Cardiovascular diseases are the leading cause of premature death worldwide, causing over 17 million deaths annually. One major risk factor for these diseases is high blood pressure (hypertension). With hypertension on the rise globally, there is an urgent need to find treatments and prevention strategies for this condition.

Our lifestyle, and especially our diet, can play an important role in managing hypertension. But how do changes to diet actually aid in regulating blood pressure? A research team led by David J. Durgan at Baylor College of Medicine, in Houston, recently showed that alternate-day fasting can reduce high blood pressure in an animal model. These beneficial effects of fasting on blood pressure were mediated through changes in the gut microbiota, the trillions of microorganisms that live inside the digestive tract.

This connection between gut microbiota and blood pressure has gained increasing attention in recent years. Individuals with high blood pressure were observed to have gut dysbiosis, a state characterized by a reduced microbial diversity, loss of beneficial microorganisms, and expansion of potentially harmful ones.

“We know that host health correlates with microbial richness, diversity and certain types of microbes that should be there," Dario R. Valenzano, a professor at the Leibniz Institute on Aging in Jena, Germany, told me. “But we still understand very little about it.” Especially when it comes to causal relationships: observing changes in gut microbiota composition does not prove that these changes are causing the disease. For moving from association to causation, animal models are particularly useful, because they allow for mechanistic investigations and controlled interventions.

One of the most widely used animal models of hypertension are spontaneously hypertensive stroke-prone (SHRSP) rats, a line of rats that develop hypertension at six weeks of age, much earlier than control animals. Like hypertensive humans, these rats show gut dysbiosis. To investigate whether gut dysbiosis contributes to the development of hypertension, the researchers transferred gut microbiota from SHRSP rats to rats with normal blood pressure. The previously healthy rats to develop high blood pressure, pointing towards a causal relationship between gut dysbiosis and hypertension.

Building on these findings, the researchers went one step further and asked whether changing the gut microbiota composition could go the other way and reduce blood pressure in the SHRSP model. For changing the gut microbiota composition, the researchers focused on the animal’s diet. “Feeding leads to massive fluctuations in the overall composition of the microbiome," Valenzano explained. Could changing the feeding pattern through fasting reduce the blood pressure of the SHRSP rats? To test this, the researchers split the SHRSP rats into two groups: one group had unlimited access to food, while the other group was fed only every other day. After nine weeks, the rats that had unlimited access to food had developed high blood pressure, as is expected for the SHRSP model. In contrast, rats that were fed only every other day did not develop high blood pressure.

How to prove causality and show that the fasting lowered blood pressure through changes to the gut microbiota? The researchers resorted to a common technique in the field: they transplanted gut microbiota from SHRSP animals that had fasted into rats that were germ-free. These germ-free rats are bred in isolators without exposure to microorganisms and have no microbiota of their own. Any effect observed after the transplant will be caused by the transferred microbiota.

The researchers observed that germ-free rats that had received microbiota from the fasting SHRSP rats had lower blood pressure than germ-free rats that had received microbiota from normal-fed SHRSP rats. With this, the researchers discovered that modulating the gut microbiota through fasting relieves high blood pressure in the SHRSP animal model. Rikeish R. Muralitharan, a graduate student at Monash University in Australia investigating the association between gut microbiota and hypertension, compliments the approach taken by the research team: “That's one important thing going forward: mechanistically linking the gut microbiome to the effect. The researchers definitely moved away from just association.”

While these findings improve our understanding of the connection between diet, gut microbiota and blood pressure, it is a long road before we can start prescribing fasting to hypertensive patients: “What I would like to see before I can say anything about potential applications in humans is whether transplants of gut contents improve blood pressure in non-hypertension animal models,” Valenzano cautions. Since age is a risk factor for hypertension, both Valenzano and Muralitharan would like to see whether the research findings also apply to naturally aged laboratory animals. “It would be very important to know what the impact of fasting on age-related blood pressure changes is. Otherwise, we may be looking at only potential applications for individuals that have hypertension for very similar causes to these rats,” Valenzano emphasizes. Thinking ahead about potential human interventions, further research in animal models as well as clinical trials are needed.

When it comes to clinical trials and translating the findings to humans, one difficulty is controlling the diet regimen itself: “You can give rats every other day feeding. But in humans, it's quite hard. You can't make someone eat the same thing every single day or make them fast and then see what happens,” Muralitharan remarks. Compliance with dietary guidelines is a major hurdle in human intervention studies.

Another inherent difficulty is demonstrating causality between diet, gut microbiota and blood pressure in humans. “A decrease in body weight also reduces blood pressure. So sometimes it's very hard to really nitpick whether the effect is really because of how the diet actually reduces blood pressure," Muralitharan explains. The effects of fasting on blood pressure might not be solely mediated through changes to the gut microbiota. While the causal relationships might be more complex in humans, gut microbiota certainly play a role.