Debunking myths on genetics and DNA

Saturday, April 26, 2014

Forget the "obesity gene": it's the "obesity microbes" that we need to fight.

Antelope Canyo ©EEG

This is going to be gross. So, if you're eating, finish up your snack first.


Let's do the following experiment: take two twins, one chubby, the other lean. Why one is chubby and the other is lean is a question we'll leave for another time. For the time being, all we do is take fecal samples from both, extract the microbiota (the bacteria living in feces) and transplant them in mice.

You'd been warned it was kinda gross.

The reason for such an experiment is that large intestine microbiota (the microorganisms that live in our bowels) have been implied in many physiological processes. I've discussed in other posts, for example, how commensal microbiota modulates the immune system. Some studies also suggest that they could be involved in the heritability of some epidemiological markers.

In a 2009 paper, Turnbaugh et al. transplanted human fecal microbiota in germ-free mice (mice that didn't have any pre-existing intestinal micriobiota) and showed that changes in the mice diets could alter the microbiota and the genes they expressed. In particular:
"Humanized mice fed the Western diet have increased adiposity; this trait is transmissible via microbiota transplantation [1]."
The human microbiota not only transplanted successfully in the mice, but it was even transmitted to the offspring, which could possibly validate the question raised in one of the epigenetic papers I discussed last week: are dietary changes that do not affect the DNA "inherited" through the gut microbiota?

Ridaura et al., in a 2013 Science paper [2], continued in this line of experiments, this time using samples from twins that differed in obesity: one was lean, the other obese. After the transplant all mice were fed the same low-fat diet. What did the researchers find?
"The increased adiposity phenotype of each obese twin in a discordant twin pair was transmissible: The change in adipose mass of mice that received an obese co-twin’s fecal microbiota was significantly greater than the change in animals receiving her lean twin’s gut community within a given experiment and was reproducible across experiments (P ≤ 0.001, one-tailed unpaired Student’s t test; n = 103 mice phenotyped) [2]."
As a further control, the researchers took the mice that had received the "obese" microbiota and transplanted them a second time with "lean" microbiota. They noticed that the excess adiposity was shed if the mice were kept at a low-fat diet, but not if the diet was high in fat and low in fiber.

The microbiota composition in the two mouse population is different, and the researchers showed that the "lean" microbiota produce higher quantities of short-chain fatty acids. One of the hypothesis raised, therefore, is that these short-chain fatty acids can protect against accumulation of fat and increase energy expenditure.

While these studies come with the usual caveat that humans are typically far more complicated than mouse models, I find them extremely fascinating, especially in light of the epigenetic papers I discussed last week that pointed at how phenotypic changes induced by diet can affect multiple generations even though they are not encoded in the genome. A possible cause for the transmissibility across generations could be the gut microbiota, paired with a high-fat diet which ends up affecting parents and children alike if they all live under the same roof.

[1] Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, & Gordon JI (2009). The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Science translational medicine, 1 (6) PMID: 20368178

[2] Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, Griffin NW, Lombard V, Henrissat B, Bain JR, Muehlbauer MJ, Ilkayeva O, Semenkovich CF, Funai K, Hayashi DK, Lyle BJ, Martini MC, Ursell LK, Clemente JC, Van Treuren W, Walters WA, Knight R, Newgard CB, Heath AC, & Gordon JI (2013). Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science (New York, N.Y.), 341 (6150) PMID: 24009397

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