High Salt Diet Helps the Microbiome To Suppress Tumors, Mouse Study Reveals

A study in mice has found that a high-salt diet may help fight tumor growth, using a mechanism that involves cells of the immune system and bacteria in the gut microbiome.

Diets high in salt are mainly associated with negative health outcomes, including increased blood pressure and effects on the cardiovascular system. But new research published today in Science Advances suggests that there may be an unexpectedly positive impact of high salt intake.

Salt and immunity

The study was conducted by a team of researchers from the NCR-Biotech Science Cluster, located in the northern Indian state of Haryana. High salt intake has previously been noted to encourage inflammation – a 2013 study noted that, in mice, high amounts of salt could drive symptoms of experimental autoimmune encephalomyelitis (EAE), a model disease for multiple sclerosis.

But inflammation is, outside of autoimmunity, a protective response by the body, and the team, led by senior author Prof. Amit Awasthi, wanted to investigate whether a salty diet could stimulate inflammation in the body’s anticancer response.

Awasthi’s team fed tumor model mice a low, medium or high-salt diet. Tumor size and cellular and metabolic makeup were closely monitored. The high-salt diet significantly restricted the growth of the mice’s tumors. The reductions noted were all the more remarkable for their robustness across multiple types of tumor. Increased survival and reduced tumor growth were seen in mice with melanoma, carcinoma and even metastatic cancer spread in the bloodstream.

Helping out killer cells

Awasthi, speaking to Technology Networks, explained that the team’s analysis showed that immune cells called natural killer (NK) cells had a 50% increase in number in mice fed the high-salt diet. These cells act as a kind of “internal affairs” division of the immune system, identifying body cells that have become virally infected or cancerous and destroying them.

“The tumor microenvironment is very immunosuppressive,” explained Awasthi. Tumors have various biochemical defenses that allow them to withstand attack by NK cells and other inflammatory processes. Therapies that override these defenses, such as immune checkpoints inhibitors, have been revolutionary for the field of cancer research.

“Everybody is talking about cancer immunotherapy,” said Awasthi. “These drugs are FDA approved and are very effective. But nobody knows why these therapies only work in certain patients. Around 30-40% of patients are responders, but the rest aren’t.”

These differences in response between seemingly well-matched patient groups has provoked much head-scratching in the field, and one concept that has been homed in on is the impact of the microbiome on treatment effectiveness. The microbiome is the community of microbes that live in and on our bodies, and the metabolism of drugs by these bacteria, which vary from person to person, could have drastic impacts on their efficacy.

To examine the microbiome of their cancer-fighting mice, the team conducted detailed metabolomic and RNA analysis on serum and fecal samples taken from the mice. The team noted that one gut bacterial species, Bifidobacterium, was highly enriched in mice fed a high-salt diet. Remarkably, the higher salt intake also increased the “leakiness” of the mice’s gut lining, meaning the now-enriched Bifidobacterium could migrate from the gut into other areas of the body, including into tumors. Once inside tumor environments, these bacteria were then observed to activate the suppressed NK cells, allowing them to improve their antitumor attack.

Human data boosts findings

But two significant obstacles remained at this point in the study:

1. Mice aren’t humans; would the findings be relevant in our bodies?
2. A high-salt diet, is, regardless of any tumor-busting effect, bad for other areas of the human body.

Luckily, human data were ready and waiting for the team, released by the lab of Nobel Prize-winning Japanese scientist Tasuku Honjo. Honjo won his award for his work into anti-PD-1 checkpoint inhibitor therapy, a cancer immunotherapy regime that targets a protein that can inadvertently stop cancer-killing cells from doing their job.

Honjo’s lab had investigated why such a significant fraction of those taking checkpoint inhibitor therapies did not respond to them and had identified that a metabolite derived from the microbiome, hippuric acid, predicted a positive response to therapy.

“We took those data and analyzed our metabolomics data,” says Awasthi. “We found that when you put the mice on a high-salt diet in a tumor condition, you also find hippuric acid is very significantly enriched. Connecting two things, we found that maybe the salt is utilizing the same pathway as those immunotherapy drugs in the human setting.” Hippurate, released by Bifidobacterium, may act as the wake-up call that reactivates suppressed NK cells.

Digging down even further, Awasthi’s team showed that a high-salt diet was able to reduce the expression of the immunosuppressive PD-1 protein, the same target of Honjo’s immunotherapy. Based on this observation, the team tried a new approach, dosing mice on a lower-salt diet (that could still slightly raise the level of salt in the mice’s bodies) with a suboptimal dose of Honjo’s immunotherapy. Here, this lower level of salt acted as a booster for the immunotherapy regime, significantly reducing tumor size. This, Awasthi points out, could lead to a regimen that reduces the effective dose of the immensely expensive immunotherapy, making it more accessible in developing countries.

Could these effects be a result of some intrinsic action of salt on NK cells? One experiment the team conducted suggests this is unlikely. In mice that had their microbiome depleted using antibiotics, the effects of a high-salt diet disappeared – suggesting that these bacteria are essential to the underlying mechanism. This raises the possibility of an approach that bypasses dietary salt altogether. The team outlined this in experiments where, instead of altering salt intake, microbiome-deleted mice were given fecal transplants from other mice fed on high-salt diets. This restored the recipients’ cancer-fighting ability.

The team now hope that a salt-and-immunotherapy regime could be brought to clinical trials, targeting patients for whom conventional therapy options have run out. Awasthi admits that patients’ salt levels would have to be closely monitored in any such trial, but the study points the way to a new treatment option for cancer that is both effectively and startlingly novel. 

Reference:

Rizvi, ZA, Dalal, R, Sadhu, S et al. High-salt diet mediates interplay between NK cells and gut microbiota to induce potent tumor immunity. Sci. Adv. 2021;7. doi: 10.1126/sciadv.abg5016