Thursday, August 29, 2013

Got mom's bacteria? Breaking the silence on the (un)sterile womb paradigm.

Thank you to science reporter Carl Zimmer and the New York Times for helping to break the silence that humans are likely not born sterile (column link), as we're so often taught.

Last week, our PLOS Biology paper came out with the evidence-full position that maternal microbial transmission is far more common than previously thought in animals and that decades of research on this topic lie ahead of us. Carl picked up the phone to chat with graduate student Lisa Funkhouser (@dnadiva87) and I about the paper. What follows below is his NY Times column that came out today. I'm quite pleased with Carl's reporting here as he covered the diversity of researchers who have produced the scientific evidence thus far.

Personally, I am most impressed by the following pieces of evidence:

  • Bacteria are readily found in umbilical cord blood 
  • Pregnant mice fed a labelled bacteria have babies with the same labelled bacteria in their meconium; controls do not
  • Preterm birth is often associated with improper bacterial colonization of the gut. Now what just might be in the guts of term babies? 

So moms, you not only pass on your genes and mitochondria, but likely your bacteria too. Can we thank you enough? My mom would most definitely say no.

Link to open access article and Related Blog Posts:


Human Microbiome May Be Seeded Before Birth

  • SAVE
  • E-MAIL

We are each home to about 100 trillion bacteria, which we carry with us from birth till death. But when Juliette C. Madan was trained as a neonatologist in the mid-2000s, her teachers told her in no uncertain terms that we only acquire those bacteria after we are born. “It was clear as day, we were told, that fetuses were sterile,” she said.
Dr. Madan is now an assistant professor of pediatrics at the Geisel School of Medicine at Dartmouth, and she’s come to a decidedly different view on the matter. “I think that the tenet that healthy fetuses are sterile is insane,” she said.
Dr. Madan and a number of other researchers are now convinced mothers seed their fetuses with microbes during pregnancy. They argue that this early inoculation may be important to the long-term health of babies. And manipulating these fetal microbes could open up new ways to treat medical conditions ranging from pre-term labor to allergies.
In 1900, the French pediatrician Henry Tissier declared unborn babies bacteria-free. Only when they started their journey down through the birth canal did they begin to get covered with microbes. The newborns then acquired more as they were handled and nursed.
“This was considered a kind of scientific dogma,” said Esther JimĂ©nez Quintana of Complutense University of Madrid.
This dogma gained strength from studies on babies born prematurely. Infections are a major risk factor in early labor. Many researchers saw this as evidence that the only bacteria in the uterus were dangerous ones.
But scientists came to this conclusion without finding out whether healthy fetuses had bacteria, too. “It became a self-fulfilling prophecy,” said Dr. Madan.
That has started to change in the past few years. In 2010, Josef Neu, a University of Florida pediatrician, examined the first stool from newborn babies, before they had their first meal. He found a diversity of bacteria in the stool, whether the babies were born on time or born prematurely.
“When we first saw this, we though it was an artifact,” said Dr. Neu. If the fetuses were indeed sterile, their stool should have been germ-free. But in follow-up studies, he has gotten the same results.
Other scientists have also found evidence indicating that healthy fetuses pick up bacteria in the womb. Dr. Quintana and her colleagues have found bacteria in the amniotic fluid of healthy babies, as well as in umbilical cord blood and placentas.
If other animals are any guide, we shouldn’t be surprised if human fetuses are laced with bacteria. In an essay published last week in the journal PLOS Biology, Seth R. Bordenstein and Lisa J. Funkhouser of Vanderbilt University observed that mothers transmitting bacteria to their offspring is the rule rather than the exception in the animal kingdom. Studying other species may give scientists clues about how human mothers inoculate their unborn children.
One open question is the route that bacteria take from mothers to their fetuses. A number of researchers suspect that immune cells in the mother’s intestines swallow up bacteria there and ferry them into the bloodstream, where they eventually wind up in the uterus.
It’s also not clear whether mothers deliver a random collection of species or a special set that are beneficial to them. Studies on children and adults have shown that our resident bacteria — collectively known as the microbiome — help us in many ways. They digest compounds in our food that would otherwise be indigestible.
Beneficial bacteria also help tutor the immune system, so that it attacks pathogens without overreacting and damaging the body itself. The microbiome can even fend of disease-causing bacteria.
Dr. Neu and other pediatricians are now investigating whether the microbiome helps fetuses before birth. He speculates that a healthy supply of bacteria in a fetus can reduce the chances of premature birth. If harmful bacteria manage to slip past those defenses, they may trigger an immune reaction that is sensed by the mother, prompting her to go into labor.
As scientists investigate the microbiome, they are also exploring ways of manipulating it to treat disorders ranging from gut infections to autoimmune disorders. Dr. Neu hopes it may be possible someday to bring the same medical help to fetuses.
“We might provide mothers with a microbial cocktail,” he said. The bacteria would pass from a mother to her fetus. Doctors might prescribe certain species to protect the fetus from infections, warding off early labor. Nurturing the fetal microbiome could help babies in other ways, like boosting their immune system.
Some scientists don’t think the evidence supports these ideas, though. Bacteria in fetuses may not have any special role to play in their health. “It could just be part of the vulnerabilities that pregnancy poses on the maternal body,” said Maria Dominguez-Bello, an associate professor at N.Y.U. Langone Medical Center.
But figuring out which explanation is right will demand the careful study of healthy fetuses — something that has only barely begun.
“The frontier is ahead of us,” said Dr. Bordenstein.

