Gut bacteria may contribute to long-term cognitive dysfunction in septic patients

 

Critically ill patients who survive and make a recovery are often left with long term cognitive deficits, causing them to struggle with day to day activities. Between one and two thirds of critical illness survivors develop some form of cognitive impairment, highlighting the need for a greater understanding of the causes of this deficit and any therapies that could be implemented to prevent it.

Sepsis is systemic inflammation, caused if an infection is able to rapidly spread throughout the body, due to a weakened immune system for example. The immune system can go into overdrive, leading to widespread inflammation that damages tissues and affects blood flow. This interference can cause the patient to become dangerously hypotensive, reducing blood flow to organs, eventually leading to septic shock and death if left untreated. 

Many patients who survive sepsis will have some form of cognitive dysfunction, sometimes for the rest of their life. It is known that sepsis causes neuroinflammation, however, there is uncertainty as to whether this is triggered by a persistent infection in the brain itself or if circulating inflammatory mediators are to blame.

A recent study published in The American Journal of Respiratory and Critical Care Medicine from the University of Michigan has investigated a potential link between gut bacteria and cognitive impairment following sepsis. "We already know from previous studies that sepsis results in long-term brain dysfunction and that neuroinflammation plays a role in brain injury during the infection," says Benjamin Singer, lead author of a study and a specialist in pulmonary disease and critical care medicine, "but we hypothesised that the brain injury is directly related to gut bacteria independently moving to the brain and perhaps triggering an immune response that leads to longer-term effects from the injury."

Singer and colleagues noted that previous research has suggested that gut microbes can increase the probability of lung inflammation during sepsis, although other organs, such as the brain, were yet to be studied. The team induced sepsis in a group of mice through cecum ligation and puncture, comparing the survivors to a sham and control group. Human brain tissue, from the University of Michigan Brain Bank, from patients who died of sepsis was compared with those who died from non-infectious causes. They then used 16S rRNA gene sequencing to identify the species of bacteria in the brain samples. This technique works by sequencing the hypervariable regions of  the16S rRNA component of the ribosome, each of which are distinct enough between bacteria that individual species can be identified.

"We can take a sample and isolate the DNA from it and sequence the 16S rRNA gene. Then we can compare the sequences of those genes to a database of known bacteria and identify many more bacteria in the tissue, instead of relying on what grows in a culture." Singer said.

 

 

We found that the bacteria we isolated from patients that died of sepsis were quite different from the run-of-the-mill bacteria that sit in the body after a person dies ? and did appear to be associated with neuroinflammation in the brain."

Benjamin Singer

They found gut bacteria present in the brains of mice 5 days after they survived sepsis, with the bacteria gone by day 14, and increased levels of the neuroinflammatory marker S100A8. These results were mirrored by the human samples, with elevated S100A8 found in the brain of deceased septic patients and the discovery of a distinct bacterial population, suggesting that gut bacteria migrate to the brain in sepsis.

"Anytime someone dies, bacteria grow out of control because the immune system is not keeping the bacteria in the body in check," Singer says, "but we found that the bacteria we isolated from patients that died of sepsis were quite different from the run-of-the-mill bacteria that sit in the body after a person dies ? and did appear to be associated with neuroinflammation in the brain."

The study concluded that translocation of gut bacteria to the brain during sepsis resulted in acute neuroinflammation, however this did not result in chronic cerebral infection, suggesting that the bacteria play a role in acute brain dysfunction during sepsis.

"The larger question raised by this study is ‘is there anything we can do to intervene and change the consequences of critical illness for survivors?’" Singer says. "Results… suggest that one, there are bacteria that are directly involved in organ injury, and two, the bacteria that have disseminated to different organs during sepsis are not always the bacteria that the clinical laboratory identifies in the blood culture and that are the target of your antibiotic treatment.”

This research, although in its early stages, might mean that giving septic patients oral antibiotics to control gut bacteria could have a positive impact on outcomes. Further studies are needed to ascertain if these principles can be effectively applied in clinical practice.

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