medical Sciences’ Jianwei Wang and colleagues recently characterized the active lung microbiome of patients with chronic obstructive pulmonary disease (COPD) as well as healthy subjects, performing metatranscriptomic sequencing of bronchial fluids.
 
Their analysis identified three distinct microbial communities that correlated with bacterial biomass, Th17 immune response and COPD exacerbation frequency.
 
“Specifically, samples with transcriptionally active Streptococcus, Rothia or Pseudomonas had bacterial loads 16 times higher than samples enriched for Escherichia and Ralstonia,” the authors noted. “These high-bacterial-load samples also tended to undergo a stronger Th17 immune response.”
 
“Furthermore, an increased proportion of lymphocytes was found in samples with active Pseudomonas,” they continued. “In addition, COPD patients with active Streptococcus or Rothia infections tended to have lower rates of exacerbations than patients with active Pseudomonas and patients with lower bacterial biomass.”
 
They noted that the differences between individuals were not just limited to microbial composition, but also to active functional elements and host immunity characteristics, offering a potential window into variations in disease susceptibility across human populations.
 
Maue also sees potential for microbiome intervention in the skin.
 
“Being able to identify strains or communities of bacteria that could confer immunosuppressive effects,” he suggests, “may serve as a potential therapy for psoriasis.”
 
Which brings the conversation around to autoimmune disorders. In particular, Maue points to recent work in the area of lupus.
 
Last April, Yale University’s Teri Greiling and colleagues noted that some human skin, gut and oral commensal bacteria produce a protein orthologue of human Ro60, an RNA-binding protein that is targeted by autoantibodies in patients with lupus. They showed that serum from anti-Ro60-positive lupus patients immunoprecipitates the orthologous proteins.
 
“Further, germ-free mice spontaneously initiated anti-human Ro60 T and B cell responses and developed glomerular immune complex deposits after monocolonization with a Ro60 orthologue-containing gut commensal, linking anti-Ro60 commensal responses in vivo with the production of human Ro60 autoantibodies and signs of autoimmunity,” the authors noted. “Together, these data support that colonization with autoantigen orthologue-producing commensal species may initiate and sustain chronic autoimmunity in genetically predisposed individuals.”
 
They further suggested that these findings could potentially lead to treatment approaches based on defined commensal species.
 
Vedanta is taking a cautious approach with these other autoimmune indications.
 
“Today, we have good evidence in clinical and preclinical that the microbiota plays an important role in the development of IBD,” stresses Olle. “Other autoimmune diseases have been less studied, so we just have less information.”
 
“The mechanisms that we’ve identified could be useful for other autoimmune diseases, specifically to multiple sclerosis, rheumatoid arthritis, lupus, etc., but since those diseases are relatively under-studied, I would like to see more evidence of the role of the microbiome in driving those pathologies before diving in and investing substantial effort into programs,” he continues. “We’re basically choosing to go first into indications that we think are more likely.”
 
For its part, ATCC has heard the call from its customers to look beyond the gut, and is working on site-specific microbiome standards.
 
“These are enriched, recreated mock communities that contain bacteria that are prevalent in specific sites—for example, the gut, oral, vaginal and skin microbiomes,” Mittar explains.
 
The organization is also looking beyond bacteria, he adds, working on virome and fungal microbiome standards that will help with assay optimization for viral and fungal profiling in the microbiome.
 
Microbes as medicine
As suggested above, much of the initial impetus for microbiomics as a clinical intervention came from early FMT efforts, and whereas some groups are happy to leave it at that, others continue to drill down into the mechanisms underlying FMT’s correction of dysbiosis and inflammatory disorders.
 
Using a mouse model of colitis, for example, European Institute of Oncology IRCCS’ Claudio Burrello and colleagues demonstrated that FMT could reduce colonic inflammation and initiate restoration of intestinal homeostasis via various immune-mediated pathways.
 
But as was noted earlier, there is much variability in microbial composition from individual to individual, which can ultimately become a confounding factor in producing a live biotherapeutic, a concern highlighted by Vedanta’s Olle.
 
“The challenge is that every time that you use feces, you have to get them from a different subject, which basically means that the composition is different every time,” he argues.
 
“Just like you can standardize the screening of blood donors, you standardize the screening of fecal donors,” he continues. “But you will never have a standard composition.”
 
Instead, Vedanta tried to respect the complexity of natural systems while also maintaining a degree of control in their final product.
 
