In mice, a diet high in salt suppresses tumor growth—but only when gut microbes are there to stimulate immune cells, a September 10 study in Science Advances reports. The findings raise tantalizing questions about the role of diet and gut microbes in human cancers, and may point to new avenues for therapeutic development.
While the study isn’t the first to connect a high-salt diet to shrinking tumors, “[the authors] have shown a unique mechanistic role of high salt induced gut microbiome changes as the central phenomenon behind their observed anti-cancer effect,” writes Venkataswarup Tiriveedhi, a biologist at Tennessee State University who has studied the effect of salt on cancer progression but was not involved in the study, in an email to The Scientist.
Amit Awasthi, an immunologist with the Translational Health Science and Technology Institute in India and corresponding author of the study, says he and his colleagues pursued this line of inquiry because previous research had linked high salt intake with autoimmune diseases, suggesting that increased salt stimulates immune cells. Meanwhile, tumors are well known to grow in immune-suppressive environments. Awasthi recalls wondering with his team: “If we put salt in the mice’s diet, maybe [the immune system in] the tumor environment becomes activated,” suppressing cancerous growth.
Indeed, a 2019 Frontiers in Immunology study from a European team led by Hasselt University immunologist Markus Kleinewietfeld reported that high-salt diets inhibited tumor growth in mice. When Awasthi and his colleagues carried out similar experiments, implanting mice with B16F10 skin melanoma cells and then feeding the tumor transplant mice diets with different salt levels, they got similar results: tumors grew slower in mice who were fed a high-salt diet.
That led to what Awasthi calls an “obvious question”: How does the immune system respond to dietary salt? To answer that, the team dissected the tumor sites and found that immune cells known as natural killer (NK) cells were enriched in the mice fed the high-salt diet compared with mice fed diets with normal or slightly elevated salt levels. When the NK cells were removed, the high-salt diet no longer led to tumor regression—an effect that wasn’t seen after depleting both T and B cells.
To drill into why salt had this effect on NK cells, Awasthi and his colleagues looked in the literature and found studies reporting that high-salt diets alter the gut microbiome, as well as others that found the gut microbiome modulates patients’ response to cancer immunotherapy. To test for a role of the resident gut bacteria in the effects of a high-salt diet on cancer growth, the researchers gave the mice antibiotics before feeding them the different diets. Sure enough, a high-salt diet no longer suppressed tumor growth. But that wasn’t all: when the team transplanted fecal material from mice fed a high-salt diet into microbe-free mice, they were surprised to find that tumors shrank, Awasthi recalls.
The researchers looked at the diversity of species in the mice’s gut and saw an increased abundance of Bifidobacterium species in mice fed a high-salt diet. Moreover, the tumors of these mice showed a sixfold increase in Bifidobacterium abundance compared with the tumors of mice on a normal diet. According to Awasthi, that suggests “Bifidobacterium is leaking out from the gut and actually reaching the tumor site,” likely the result of salt-induced gut permeability.
In mice fed a normal diet, injection of Bifidobacterium into tumors led to tumor regression, an effect that disappeared if the researchers removed the animals’ NK cells, they reported. Awasthi says that might mean there’s a way to capitalize on the tumor-fighting qualities of a high-salt diet while avoiding the potential downsides, such as autoimmune issues or hypertension: “we can replace the salt with the Bifidobacterium.”
Kleinewietfeld says the new study is in line with his 2019 study and previous work showing that salt can affect the gut microbiota. Still, he writes in an email to The Scientist, “The microbiome part of this paper seems a bit preliminary . . . and some data are yet hard to interpret with the information provided in the manuscript.”
A perplexing problem, writes Tiriveedhi, “is the dual nature of the impact of salt on solid tumors.” While salt may suppress cancer by enhancing antitumor immune responses, Tiriveedhi points to studies by his group that find salt can also induce cancer progression and proliferation. According to Tiriveedhi, these results “suggest a temporal role of salt on cancer progression.” In the short term, salt might trigger anticancer mechanisms, he says, but “over a prolonged chronic period of time, salt might switch sides and exert a pro-cancer effect.”
Even with such questions outstanding, Awasthi says that his group’s results could provide the basis of a new form of cancer therapy, and the team is already planning clinical trials in collaboration with oncologists. Whether those trials will validate the antitumor activities of salt or Bifidobacterium remains to be seen.
“[I]t’s an exciting field of research, though still in its infancy,” writes Kleinewietfeld, adding “more studies [are] needed to understand the complex interactions of nutrition, microbiome and immunity in the context of cancer. Thus, future studies will show if new findings could indeed lead to novel treatment options for patients.”