Reading a Biological Clock in the Dark

Proper coordination between our gut bacteria and our biological clocks may be crucial for preventing obesity and glucose intolerance.

Our species’ waking and sleeping cycles – shaped in millions of years of evolution – have been turned upside down within a single century with the advent of electric lighting and airplanes. As a result, millions of people regularly disrupt their biological clocks – for example, shift workers and frequent flyers – and these have been known to be at high risk for such common metabolic diseases as obesity, diabetes and heart disease. A new study published in Cell, led by Weizmann Institute scientists, reveals for the first time that our biological clocks work in tandem with the populations of bacteria residing in our intestines, and that these microorganisms vary their activities over the course of the day. The findings show that mice and humans with disrupted daily wake-sleep patterns exhibit changes in the composition and function of their gut bacteria, thereby increasing their risk for obesity and glucose intolerance.

A consensus has been growing in recent years that the populations of microbes living in and on our bodies function as an extra “organ” that has wide-ranging impacts on our health. Christoph Thaiss, a research student in the lab of Dr. Eran Elinav of the Weizmann Institute’s Immunology Department, led this research into the daily cycles of gut bacteria. Working together with David Zeevi in the lab of Prof. Eran Segal of the Computer Science and Applied Mathematics Department, and Maayan Levy of Elinav’s lab, he found a regular day-night cycle in both the composition and the function of certain populations of gut bacteria in mice. Despite living in the total darkness of the digestive system, the gut microbes were able to time their activity to the mouse’s feeding cycles, coordinating daily microbial activities to those of their host.

This image shows the outline of a man with a colorful clock face across his back.
Researchers report our biological clock work in tandem with the populations of bacteria residing in our intestines, and that these microorganisms vary their activities over the course of the day. Credit Weizmann Institute of Science.

Does this finding have any medical significance? To further investigate, the researchers looked at “jet-lagged” mice, whose day-night rhythms were altered by exposing them to light and dark at different intervals. The jet-lagged mice stopped eating at regular times, and this interrupted the cyclic rhythms of their internal bacteria, leading to weight gain and high blood sugar levels. To verify these results, the scientists transferred bacteria from the jet-lagged mice into sterile mice; those receiving the “jet-lagged microbes” also gained weight and developed high blood sugar levels.

The research group then turned to human gut bacteria, identifying a similar daily shift in their microbial populations and function. To conduct a jet-lag experiment in humans, the researchers collected bacterial samples from two people flying from the US to Israel – once before the flight, once a day after landing when jet lag was at its peak, and once two weeks later when the jet lag had worn off. The researchers then implanted these bacteria into sterile mice. Mice receiving the jet-lagged humans’ bacteria exhibited significant weight gain and high blood sugar levels, while mice getting bacteria from either before or after the jet lag had worn off did not. These results suggest that the long-term disruption of the biological clock leads to a disturbance in their bacteria’s function that may, in turn, increase the risk for such common conditions as obesity and imbalances in blood sugar levels.

Segal: “Our gut bacteria’s ability to coordinate their functions with our biological clock demonstrates, once again, the ties that bind us to our bacterial population and the fact that disturbances in these ties can have consequences for our health.”

Elinav: “Our inner microbial rhythm represents a new therapeutic target that may be exploited in future studies to normalize the microbiota in people whose life style involves frequent alterations in sleep patterns, hopefully to reduce or even prevent their risk of developing obesity and its complications.”

Notes about this neuroscience research

Also participating in this research were Gili Zilberman-Schapira, Jotham Suez, Anouk Tengeler, Lior Abramson, Meirav Katz and Dr. Hagit Shapiro in Elinav’s lab; Tal Korem in Segal’s lab; Prof. Alon Harmelin, Dr. Yael Kuperman and Dr. Inbal Biton of the Veterinary Resources Department, Dr. Shlomit Gilad of the Nancy and Stephen Grand Israel National Center for Personalized Medicine; and Prof. Zamir Halpern and Dr. Niv Zmora of the Sourasky Medical Center and Tel Aviv University.

Dr. Eran Elinav’s research is supported by the Abisch Frenkel Foundation for the Promotion of Life Sciences; the Benoziyo Endowment Fund for the Advancement of Science; the Gurwin Family Fund for Scientific Research; the Leona M. and Harry B. Helmsley Charitable Trust; the Adelis Foundation; Yael and Rami Ungar, Israel; the Crown Endowment Fund for Immunological Research; John L. and Vera Schwartz, Pacific Palisades, CA; the Rising Tide Foundation; Alan Markovitz, Canada; Cynthia Adelson, Canada; the estate of Jack Gitlitz; the estate of Lydia Hershkovich; the European Research Council; CNRS – Centre National de la Recherche Scientifique; the estate of Samuel and Alwyn J. Weber; and Mr. and Mrs. Donald L. Schwarz, Sherman Oaks, CA. Dr. Elinav is the Incumbent of the Rina Gudinski Career Development Chair.

Prof. Eran Segal’s research is supported by the Kahn Family Research Center for Systems Biology of the Human Cell; the Cecil and Hilda Lewis Charitable Trust; the European Research Council; and Mr. and Mrs. Donald L. Schwarz, Sherman Oaks, CA.

Contact: Yivsam Azgad – Weizmann Institute of Science
Source: Weizmann Institute of Science press release
Image Source: The image is adapted from the Weizmann Institute of Science press release
Original Research: Full open access research for “Transkingdom Control of Microbiota Diurnal Oscillations Promotes Metabolic Homeostasis” by Christoph A. Thaiss, David Zeevi, Maayan Levy, Gili Zilberman-Schapira, Jotham Suez, Anouk C. Tengeler, Lior Abramson, Meirav N. Katz, Tal Korem, Niv Zmora, Yael Kuperman, Inbal Biton, Shlomit Gilad, Alon Harmelin, Hagit Shapiro, Zamir Halpern, Eran Segal, and Eran Elinav in Cell. Published online October 16 2014 doi:10.1016/j.cell.2014.09.048

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