Carl Zimmer’s “Matter” column appears on Thursdays. Follow him on Twitter:@carlzimmer.

Tuesday, August 20, 2013

The Story Behind "Mom Knows Best: The Universality of Maternal Microbial Transmission"

Image credit to Robert M. Brucker
What types of microbes do mothers transmit to their newborns and how universal is maternal microbial transmission throughout animals, including from your mother?

In this new paper in PLOS Biology, PhD student and NSF graduate research fellow Lisa Funkhouser (@DNAdiva87) and I propose that the existing evidence from disparate study systems and diverse subdisciplines compels a substantial phase of study on the ubiquity of maternal microbial transmission in animals, and it has critical implications for health, evolution and the hologenome concept.

The term “maternal transmission” has traditionally referred to strict vertical transmission of a microbial symbiont from mother to offspring in invertebrates, usually through the incorporation of symbionts into developing oocytes or embryos. It is likely viewed in this context due to the pioneering work of Paul Buchner, whose seminal book Endosymbiosis of Animals with Plant Microorganisms dissects in exquisite detail symbiont transfer in an expansive range of invertebrates, especially insects. For a nice summary of Buchner, see Prof. Jan Sapp's 2002 paper on him. Since the English publication of Buchner’s work in 1965, elegant studies in insect models have further emphasized the importance of maternal transmission in maintaining obligate mutualistic relationships in invertebrates (see this 2006 primer on the topic from Nancy Moran). 

Conversely, in humans, “mother-to-child” transmission is commonly used in a negative context to describe the transfer of a pathogen, parasite or virus from an infected mother to her infant. However, current interest in the human microbiome has refocused attention on the transfer of commensal and beneficial bacteria from mother to child. Importantly, increasing evidence indicates that valuable maternal microbes are transferred before, during, and after birth to vaginally-delivered, breast-fed infants, while disruption of natural maternal transfer through Cesarean sections and formula-feeding puts children at significantly higher risk for immune-mediated diseases, such as asthma, celiac disease, and inflammatory bowel disease, as well as for childhood obesity.

In this paper, Lisa and I explore the emergent paradigm that maternal microbial transmission in animals is a universal phenomenon that ensures transgenerational maintenance of important host-microbe partnerships or functions over evolutionary time scales. To our knowledge, ours is the first literature review to encompass all forms of maternal transmission across the animal kingdom. Some of the stories we scavenged from the literature surprised even us. Thus, we have classified maternal transmission into two broad categories that reflect route of transmission (internal versus external) in order to facilitate future discussion of maternal transmission mechanisms in both invertebrates and vertebrates. We have defined internal maternal transmission as any transfer of microbes to an oocyte or embryo while still developing within the maternal body cavity, while external maternal transmission refers to the ingestion of maternal microbes after delivery, such as breastfeeding in humans or “egg smearing” in insects. As such, the content of this review 
  1. Illustrates the universality of maternal symbiont transmission by highlighting diverse systems that maintain symbionts through maternal transmission
  2. Dissects the mechanisms by which maternal transmission is achieved in these systems
  3. Assesses sources of potential maternal transmission in humans and their effect on human health.
See the paper for more details on maternal microbial transmission from all perimeters of the animal kingdom.

Monday, August 19, 2013

Gut-Microbe Homeostasis in Mammals

Out of many, one.

Animals harbor a melting pot of beneficial microbes in their guts and they confer numerous fitness adaptations. 