“We explored broadly many different modalities that could be harnessed to accomplish that, including using small molecules, using single bacteria, using consortia bacteria and even using fecal communities,” explains Olle. “Empirically, we arrived at defined bacterial consortia as being the best, most potent, reproducible way of accomplishing a modulation of the gut microbiota in a way that could be helpful for changing the immune response.”
 
“We don’t get the material directly from donors and put it into a capsule,” he says. “We actually start with pure clonal cell lines and do synthetic fermentation to arrive at our composition, which means that we basically have a scalable approach, but also a homogeneous composition that’s always going to be the same.”
 
Much of the foundational work at Vedanta arises from the lab of co-founder Kenya Honda of the University of Keio, who identified a group of intestinal bacteria involved in Treg activation.
 
“These T cells with a regulatory phenotype are essential to turn down the immune response,” Olle notes, “the same immune response that goes off-check and is excessive in autoimmunity and in allergy, resulting in the body attacking its own tissues or responding too aggressively to a food antigen that should otherwise be considered harmless.”
 
With this information, the company has produced two different microbial consortia—one for IBD, one for food allergy—that they are now putting into the clinic.
 
Along with Olle, Honda and other colleagues, Harvard’s Richard Stein recently described computer-aided efforts to optimize these consortia.
 
“The model incorporated data from regulatory T cells and microbes gathered from mice to estimate the contribution that different strains of bacteria make to regulatory T cell numbers,” the authors wrote. “This then fed into an ecological model predicted how different combinations of bacteria would behave in mice.”
 
Two criteria were key. First, they wanted combinations that could form stable, long-term colonies even in the face of competing microbes. And secondly, combinations that would boost Tregs such that they corrected the immune imbalance.
 
“To test the predictions, mice received combinations of bacteria suggested by the model,” the researchers added. “The model had predicted some combinations to be ‘weak’ at inducing regulatory T cells, some ‘intermediate’ and some ‘strong’.”
 
The results matched the predictions.
 
In November, Vedanta and Janssen R&D initiated a Phase 1 clinical study of the IBD candidate VE202. And a few months before that, Vedanta received financial support from the Crohn’s & Colitis Foundation.
 
As highlighted by the Pushalkar research into pancreatic cancer, there is also potential for microbiomic intervention into immuno-oncology.
 
In a recent survey of microbiota and cancer, Laurence Zitvogel and colleagues at Institut Gustave Roussy offered several preclinical examples of the influence of gut microbes on various immunotherapies.
 
“The immunotherapeutic response of colon cancers to anti-IL-10/CpG was improved in tumor bearers that received an oral gavage with A. shahii, as compared to antibiotics-treated mice,” they noted, adding that anti-CTLA-4 reduced the growth of subcutaneous sarcomas and colon cancers in mice fed normal chow, but not in germ-free or antibiotic-treated mice.
 
“This defect was overcome by mono-association with B. fragilis as well as by adoptive transfer of B. fragilis-specific CD4+ T cells,” they explained. “B. fragilis stimulated the production of IL-12 by bone-marrow-derived dendritic cells in vitro. Moreover, neutralization of IL-12 prevented the anticancer effects of B. fragilis in the context of CTLA-4 blockade in vivo.”
 
Vedanta is similarly pursuing a cancer program, again following on the work of Honda, who noted gut microbiota that induced and activated cytotoxic CD8+ T cells.
 
“Instead of promoting peace or immunoregulation like regulatory T cells do, these do the opposite,” Olle explains. “They create a stronger, more potent immune response.”
 
“And while that would not be a good thing for patients who have IBD, it’s exactly what you want for cancer immunotherapy,” he continues. “In cancer immunotherapy, you’re trying to activate the immune system to fight the cancer.”
 
“It turns out that the clinical efficacy of these new types of drugs called checkpoint inhibitors are largely dependent on the ability of cytotoxic CD8 cells to infiltrate the tumor,” Olle enthuses. “In other words, if those CD8 cells are getting into the tumor, you’re likely to have a good clinical response to checkpoint inhibitors. And if they’re not, you’re likely to be a non-responder.”
 
Vedanta’s chief scientific officer, Bruce Roberts, presented preclinical findings of its lead candidate VE800 at the Society for Immunotherapy of Cancer meeting in November, demonstrating anti-tumor immune response with the defined consortium as a monotherapy and its ability to enhance the effects of both anti-PD-1 and anti-CTLA4 immunotherapies.
 
Weeks later, the company announced it would initiate a clinical program with BMS to test VE800 in combination with anti-PD-1 nivolumab in advanced and metastatic cancers.
 
