Gut flora may play an important role in protecting against sepsis through their influence on blood levels of certain antibodies.

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Sepsis is often caused by bacterial infections and affects the blood.

This was the conclusion that researchers at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia reached after exploring gut flora, immunoglobulin A (IgA) antibodies, and sepsis in mice.

They found that blood levels of IgA rose when mice were exposed to a particular variety of gut flora that included microbes from the Proteobacteria division.

In a paper due to be published in the journal Cell Host & Microbe, senior study author David Allman — a professor of pathology and laboratory medicine in the Perelman School of Medicine — and his colleagues explain that mice became resistant to sepsis when their guts were particularly rich in Proteobacteria.

Sepsis is a “serious medical condition” that arises when the body’s immune response to infection becomes overwhelming. It is unpredictable and can progress very quickly.

In sepsis, the immune response floods the bloodstream with chemicals that give rise to widespread inflammation that, in turn, cause blood vessels to leak and blood clots to form. This chain of events prevents nourishing blood from reaching organs, resulting in organ damage, and, in severe cases, organ failure.

If not diagnosed and treated promptly, sepsis can lead to shock, widespread organ failure, and death.

Every year, sepsis affects around 30 million people worldwide and causes 6–9 million deaths. It is a leading cause of death in hospitals.

Sepsis results from infections that are caused by a range of microbes, including viruses, fungi, and — more commonly — bacteria. Severe cases often arise from infection that has spread to all parts of the body through the blood.

Infections that lead to sepsis can start in the urinary tract, the lungs, the appendix (and other parts of the abdomen), and the skin. They may also result from medical procedures that can introduce microbes directly into the bloodstream, such as when a tube is inserted into a vein.

Although sepsis can affect anyone, it is more common in the elderly, babies, children, and people with certain illnesses and injuries.

Prof. Allman and colleagues set out to investigate IgA and gut flora because previous research has suggested that they are linked and that IgA may be related to specific types of gut bacteria in mice.

It is also known that sepsis is more common in those with insufficient IgA, and evidence from older studies revealed that bacteria in the blood can quickly trigger immunoglobulin M antibodies, and that surges in immunoglobulin G antibodies triggered by gut flora can arrest bacterial infections.

However, what has not been clear is whether these results are connected. In other words, can gut bacteria influence sepsis risk through their effect on IgA?

The researchers also wondered whether or not blood IgA might help to protect against invading bacteria without triggering inflammation.

Their investigation revealed that certain gut microbes “induce several facets of systemic IgA-mediated immunity.”

Exposing normal mice to a “unique but natural” gut flora that held several Proteobacteria members led to two significant results: it raised levels of T cell-dependent IgA in the blood; and in the bone marrow, it induced “large numbers of IgA-secreting plasma cells.”

Tests on the resulting blood IgA revealed that they were effective against a “restricted collection” of bacteria. They also showed that the mice were able to produce IgA in specific response to “intestinal colonization” of the gut bacterium Helicobacter muridarum.

The team also found that enriching mice’s gut flora with Proteobacteria made them resistant to “polymicrobial sepsis,” and that this resistance was conferred through IgA in the blood.

Finally, they showed that transferring blood without IgA into mice with sepsis led to the deaths of all but one of the animals within 48 hours, whereas sepsis mice that received IgA-enriched blood lived much longer.

Bringing these results together, the study authors conclude that gut flora “overtly influence” blood levels of IgA, “resulting in constitutive protection against bacterial sepsis.”

Prof. Allman explains that the team’s findings are “limited by the fact that the microbiome in every person or animal is unique to some degree,” and that the study was confined to animals in their facility.

He and his colleagues now want to gain a better understanding of the mechanism through which IgA antibodies protect against sepsis, and why certain gut microbes induce the appropriate IgA responses.

In the meantime, they urge caution in applying these very early findings to human disease.

While IgA protected mice in our study, it should not be assumed that IgA could replace standard treatments provided to patients in a clinical setting.”

Prof. David Allman