Microbes living in the guts of both people and animals can make all the difference when we (or they) step on the scale. “If you put mice on what we might characterize as a McDonald’s diet—high fat and high sugar — mice without microbes are protected,” says Lora Hooper, an immunologist at the University of Texas Southwestern Medical Center in Dallas. By comparison, mice with a more normal microbial collection, or microbiome, pack on extra pounds.
A new study by Hooper’s team helps explain exactly how these gut bacteria influence our weight. The findings, published September 1 in the journal Science, offer clues to another vexing problem: why people who work night shifts or travel internationally tend to gain weight too. Hooper’s research shows that gut microbes use a transcription factor protein called NFIL3 to tell intestinal cells how much fat to absorb and store. But NFIL3 levels are also driven by the circadian clock, which keeps the body running according to a roughly 24-hour daily schedule. When the composition of gut microbes or the circadian clock are out of sync in the body, NFIL3 and downstream metabolic pathways can also get derailed, the new findings suggest.
“[NFIL3] is the link between the circadian clock and these metabolic pathways,” Hooper says. “It’s receiving information about light and the microbiome and using it to regulate these metabolic pathways that are so crucial for determining whether we get fat or not.”
Evidence linking the gut microbiome’s effects to this internal cycle of wakefulness and sleep has accumulated over the years. Earlier studies conducted by Vanessa Leone, a biologist at the University of Chicago, showed that the microbiome follows its own daily rhythm. The composition and activities of gut microbes regularly vary over the course of the day. Metabolites produced by those microbes can then affect the circadian clocks of their hosts.
But the host’s circadian cycle can also influence gut microbes. Researchers at the Weizmann Institute of Science in Israel found that when mice lack a regular feeding time, their gut bacteria lose their normal fluctuations over the course of each day. Further studies showed that similar disruptions to the microbiome occur when mice lack a regular bedtime. As a result, mice with altered circadian rhythms and messed up microbiomes gain more and more weight.
The Israeli group confirmed in studies of two people that the human microbiome follows a similar daily rhythm. As expected, the human body clock was also disrupted by international air travel and associated jet lag. Remarkably, when the researchers transplanted the jet-lagged microbiomes into the guts of germ- and jet lag-free mice, those animals became increasingly prone to weight gain too.
“If you screw around with either of these finely tuned systems — the circadian clock or the microbiome — you can get obesity,” Hooper says. But researchers didn’t know exactly how these systems were signaling changes to metabolism.
Hooper’s new study finally provides a mechanism for how microbes may be communicating to the host circadian system and affecting weight. Her team found that the daily rise and fall of the transcription factor NFIL3 flattens out in germ-free mice raised in sterile enclosures. That shift in NFIL3 leads to a domino effect of other changes in intestinal cells that line the gut and influence the amount of fat that cells absorb from food. Mice don’t put on fat when they eat a high-fat diet unless they have both NFIL3 and an intact microbiome.
This communication involving NFIL3 isn’t direct though. Gut bacteria send their messages to intestinal cells via the immune system. “It’s like if I call you and the phone company gets involved,” Hooper says. First, immune cells in the gut detect the presence of microbes, and they talk to each other. Then, immune cells amplify that signal and pass it on to the intestinal cells, she says. Finally, the intestinal cells respond by ramping up the production of cellular machinery that helps take in lipids.
“If you start jamming [more] lipids into cells that line the intestine, that lipid has to come out the other side,” Leone says. Some of the excess lipids are stored as body fat. As these lipids accumulate, they set the stage for obesity and other metabolic conditions, such as diabetes and fatty liver, she says.
The new study findings may point the way to new strategies for preventing or treating metabolic conditions, through drugs designed to target NFIL3, the circadian clock, the microbiome, or some combination of the three.
“The thinking is that maybe for people who are experiencing either jet lag via international travel or shift work, just by changing their circadian behavior, already their gut microbes become disrupted,” Leone says. “Then once the microbes are disrupted they’re sending bad signals to our cells, which further perpetuates this loop. If we can figure out what those signals are [then] maybe we can block them or figure out how to make our cells ignore them so that even when people have to experience some sort of circadian disruption, we can circumvent the problem.”
Who knows? Maybe one day we can have our jet lag and keep our waistlines trim too.