Vedanta is hardly alone in its approach to build a consortia of microbes as a live biotherapeutic. Seres Therapeutics also takes a community approach with its Ecobiotic drugs.
 
Unlike Vedanta’s isolated and cultured microbes, however, Seres derives its therapeutics from healthy donors, putting its approach somewhere between FMT and defined consortia.
 
In a Phase 1b clinical trial described one year ago, Seres showed that its candidate SER-287 could successfully engraft in patients with ulcerative colitis, and that the best engraftment correlated with the most significant clinical benefits.
 
A few months later, at the American Association for Cancer Research meeting in Chicago, Seres described preclinical data of its SER-401 candidate in combination with anti-PD-1. As in many other such studies, germ-free or antibiotic-treated mice failed to mount much of an anti-tumor response following treatment with anti-PD-1 immunotherapy. Responses improved greatly, however, with the addition of a diverse microbiome, largely due to increased infiltration by CD8+ T effector cells.
 
As of November, the company had plans to initiate a clinical trial of SER-401 to augment checkpoint inhibitor response in patients with metastatic melanoma in collaboration with the Parker Institute for Cancer Immunotherapy and MD Anderson Cancer Center.
 
For its part, Evelo Biosciences is attempting to reduce the number of moving parts in its live biotherapeutics, focusing on single microbe species—monoclonal microbials—to modulate immune activity.
 
In November, the company announced a collaboration with Merck to initiate a Phase 1/2 clinical trial of EDP1503 and anti-PD-1 Keytruda in microsatellite-stable colorectal cancer, triple-negative breast cancer and tumors that have relapsed on anti-PD-(L)1 therapy. The trial is expected to start in the first half of this year.
 
Meaningful movements
“The next step for the approach, and for the field too, is to really show the breadth of applicability,” says Vedanta’s Olle.
 
“The academic work is tremendously important in helping further the understanding of mechanisms, roles of microbiome in disease, etc.,” he presses. “But to me, what’s really going to change the field fundamentally is positive clinical data in efficacy studies. In that sense, 2019 is going to be a very rich year, because there are going to be multiple clinical readouts from Vedanta but also from other microbiome companies that will give a fuller picture of the clinical potential of the approach.”
 

Bringing out baby
 
That there is an interplay between microbes and the immune system within an individual is perhaps not surprising. There is growing evidence, however, to suggest that this dance extends to future generations, as well.
 
It seems that this connection is also critical to the developing immune systems of newborns—who, until birth, largely rely on their mother’s immune system for protection.
 
This is highlighted in the differences between infants born via vaginal delivery (VD) or Caesarian section delivery (CSD).
 
Laboratoire National de Santé’s Linda Wampach and colleagues recently compared the earliest microbial colonization of the neonatal gut with the vaginal and gut microbiomes of the newborn’s mother, looking for differences between VD and CSD neonates.
 
“Our results based on both 16S rRNA gene amplicon and metagenomic sequencing, and supported by multivariate analyses, demonstrate that early differences exist in the gut microbiomes of neonates and that these differences are predominantly driven by the mode of delivery,” the researchers noted.
 
By impeding vertical transmission of the material gut microbiome, they suggested, CSD significantly affects the functional gene complement in early neonates, adding that the newborn’s gut microbiome is likely a product of other microbial sources such as breast milk, skin or saliva.
 
Interestingly, they noted that the vaginal microbiome showed little potential to stably colonize the neonatal gut, arguing that this was likely due to differences in environmental niches; i.e., anaerobic vs. microaerobic.
 
Beyond the microbes themselves, there were also differences in prevalence of certain biosynthetic pathways in CSD vs. VD neonates, including lipopolysaccharide, which is linked to secretion of pro-inflammatory cytokines and immune system priming.
 
“Our study highlights differences in immunostimulatory potential of the earliest gut microbiome according to delivery mode,” the authors pressed. “This occurs during a critical window of immune system priming. Notably, alterations to early immune system stimulation may be linked to the higher propensity of CSD infants to develop chronic diseases in later life.”
 
Exactly how gut strains are transferred from mother to newborn is another important question to explore, the researchers suggested.
 
“Such mechanistic understanding will be important for devising future clinical interventions principally aimed at restoring a VD-like pioneering microbiota in the case of CSD,” they wrote. “An alternative approach may consist of ensuring appropriate early priming of the neonatal immune system by the controlled provision of microbial antigens.”
 
Both avenues, they concluded, could facilitate preventative strategies for CSD-related adverse health effects.
 
Code: E011935

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