In an effort to isolate the molecular mechanisms that underpin highly specific host-microbe interactions in this community, a recent paper in Nature studied the intimate interplay between gut microbes and their hosts. This research concentrated on identifying the key colonization genes in the bacteria that make a home out of mouse guts.
  • First, they showed that vertebrate beneficial microbes, like that of Bacteroides fragilis, exhibit colonization resistance against themselves, i.e., resident clones inside the mouse gut are resistant to inoculations of additional clones, as if there is a shortage of space or nutrients and the bacteria know it. However, clones of one bacterial species readily get displaced by other species of Bacteroides. Its kind of like you living in a home and keeping other people out of it by not opening the door. But if a pack of chimpanzees knock on the door, and you dont notice them and open it, they could easily outcompete you and cause you to flee out your windows. So what is the molecular mechanism of the bacteria that allows them to detect self and keep the door closed?
  • By iteratively inserting genetic regions of Bacterioides fragilis into the genome of B. vulgatus and inoculating these transgenic bacteria back into B. fragilis-infected guts, the team found the specific regions of the genome that control colonization inhibition against itself. The genes encode SusC and SusD-like proteins involved in outer membranes. They likely bind to starches. Here they were termed commensal colonization factors. Not sure about the use of the word "commensal" here as these bacteria do play a beneficial role in fitness. 
  • These genes are highly expressed in bacteria tethered to the colon and appear to lack expression in in vitro laboratory culture. They also hang out in mucosal tissue and particularly prefer the crypts of the colon. The wild type bacteria better colonize these crypts than the mutants carrying deletions in these same genes. And even after low dose antibiotic treatment, crypt-associated clones of Bacteroides were still present in the host colon, whereas those that were mutated in these key genes were washed away by the antibiotics. Seems like the wild type beneficial bacteria are indeed better niche colonizers.
They conclude that these genes evolved to promote long-term symbiosis between specific strains of bacteria an the host gut. I question whether they know anything about long-term symbiosis as these studies were not done in a comparative functional context. I do agree, however, with their last statement:
Discovery of a molecular mechanism for colonization fitness by gut bacteria provides a glimpse into the evolutionary forces that have shaped the assembly and dynamics of the human microbiome.
An interesting after-thought on this study that appeared in this press release is that many typical gut bacteria do not have genes similar to commensal colonization factors. So how universal this mechanism will be is up for future study.

Source: Bacterial colonization factors control specificity and stability of the gut microbiota by Lee et al, 2013, Nature.

Video from the senior author describing this research

Related Posts:

Wednesday, August 14, 2013

Announcement: Round Table Discussion on the Hologenome

Where: Google+ Hangout (Link to join the round table); *note: You may need a direct invite to join the hangout. Just send me your email or circle me on google+ so I can send you an invite. Silly restriction but that should fix it.

When: August 28th, 10am Central Standard Time

Is there enough scientific evidence to conclude that the nuclear genome, mitochondria and microbiome of an animal or plant represent an interwoven evolutionary unit called the "hologenome"? This google + hangout seeks to assemble diverse opinions on the topic in order to broadcast the pros and cons of the evidence and reason a consensus from different vantage points.

Key agenda items will include:

  1. Is the word "hologenome" jargon or useful to the life sciences?
  2. What additional evidence is required to broadly substantiate the hologenome concept of Life?
  3. What will be the rules, if there are any rules, of the hologenome?
  4. Is the hologenome part of a New Synthesis in biology?

We welcome everyone's input. Please join us on August 28th and share the announcement.

Monday, August 12, 2013

Progress To Date On Eliminate Dengue Project

The Eliminate Dengue Project (EDP) is a worldwide effort to introduce bacteria-carrying mosquitoes into areas plagued by outbreaks of mosquitoes that cause Dengue fever. The basic idea is that the bacteria Wolbachia, a natural symbiont of insects, make mosquitoes incompetent to harbor or transmit dengue virus to humans. Several ongoing trails in Australia have just released new results, and I collated them together in the map below. The EDP goal is to achieve 100% replacement of resident, uninfected mosquitoes with ones that are Wolbachia-infected.

EDP is a stunning example of how insects and their bacterial symbionts can be used  to potentially reduce the incidence of Dengue fever cases. I say potentially because while the mosquito/Wolbachia combinations are being released with success, i.e., every release site in Austrailia has between 50-90% infection frequency of Wolbachia, data on whether this effort reduces Dengue transmission will have to be collected over several years in order to make any inferences on the impact to human health. My graduate student Daniel LePage (@lepage_d on Twitter) recently published a review (Wolbachia: can we save lives with a great pandemic?) on this effort and others.