A minor injury, a serious infection, or even the flu can send the body down very different paths. Some people recover quickly, while others become severely ill or die. Scientists call this path a disease trajectory, and it can be shaped by many factors, including age, sex, health history, and biology.
At the Salk Institute, Janelle Ayres, PhD, has spent years studying why people respond so differently to illness and injury. Her work focuses on how the body can be guided away from disease and death and toward recovery and survival.
Inflammation and Disease Survival
Inflammation is often a major force behind the body’s decline during infections and injuries. It is essential for protection because it alerts the immune system and brings immune cells to where they are needed. But when inflammation becomes excessive, it can damage tissues and contribute to death.
Because infections can trigger especially harmful inflammation, the Salk team studied mice with an infection. They found that adding the amino acid methionine to the animals’ diet protected them from wasting, blood-brain barrier problems, and death linked to inflammation.
The benefit came through an unexpected route. Methionine improved kidney filtration, showing that the kidneys may play a larger role than previously recognized in helping the body move from infection toward recovery.
The findings, published in Cell Metabolism, suggest that small changes in nutrition can strongly influence disease outcomes. Methionine supplementation may have potential for inflammatory conditions, kidney disease, kidney failure, and patients receiving dialysis, although more research is needed.
“Our study indicates that small biological differences, including dietary factors, can have large effects on disease outcomes,” says senior author Ayres, professor and holder of the Salk Institute Legacy Chair at Salk, as well as a Hughes Medical Institute Investigator. “Our discovery of a kidney-driven mechanism that limits inflammation, together with the protective effects of methionine supplementation in mice, points toward the potential of nutrition as a mechanistically informed medical intervention that can direct and optimize the paths people take in response to insults that cause disease.”
How Inflammation Works
Inflammation is the immune system’s reaction to a threat. That threat could be a pathogen inside the body or something as simple as a splinter. Immune cells move toward the problem and help drive healing.
As those immune cells arrive, they increase the body’s alarm signals through proteins known as pro-inflammatory cytokines.
The body must keep inflammation in a careful balance. Too little inflammation may fail to control a threat, while too much can harm healthy tissue. Much of the research in this area has focused on how immune responses are turned on or off.
Ayres’s team is examining a different question. Instead of focusing only on immune switches, they are studying how the body adjusts the strength of inflammation by controlling the release and buildup of pro-inflammatory cytokines.
“Pro-inflammatory cytokines are ultimately what leads to sickness and death in a lot of cases,” says first author Katia Troha, PhD, a postdoctoral researcher in Ayres’s lab. “The immune system has to balance inflammation to attack the invader without harming healthy cells in the body. Our job is to find the mechanisms it uses to do that, so that we can target them to improve patient outcomes.”
Methionine and Kidney Filtration
To investigate how the body manages cytokine levels, the researchers used a mouse model of systemic inflammation caused by the pathogen Yersinia pseudotuberculosis.
One of the first changes they observed was reduced eating in infected mice, which suggested that the animals’ metabolism had shifted. To better understand their nutritional state, the researchers measured amino acids circulating in the blood. Amino acids are the building blocks of proteins and support healthy cell function throughout the body.
The infected mice had low levels of methionine, an essential amino acid that people normally get through food. Troha then gave another group of mice chow supplemented with methionine. Unexpectedly, these mice were protected from the infection.
Additional experiments revealed that methionine lowered cytokine levels in the blood by working through the kidneys. It increased the kidneys’ filtration capacity, improved blood flow, and helped the body remove pro-inflammatory cytokines in urine.
Importantly, this process cleared extra cytokines without interfering with other important parts of the immune response.
The team also tested whether methionine had similar effects in other conditions. In models of sepsis and kidney injury, methionine again protected mice, suggesting that it could be relevant for other inflammatory disease settings.
Nutrition, Kidneys, and Recovery
When Salk scientists added methionine to the diets of infected mice, the animals followed a very different disease trajectory. Their kidney function improved, and they were protected from wasting, blood-brain barrier dysfunction, and death. At the same time, they remained able to fight and kill Yersinia pseudotuberculosis.
The results from sepsis and kidney injury models suggest the effect may extend beyond one infection. This points to methionine as a possible tool for infectious diseases and inflammatory conditions, especially in people with kidney disease, kidney failure, or those undergoing dialysis.
“Our findings add to a growing body of evidence that common dietary elements can be used as medicine,” says Ayres. “By studying these basic protective mechanisms, we reveal surprising new ways to shift individuals that are fated to develop disease and die onto trajectories of health and survival. It may one day be possible for something as simple as a supplement with dinner to make the difference between life and death for a patient.”
The researchers emphasize that the results are promising but have not yet been tested for effectiveness in humans. For that reason, people should not start taking methionine supplements based on this study alone.
Future studies will look more closely at how methionine works, whether other amino acids may produce similar or complementary effects, and how the findings might translate to people.
Other authors include Shrikaar Kambhampati, Arianna Insenga, and Christian Metallo of Salk.
The work was supported internally by two Salk Women & Science Special Awards and a Collaboration Grant, also a Salk Innovator Award, Howard Hughes Medical Institute, Pioneer Fund Postdoctoral Scholar Fellowship, as well as by the National Institutes of Health (AI144249, AI14929), Keck Foundation, NOMIS Foundation, and Lowry Medical Research Institute.
