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Microbiome: The critters within

Your gut microflora might be aiding and abetting diabetes.

In 2004, Fredrik Bäckhed and his colleagues at Washington University in St Louis, Missouri, noticed that gnotobiotic mice — born and raised to be free of germs — tended to be slimmer than their conventional counterparts. After they transplanted the feces of normal mice to germ-free ones, the rodents gained weight and their insulin was less effective at lowering blood sugar levels1. Some of the same researchers later transplanted bacteria from the intestines of either lean or obese mice into the guts of gnotobiotic mice; those animals that received bacteria from obese mice gained nearly twice as much weight as mice on the same diet that received bacteria from lean donors2. These studies jump-started research that is transforming the way we think about obesity and diabetes.

The average human gut is home to trillions of bacteria. They outnumber the cells of their human host by a factor of ten to one, and collectively their genes outnumber human genes one hundred-fold. Together, they function as another organ, complementing and interacting with human metabolism in ways not fully understood. But one thing is becoming clear: the composition of bacterial species in the gut can influence the course of diabetes and its treatment.

“I have been studying diabetes for the past 25 years, and this is the most important discovery that has been made in my field,” says Rémy Burcelin, research director at the French National Medical Research Institute (INSERM) in Toulouse. “We've discovered a new organ. We know there is a brain, a pancreas, a liver. Now we also know there are microbiota.”

Segmented filamentous bacteria (SFB) in the terminal ileum of an 8-week old Taconic B6 mouse. Credit: ALICE LIANG, DOUG WEI, ERIC ROTH, NYU.

Humans and the microbiome — the bacteria that reside in and on us — have co-evolved for millennia. But lately we have been messing with the delicate balance between our flora and ourselves by eating more fats and sugars, by washing with antibacterial soap, and by taking antibiotics at the faintest hint of infection. This shift in behaviour has coincided with an increase in the incidence of type 1 and type 2 diabetes, both of which are rising at a pace that cannot be down to genetics alone (see 'Cause and effect' page S10).

“There's an order of magnitude more bugs in our gut then there are cells in our bodies, so it's not very difficult to imagine that they would have a profound impact on metabolic balance and metabolic activity,” says Christopher Newgard, a metabolism researcher at Duke University in Durham, North Carolina. “But, as attractive and enticing as the theory may be, it has not yet been proven in a systematic way.”

Finding a foothold

Researchers know that certain phyla of bacteria are more populous in obese mice, whereas others are more common in lean ones, and the same seems to hold true in people. Moreover, bacterial composition in the gut can improve or worsen insulin resistance in mice and, initial results suggest, in people. There also appears to be a connection between inflammation and the development of insulin resistance — some of the bacteria in obese and insulin-resistant people have the potential to trigger chronic, low-grade inflammation. What researchers don't know is how all these pieces fit together.

Two questions loom large. First, what is cause and what is effect? That is, do altered bacterial populations trigger insulin resistance or are they the product of something else in the body — and to what extent does an atypical microbiome affect the metabolism of it human host?

And second, what mechanisms are involved in any metabolic change? The answers to these questions will ultimately inform research on both the prevention and treatment of diabetes.

At the moment, researchers are trying to figure out precisely how the gut microbiome is influencing the metabolism, and thus the development of diabetes, of its human host. Several theories exist. One, for instance, blames the metabolites and other chemicals excreted by the bacteria. Another theory implicates the immune system's reaction to the bacterial cells themselves (see 'Microbial influence').

Whatever the mechanism, the bacterial changes that precede insulin resistance can often be attributed to changes in diet. In mice, it takes only one day after switching from a low-fat to high-fat diet for insulin resistance to be detectable3. In type 2 diabetes, many researchers believe there is a web of complex interactions between a person's genome and gut flora. Some people are genetically predisposed to have more beneficial bacteria, while others people's guts may be hospitable to pathogenic strains and may be more likely to develop diabetes when they eat high-fat foods. “Your own human nuclear genome controls a considerable part of your individual gut microflora,” says Oluf Pedersen, head of diabetes genetics research at the Hagedorn Research Institute in Gentofte, Denmark. “But if your microbiota go off kilter then they can be causative and, at least in rodent models, effect a major change in phenotype.” Such phenotypic changes might include weight gain and the development of metabolic syndrome — a precursor to diabetes.

