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Study of Twins Finds Host Genetics Influence Gut Microbes, Though Both Affect Body Weight

NEW YORK (GenomeWeb) – Host genetics shape what microbes take up residence in the human gut and together influence host weight, according to a new study appearing in Cell from Cornell University's Ruth Ley and colleagues.

Ley and her team compared the microbes found within more than a thousand fecal samples obtained from TwinsUK project participants, finding that monozygotic twins had more similar numbers of certain microbes than did dizygotic twins, indicating that human genes influence the composition of the gut microbiome.

"Up until now, variation in the abundances of gut microbes has been explained by diet, the environment, lifestyle, and health," said Ley in a statement. "This is the first study to firmly establish that certain types of gut microbes are heritable — that their variation across a population is in part due to host genotype variation, not just environmental influences."

Further, she and her colleagues reported that that the most heritable bacteria — members of the Christensenellaceae family — are found in higher numbers in people with low body-mass index, and that adding Christensenella minuta into the microbial mix of germ-free mice otherwise inoculated with obesity-related microbiomes led to reduced weight gain.

Ley and her team collected 1,081 fecal samples from 977 people, including 171 monozygotic twin pairs and 245 dizygotic twin pairs. For 98 participants, the researchers collected more than one sample. After extracting DNA from the samples and amplifying and sequencing the 16S rRNA genes, the researchers sorted their data into more than 9,600 operational taxonomic units (OTUs).

These OTUs revealed a typical Western microbiome profile — one that is dominated by Firmicutes and Bacteroidetes, followed by Proteobacteria, the researchers reported. The most commonly shared methanogen, they noted, was Methanobrevibacter smithii.

Microbiomes, they further reported, were more similar within individuals than between individuals, but were also more similar within twin pairs. Monozygotic twins had more similar gut microbiomes than dizygotic twin pairs, suggesting to the researchers that host genetics influence what taxa make up the microbiome.

Using the twin-based ACE model that divides variance into three components — genetics, common environment, and unique environment — Ley and her colleagues estimated the heritability of these OTUs. While the largest portion of OTU variance could be attributed to the twins' unique environments, for more than 60 percent of the OTUs the proportion of variation ascribed to genetic effects was greater than that ascribed to the common environment.

The researchers also applied the ACE model to the microbial phylogeny, finding that the nodes with the strongest heritability were within the Ruminococcaceae and Lachnospiraceae families. The Bacteroidetes, meanwhile, were mostly environmentally determined.

The most highly heritable taxon was the Christensenellaceae family, they found. It forms a hub with other heritable families like the Methanobacteriaceae and the Dehalobacteriaceae, though is negatively correlated with the Bacteriodacea and Bifidobacteriaceae.

Additionally, the Christensenellaceae family was enriched in participants with a lean body mass index, as were other members of the related hub. Methanogens, the researchers noted, have been linked to lean BMI in the past. Though M. smithii was not significantly heritable, it, too, was linked with lean BMI, the researchers said.

To examine the interplay of the Christensenellaceae family and methanogens on lean phenotype, Ley and her colleagues transferred fecal samples from 21 participants to germ-free mice. These donors included participants who were lean with methanogens, lean without methanogens, obese with methanogens, and obese without methanogens.

By analyzing the microbiomes of the mice, the researchers found that Christensenellaceae is associated with lower weight gain in mice that received fecal transplants and that while methanogens may be a marker for low BMI, they are not required for a lean phenotype.

In a separate set of mouse studies, Ley and her colleagues found that adding Christensenellaceae, more particularly C. minuta, into obese donor stool that otherwise lacked it led to decreased weight gain in the recipient mice.

This, they noted, indicates that members of the Christensenellaceae are associated with a lean phenotype. Addition of C. minuta also appeared to reshape gut microbe community diversity, they said.

"Our results show that bacterial abundances run in families may be useful for disease risk prediction," Ley said. "The microbiome is also an attractive target for therapeutic manipulation. By understanding the nature of our association with these health-associated bacteria, we could eventually exploit them to promote health."

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