The Future of the Microbiome

The last decade has brought vast amounts of new information about the microbiome, the collective name for the trillions of bacteria and other tiny organisms, such as yeast, living mostly in our gut but also on our skin and in other areas. The microbiome essentially functions as another organ in the body, playing a part in regulating digestion, the immune system, the nervous system, and even susceptibility to stress. Scientists are exploring how manipulating it could help combat problems ranging from gastrointestinal disturbances to autoimmune diseases to psychiatric disorders.

While much attention has focused on the beneficial or detrimental effects of specific strains of gut microbes and the value of a diverse population of bugs in the gut, a new view of the microbiome is emerging: What is important is not each species itself, but the role it plays among the other species. In short, the microbiome is an ecosystem within each person, and it has to be looked at as a whole.

Just as in Earth’s ecosystems, where different animals in different places play similar roles (for example, reindeer and bison are the ruminants in the far north, wood deer and goats in the southwest, kangaroos in Australia), so it is in the microbiome: Different bugs play similar roles in different people. While such understanding complicates study of the microbiome, researchers have a new way to probe it—by looking at the metabolic end products of the microbes (the metabolome), the biologically active substances churned out by the cell processes of the bugs. Such study is called metabolomics.

Metabolomics requires measuring metabolic end products excreted in people’s urine and feces, typically with mass spectrometry, gas or liquid chromatography, or nuclear magnetic resonance spectroscopy. From this information, scientists can determine which metabolic end products are associated with healthier humans, which microbiota are the reindeer of your microbiome. By determining which microbes produce which chemicals, researchers can connect the structure of the microbiome to a big part of its function: making metabolites, many of which are passed on to us.

The study of metabolomics brings its own biochemically significant vocabulary—such as betaine, proprionate, acetate, butyrate—and a new understanding of what it means for a microbiome to be “good” or “bad.” Following the metabolomics in human health and disease may be far more helpful than classifying the microbiome down to every single bacterium.

The good news is, there are far fewer metabolic end products than there are bacteria, yeast, and other microbes, so the study of metabolomics could vastly simplify microbiome research questions. Two unrelated people typically share only 40 percent of their microbial species—but those same two people share more than 80 percent of their metabolites.

In fact, researchers have recently discovered there are 40 percent more types of microbes in the gut than previously known. All this time, scientists have been classifying gut bugs by looking at a sequence of their DNA. More efficient techniques and faster computing power have enabled the sequencing of far more genes—and the discovery of far more microorganisms.

But even supercomputers could not handle what turns out to be a major flaw in classifying microbes this way. While you and I are stuck with the genes our parents granted us, bacteria can swap genes back and forth. Tiny viruses called bacteriophages can grab some DNA or RNA from one bacterium and give it to another.

Bacteria swap genes with profligate glee. In a recent study, Eran Segal and colleagues at the Weizmann Institute of Science in Israel documented gene swaps, additions, and deletions in every bacterial strain of the human microbiota they analyzed.

While new genes from bacteriophages can turn harmless bacteria into vectors for cholera or diphtheria, gene swaps can also change a bacterium that was just minding its own business into a welcome producer of beneficial biologically active compounds.

Segal’s group found a microbe named Anaerostipes hadrus in the gut of most people. But in some, the population of A. hadrus had five deleted genes, and those people were heavier than the others. The effect is due not to the microbe but to its changed genes, Segal says. “We found a [genetic] region in A. hadrus that was deleted in 40 percent of people, and those people weighed on average six kilograms more than people whose A. hadrus microbe retained this region.” The region is responsible for the production of butyrate, a short-chain fatty acid resulting from microbial fermentation of dietary fiber and known to be neurally and immunologically active.

It isn’t possible to know the source of the weight difference by studying the bacterial genes alone. Just because a microbe has the genetic programming to make a certain metabolite doesn’t mean that process is active.

The Holy Grail of microbiome research has shifted from finding the perfect species profile conferring health to finding the right microbial ecosystem with the collection of genes and metabolites that best fits with a person’s lifestyle and disease risk.

Understanding the gut-brain connection requires looking at gut microbes as interchangeable gene carriers. The unique metabolic pathways that lead to production of brain-active chemicals like butyrate, dopamine, and serotonin may be the real keys to mental health. The metabolome and whole genomes offer new ways of looking at the gut-brain axis and promise answers to important questions about physical and mental health.

What are the consequences for maintaining a healthy microbiome? Should you stop taking that probiotic? If it is working for you, then keep it up. But the description on the jar doesn’t indicate all the genes the species contain and what they can or can’t do.