If researchers can figure out which bacterial species of the mammalian gut are beneficial and which are pathogenic, they might be able to nudge the population away from diabetes or even cure it. But with such a vast number of species, many of them never before identified and nearly impossible to culture, developing an extensive profile of the bacteria associated with lean versus insulin-resistant individuals is proving to be monstrously difficult.

Pedersen is tackling that task in his work with the MetaHIT (Metagenomics of the Human Intestinal Tract) consortium, a collaboration of 13 institutions working to understand how genes and intestinal microbiota interact to influence health and disease. As head of MetaHIT's obesity effort, he is sorting people according to their metabolic traits, including insulin resistance, and trying to correlate those to their gut bacteria. In parsing the data, Pedersen and his colleagues are finding that they can sort people into two groups according to the quantity of bacterial genes they have. Roughly one-third of their obese subjects fall into the 'low-gene-count' group. These individuals are more likely to have signs of inflammation, such as high white-blood-cell counts and elevated levels of C-reactive protein. In the general population, about the same fraction of obese people, 30% to 40%, are at risk of developing diabetes. “We seem to have identified a subgroup of obese individuals who have a greater risk of progressing to type 2 diabetes,” Pedersen says.

Harnessing a microbe

Establishing that gut flora play a role in causing diabetes is a start, but until scientists can pin responsibility on specific bacterial species or genera, it will be difficult to apply this knowledge to developing diabetes treatments.

One research group took the fecal transplant method that Bäckhed and others had used in mice and adapted them for human testing. Max Nieuwdorp, an endocrinologist at the Academic Medical Center in Amsterdam, the Netherlands, led a team that tested fecal transplants in a trial of 18 men recently diagnosed with metabolic syndrome. Nine men received gut biota from lean donors, while the others had their own microbiota returned to them via a fecal transplant, similar to the procedure used in mice. Initial results provide tantalizing hints that manipulating gut microflora can improve health. After 6 weeks, the men who received transplants from lean donors showed improved insulin sensitivity — an indication that their road to type 2 diabetes had slowed or even halted. One year later, however, the subjects' microbiomes, and their insulin sensitivity, had returned to their original states4.

Fecal transplants in their current form aren't a practical cure for diabetes or obesity; there are too many risks, including the transfer of bacterial infections from donor to recipient. But these transplants do confirm the impact of bacterial composition on blood sugar regulation in humans. And if researchers can figure out which bacteria are beneficial, and why, they might be able to develop drugs or bacterial supplements that mimic those effects. “No one knows whether there's a causal relationship between bacteria and diabetes,” Nieuwdorp says. “We tried to show it with the fecal transplant, but the only thing we can say is that there seems to be a transmissible trait.” Nieuwdorp has already begun a longer trial of 45 people in conjunction with gene-chip testing to discover whether multiple transplants might produce a longer-lasting effect and to identify the bacterial species involved.

If scientists can determine which bacteria are associated with which metabolic profile (lean and insulin sensitive versus overweight and insulin resistant), they might be able to supplement accordingly. Probiotics (live bacteria) and prebiotics (which encourage the growth of beneficial bacteria) could be used to tune a person's microbiome towards greater insulin sensitivity. Antibiotics could be designed to target pathogenic species, or prescribed in conjunction with supplements of beneficial bacteria to prevent irreparable harm. And if researchers can identify the mechanisms of action, they should be able to develop drugs that mimic the chemicals produced by the bacteria found in lean people's guts, or inhibit the metabolites or other molecules that lead to insulin resistance and diabetes.

“We don't think the gut microbes are acting by one mechanism but by a contribution of several,” says Bäckhed, now at the University of Gothenberg in Sweden. “We don't know what we do when we change the microbiota yet — we might cure type 2 diabetes and predispose someone to type 1. I wouldn't say that changing the microbiota could cure everybody, but I think that together with lifestyle changes it could help a lot of people.”


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Gravitz, L. Microbiome: The critters within. Nature 485, S12–S13 (2012).

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