Salmonella Promote Host Survival During Infection

Loss of appetite is a common response to gastrointestinal infections, but not too much is understood about the function of this response in our ability to fight off infection. Where at times eating less may encourage faster recovery, sometimes loss of appetite can be harmful—an example of this would be when HIV-positive patients or cancer patients develop wasting.

Recently, researchers from the Salk Institute made a surprising discovery regarding the link between appetite and infection; when it comes to Salmonella Typhimurium, the bacteria will actually block the body’s appetite loss response, thus encouraging survival of the host so that it can increase its own transmission to other hosts. Their findings, published in the journal Cell, could have a number of implications when it comes to treating infectious diseases.

According to Janelle Ayres, PhD, assistant professor at Salk Institute’s Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis, the main goal of the study was to understand the role of sickness-induced behaviors—such as anorexia, loss of appetite, disruption in sleep—in how the body fights off infection.

To do this, Dr. Ayres and her team infected mice with the bacteria Salmonella Typhimurium. They did this because appetite loss is a common response in mice who are infected with the bacteria; as the bacteria becomes more virulent, spreading from the intestines to other organs in the body, the mice will become sicker. However, by feeding the sick mice, despite their loss of appetite, they found that the mice were able to survive longer. In a video explaining the research, Dr. Ayres said, “If we fed [the] animals, so that we could override the anorexic response, the animals actually survived the infection. If we nutritionally-restricted [the] animals during infection, they actually fared worse.”

However, their survival was not based on a stronger immune response afforded by the nutrients supplied by the food. According to Dr. Ayres, “What was really surprising to us was that it wasn’t the host defense response to the infection that was changing. What we found was the strategy that the Salmonella actually employs during the infection to block this anorexic response, to actually prevent it from causing disease in the host—so, it was promoting survival of the host during the infection.”

This discovery raised a number of questions: Why was the bacteria becoming less virulent—not spreading to other organs? Why was Salmonella working to keep the host healthy? The researchers found that even though the bacteria were becoming less virulent, they were working to increase transmission to multiple new hosts.

In the press release, first author Sheila Rao, a Salk research associate, explained, “What we found was that appetite loss makes the Salmonella more virulent, perhaps because it needs to go beyond the intestines to find nutrients for itself. This increased virulence kills its host too fast, which compromises the bacteria’s ability to spread to new hosts. The tradeoff between transmission and virulence has not been appreciated before—it was previously thought that virulence and transmission were coupled.”

By consuming more food during infection, the hosts were able to prolong survival, which worked in favor of the Salmonella. Through feces, the Salmonella were able to spread to other animals, thus, increasing its transmission to a number of hosts, something that the bacteria would not have been able to do if the mice did not eat and “died sooner due to heightened bacterial virulence.”

So, how are the bacteria able to inhibit the appetite loss response? According to Rao, “in the intestine, the bacteria Salmonella inhibits a specific cytokine, known as SIrP, and this SIrP, can transmit signals to the brain. The brain then induces this loss of appetite and causes this anorexic response. So, the Salmonella basically inhibits this process, or slows down this process from occurring.” The researchers found that infected mice who could not make SIrP consumed less food, and thus, lost more weight and perished faster.

Although “the same gut-brain pathway” linked to loss of appetite also exists in humans as it does in mice, Dr. Ayres noted that responses to infection depend on a number of different factors. The impact that appetite loss has on an individual’s health during illness is dependent mainly on whatever the causative agent of the infection is.

In order to learn more about this link between appetite loss and infection, Dr. Ayres and her team want to look more closely at the human microbiome and identify other microbes that may affect the gut-brain pathways in a similar way. Through this exploration, the researchers hope to use their findings to inform new therapies related to appetite loss.

When speaking of the implications of their work, Dr. Ayres said, “This has a number of potentially important implications for human diseases. Again, we know that the anorexic response is a very common response in infectious diseases in humans and also cancer, inflammatory conditions, [and] the aging population; it’s also a very serious response or consequence of current medical interventions that we have. For example, chemotherapy causes an anorexic response.” She continued, “Understanding this gut-brain axis and how this is regulating appetite provides us [with] a means where we can go in and manipulate the gut-brain circuitry to perhaps inhibit the anorexic response in these patient populations.”

In addition, the research also may offer an alternative avenue when it comes to the treatment of infectious disease, one that uses nutritional intervention rather than antibiotics. With more than two million individuals infected each year by strains of bacteria that have managed to develop resistance to antibiotics, an alternative treatment option could really be a game changer in the fight against antibiotic resistance.

Editor’s Note: Read more about how bacteria creatively manipulate their hosts here.