Too sterile for science? Gut bacteria transplants boost health in lab mice
Have you ever wondered why experiments in lab mice, such as vaccine studies, turn out very differently in humans or other animals? According to US researchers, the problem lies with the test subjects’ gut bacteria.
All mammals depend on their microbiota, the collection of microorganisms they host in and on their bodies. Evolution shapes each animal’s microbiota, favouring populations of microorganisms that help the animal survive their environment and diseases they encounter.
But laboratory mice aren’t random house mice. They are carefully bred, fed and raised in tightly controlled conditions so that each mouse has predictable traits and genetics. This is a great advantage in basic biology research, but creating that predictability means that a controlled environment, and not the survival pressures of the outside world, shaped the microbiotas of laboratory mice.
“We hypothesised that this might explain why laboratory mice, while paramount for understanding basic biological phenomena, are limited in their predictive utility for modelling complex diseases of humans and other free-living mammals,” said Stephan Rosshart, a postdoctoral fellow at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and first author on the new research.
Rosshart and his colleagues decided to give laboratory mice back what they have lost: a naturally co-evolved wild mouse gut microbiota. To achieve this, the researchers trapped more than 800 wild mice from eight locations to find healthy, suitable candidates for a gut microbiota donation. They then tested and compared the gut microbiomes of the wild mice (Mus musculusdomesticus) and a common strain of laboratory mice, called C57BL/6, from multiple sources.
Writing in the journal Cell, the researchers confirmed that C57BL/6 mice had distinct gut microbiomes from wild mice.
The researchers engrafted the microbiota of wild mice to pregnant, germ-free C57BL/6 mice, which are raised in a sterile environment and don’t have microbiomes of their own. For a control group comparison, the researchers also engrafted microbiota from regular C57BL/6 mice into a separate group of pregnant, germ-free mice. Four generations later, the mice still carried either the wild microbiomes or the control laboratory microbiomes passed down from their foremothers.
When exposed to a high dose of influenza virus, 92% of the laboratory mice with wild microbiomes survived, whereas only 17% of laboratory mice and mice in the control group survived. In other experiments, the laboratory mice with wild microbiomes had better outcomes in the face of induced colorectal tumours, whereas the other mice had a greater number of tumours and more severe disease. The beneficial effects of the wild microbiota were associated with reduced inflammation in both models.
With more work and evaluation needed for definitive results, the researchers hope to improve and expand on the method of using natural microbiomes in laboratory mice. As noted by senior author Barbara Rehermann, “We think that by restoring the natural ‘microbial identity’ of laboratory mice, we will improve the modelling of complex diseases of free-living mammals, which includes humans and their diseases.”
“By being so different, natural microbiota will help us to discover protective mechanisms that are relevant in the natural world and absent in the laboratory,” added Rosshart.
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