BIO-TECHNOLOGY

Bugs and the Body

Do bacteria contribute to human health, and how?

As organizers and participants gear up for the Fourth International Human Microbiome Congress 2013 in Hangzhou, September 13th–15th, research reports continue to document the critical role of bacteria in human health. At the same time, a wealth of probiotic mythology promising that good gut bacteria can cure everything from Crohn’s disease and obesity to cancer continues to be misleading.
But there is some truth in advertising, if the power of the biome could be harnessed in a rational way. As Martin J. Blaser, M.D., Muriel G. and George W. Singer professor of translational medicine and director of Human Microbiome Program at the New York University School of Medicine, put it in an interview for a New Yorker article, “Germs make us sick. But everyone focuses on the harm. And it’s not that simple, because without most of these organisms we could never survive.”
The almost ten thousand bacterial species we share our bodies with, scientists say, outnumber our own by ten to one, and weigh about three pounds—the same as our brain. This “microbiome” plays such a crucial role in our lives that scientists like Blaser have begun to reconsider “what it means to be human.”

The Human Microbiome Project

In Nature last January, David A. Relman, M.D., and his colleagues commented that “the shared evolutionary fate of humans and their symbiotic bacteria has selected for mutualistic interactions that are essential for human health, and ecological or genetic changes that uncouple this shared fate can result in disease. In this way, looking to ecological and evolutionary principles might provide new strategies for restoring and maintaining human health.”

But while knowledge continues to accumulate detailing how bacteria interact among themselves, with human cells, and how their metabolism affects their human habitats, “there are relatively few circumstances where you can meet a patient who is benefitting from this,” says Dr. Relman, adding that our biome is “a complex and dynamic network.” Dr. Relman is a professor of medicine and of microbiology & immunology at Stanford University, and his research program focuses on the human microbiome.

And an individual’s microbiome is as unique as the DNA in their cells, investigators are discovering. In June 2012, in an article in Nature entitled “Structure, function, and diversity of the healthy human microbiome,” results of studies conducted by the Human Microbiome Project reported, “We found the diversity and abundance of each habitat’s signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals,” niche meaning the intestinal tract and other body mucosa that microbes habitually inhabit.

The five-year NIH-funded $157 million project sequenced and classified 900 microbes believed to play a role in human health. Goals of the project included development of microbiome taxonomic, metagenomic, and functional data from clinical biospecimens obtained from a cohort(s) of carefully phenotyped subjects with a specific disease or health state, and the combination of the microbiome and host data to produce a community resource.

But Dr. Relman noted with regard to expectations generated around the information produced from the microbiome project, “There’s sensitivity about the expected returns. We need to be grounded about what it is we’ll be able to gain at what point in time. I think the shorter-term gains may be around diagnostics, and novel ways of classifying both health and disease.”

The long-term objective of the initiative is to develop a dataset that the community can utilize to explore whether study of the human microbiome beyond sequenced-based analyses will yield important new insights in understanding human health and disease.

The consortium of scientists have already found the diversity and abundance of each habitat’s (gut, skin, and vagina) signature microbes varied widely even among healthy subjects, with strong niche specialization both within and among individuals.

The project encountered an estimated 81–99% of the genera, enzyme families, and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata.

Analysis of the sequences of the first 178 microbes, which was published in the May 21, 2010, issue of Science, “held some surprises” particularly with regard to the extent and complexity of microbial diversity. About 90% of their DNA was previously unknown. The study also identified novel genes and proteins that contribute to human health and disease.

Data emerging from this project, consortium investigators hope, could lead to development of new diagnostic tests because individual biomes are as unique, some scientists say, as an individual’s DNA.

Quantitative Metagenomics

And this data is already enabling new research. Earlier this year, Danish research, citing the obesity epidemic in developed nations, reported the human gut microbial composition in a population sample of 123 nonobese and 169 obese Danish individuals. Establishment of a catalog of bacterial genes from the human gut, the researchers said, encouraged them to ask whether variation in the gut microbiome at gene and species levels defines subsets of individuals in the adult population who are at increased risk of obesity-related metabolic disorders.

The abundance of known intestinal bacteria can be assessed, the authors said, by the mapping of a large number of sequencing reads from total fecal DNA onto a reference set of their genomes. This “quantitative metagenomics” approach was extended by the authors to assess the abundance of genes from the reference catalog in a cohort of 292 nonobese and obese individuals.

They found that two groups of individuals differed by the number of gut microbial genes and therefore, gut bacterial richness. Individuals with a low bacterial richness (23% of the population) were characterized by more marked overall adiposity, insulin resistance, and dyslipidemia and a more pronounced inflammatory phenotype when compared with high bacterial richness individuals.

The obese individuals among the lower bacterial richness group also gain more weight over time. Only a few bacterial species are sufficient to distinguish between individuals with high and low bacterial richness, and even between lean and obese participants. Our classifications based on variation in the gut microbiome identify subsets of individuals in the general white adult population who may be at increased risk of progressing to adiposity-associated comorbidities.

Probiotics

The implications individual microbiomes has, investigators discovered, clear implications for health and disease. Jeffrey Gordon, M.D., director of the Center for Genome Sciences and Systems Biology, Washington University School of Medicine, and his researchers in his laboratory at Washington University, who this August reported experiments introducing gut microbiomes from lean and obese humans into mice with some unexpected results, showed the bacteria could transfer characteristic of lean animals into obese animal, or prevent the development of obesity.

Several years ago, in another study, Dr. Gordon described two groups of beneficial bacteria that are dominant in the human gut, the Bacteroidetes and the Firmicutes. When Gordon’s team had 12 obese people follow either a low-fat or a low-carb diet to lose weight, the result was more Bacteroidetes and fewer Firmicutes—the profile of slim people. The more Bacteroidetes, the more weight the volunteers lost.

The scientists showed that the relative proportion of Bacteroidetes is decreased in obese people by comparison with lean people, and that this proportion increases with weight loss on two types of low-calorie diet. Their findings indicate that obesity has a microbial component, which might have potential therapeutic implications. But these findings, and relatively simplistic interpretations, helped fuel the frenzy to sell probiotics, rationally or not, despite Dr. Gordon’s clear statements about the importance of how the microbiome operates in relation to diet.

But according to Dr. Gordon, at the moment, a far more complicated picture has emerged than just ingesting the right bacteria. He says, “There’s an intricate relationship between our diet and how our gut bugs alternately affect us.”

“Cocktails of classic probiotics, which people have been trying for years, may have some benefit but the effect seems to be quite small,” says Dr. Relman. A targeted approach that manipulates specific species could be more effective, but, Relman adds, “I don’t think we’re there yet”.