Microbiome medley

Three interesting papers about the role of the microbiome in human health and disease have floated across my desk this week. The first is from June Round and Jason Kubinak of the University of Utah. (Round has worked on the microbiome and the immune system, in the past, with Sarkis Mazmanian from Caltech.) They give a glimpse of one possible microbiota-based therapy of the near future. Specifically they propose that antibodies generated in response to microbial colonization of the gut shape the composition of the microbiota to benefit the health of the host through a process that they term antibody-mediated immunoselection (AMIS). Immunoselection, they say, refers to a process of natural selection within a host organism that is mediated by the immune system to influence microbial fitness, and consequently microbial ecology and evolution.

Even otherwise genetically identical individuals can develop antibody repertoires that do not overlap. This means that, as antibody repertoires are unique to any individual, so is the immunoselection on microorganisms they exert, and this is why each individual ends up with a personalized microbiota. For instance, one experiment they cite showed that there were significant differences in gut microbiota composition between normal wild-type mice and mice genetically engineered to be deficient in polymeric immunoglobulin receptor protein – which meant they were unable to secrete antibodies into the gut lumen. There were clear decreases in “friendly” bacterial species like Bifidobacterium, and notable increases in pathobiont species like Helicobacter. Microbiota altered as in the latter case were associated with a greater susceptibility to severe colitis in an experimental situation. It was further established that deficient antibody responses like this allowed bacteria in the gut to escape into host tissue and become systemic infections. Alternatively, appropriate antibody responses in the gut decreased microbial virulence.

Here’s their wind-up: “Collectively, we believe these studies support an important role for AMIS of the microbiota to promote diversity while also constraining fluctuations that might result in loss of beneficial microorganisms. AMIS of the microbiota also functions to prune the expression of potentially harmful epitopes of commensals and prevent lethal dissemination by controlling mucosa-associated communities. Thus, we believe AMIS of the microbiota is a critical host mechanism, which mediates symbiosis that could be exploited therapeutically to improve health.”

In a paper in Cell Host & Microbe, Marty Blaser and Maria Dominguez-Bello (she of the treatment of Cesarian-delivered babies with swabs incubated in Lactobacillus-rich maternal vaginas) review what is known about how a healthy gut microbiota is established in babies. How does the human microbiome begin, they ask. What is the contribution of the mother? How does pregnancy change the mother’s microbiome, and what is transmitted to the infant?

Recent studies, they say, show a close correspondence between the overall phylogeny of fecal microbiota and host phylogeny going back 8 million years, and studies of two marker taxa that we know are acquired early on in life (Bacteroidaceae and Bifidobacteriaceae) show a similar correspondence which reaches back to a common primate ancestor over 15 million years ago. Our gut microbiota, they say, has been vertically transmitted across a period of millions of years, representing hundreds of thousands of host generations and untold billions of bacterial generations.

Changes in the composition of the gut microbiota shifts markedly between first and third trimester of pregnancy, favouring conserved populations and suggesting selection for species with particular host-beneficial functions. “We speculate that this shift works to increase immunoregulatory T regulatory (T-reg) cells, which may reduce the likelihood of maternal rejection of the fetal allograft, a central problem in mammalian biology.” In the third trimester there is an increase in species heterogeneity such that each mother-to-be transmits her personalized microbiota to her offspring. In the vagina, diversity is reduced and the microbiome centres around 4 related species of Lactobacillus.

The microbiome of babies born via C-section is no more closely related to their mothers than any other mother, whereas vaginally delivered babies’ microbiomes emulate their mothers’ much more closely. The effects of antibiotics upon this vertical transmission are profound. More than 50% of women in the US receive broad-spectrum antibiotics during pregnancy so they exert a tremendous selective force on the maternal gut microbiota. Antibiotic can also cross the placenta and exert effects on the baby’s microbiota and there will be residual antibiotic in breast-milk. Because women electing for C-section have peri-partum antibiotics their babies receive a double negative whammy – loss of microbial transmission from their mother’s vaginas and further insult from antibiotics in milk and transfer from maternal bloodstream.

“Because this period represents such a critical junction in the life and development of an infant, we must learn more about how the microbiota and its functions shift during pregnancy and post-partum and to identify the critical factors that might be restored or modified to optimize longterm health”, they say. “From such studies and carefully conducted clinical trials will come new approaches to restoring key members of our ancient inheritance to optimize the health of the next generation.”

I have a pdf of this paper, should your institution not allow you entrance through the paywall. Email me on [email protected].

Elsewhere, scientists at the University of Montreal claim that changes in the gut microbiota, in this case induced by a high-fat diet, can lead to long-term low grade body inflammation and the onset of wet macular degeneration in the eye.