Vaccine and Infectious Disease Division

The Human Microbiome (aka the Small but Silent Majority) with David Fredricks

Dr. David Fredricks

Dr. David Fredricks came to the Hutchinson Center from Stanford, where he was an infectious disease fellow for 7 years. He uses novel methodologies for defining the risk factors and pathogenic microbes responsible for bacterial vaginosis. He joined the large STI scientific community here in Seattle that provides a wealth of resources, including the STD clinic and local colleagues who study a variety of sexually transmitted infections. He has been at the Center for 11 years.

In the past decade, the concept of the ‘microbiome’ has come to the forefront of biomedical research. In the human body, microorganisms out-number our own cells 10:1, and the notion that a person’s genetic make-up is not limited to human cells’ DNA, but also the DNA of every microbe residing within/on that individual has spurred hypotheses about how our individual microbiomes affect our physiology and function.

The microbiome is immensely diverse across different body sites, where each site is colonized by bacteria adapted to that particular environment. VIDD Associate Member David Fredricks, whose lab studies bacterial vaginosis (BV), serves as VIDD’s unofficial authority on the human microbiome.

“It is a desert versus rainforest,” Fredricks said as he described the vast difference between the skin and intestinal tract niches. “In fact,” he continued, “stool has the highest density of microbes of any known ecosystem on our planet.”

Five years ago, as part of the NIH’s roadmap, the Human Microbiome Project (HMP) was established; a consortium of scientists to sequence and characterize the human microbiome. A multitude of HMP studies have recently been published within the last 10 months that identified bacterial communities in healthy individuals, those associated with certain diseases, and the differences between communities at different body sites, to name a few. The HMP awarded Fredricks two grants to develop 1) novel computational tools for efficiently analyzing the enormity of data generated from these studies, and 2) innovative methods for propagating heretofore non-culturable organisms.

The Fredricks lab focuses on using these technologies to study BV. Unlike many other vaginal diseases such as chlamydia or gonorrhea, BV is defined symptomatically rather than by one specific bacterial species. Because few bacterial taxa can withstand the low vaginal pH (4.5), Lactobacillus species, which can tolerate high acidity, make up the majority of the normal microbiota. In fact, increased vaginal pH is one finding in BV and is associated with a reduction of lactobacilli and an overgrowth of various anaerobes, such as Gardnerella vaginalis, Atopobium vaginae, and Prevotella species, that can tolerate this less acidic environment.

Giving great consternation to scientists and clinicians, the etiology of BV remains unknown. Because BV is idiopathic, heterogeneous, and stochastic, many conventional methods are insufficient for identifying the concomitant risk factors and/or bacterial culprits responsible for disease onset.

One molecular method Fredricks utilizes to overcome this hurdle is high throughput sequencing of bacterial genomes at the 16S rRNA region, which has conserved regions in all bacteria but also contains unique genetic signatures that act as bacterial barcodes. This highly sensitive and efficient sequencing method can identify a plentitude of species from one vaginal swab and is therefore useful for experiments that seek to more completely characterize the composition of these complex microbial communities.

Each horizontal line is a different subject from the 220 women and each bacterial species is represented by a different color. The clinically healthy (no BV) females were colonized by almost exclusively Lactobacillus species (orange and red). Females who tested BV positive by clinical criteria had a huge variety of bacterial species with little lactobacilli. Adapted from Srinivasan S, et al. PLoS One. 2012;7(6):e37818.

Fredricks recently published a study analyzing the vaginal microbiome from 220 women who visited the STD clinic at Harborview Medical Center in downtown Seattle. They found that 93% of women without BV were dominated by lactobacillus species, primarily L. crispatus and L. iners. In contrast, women with BV were colonized by highly diverse, heterogeneous communities.

“What was so fascinating to us was that women with BV didn’t have the same profile; we found a great deal of species variation between the subjects,” Fredricks said. “This made us think: is this heterogeneity driving the heterogeneity in clinical symptoms that women have?”

The implications of the HMP studies are far reaching. We cannot change our own genome, but we can change the microbiome. Future analyses of these microbial communities will move beyond the cataloging of sequences and delve into studying gene and community function.

“Humans have around 22,000 genes,” said Fredricks. “A typical microbiome consists of up to 3 million microbial genes.” Many of these genes play important roles in our metabolism, such as by helping with the digestion of food in our gut, or through synthesis of vitamins.