Trillions of microbes live in the human gastrointestinal tract, where they play critical roles in our health and biology; they can help us break down food, absorb nutrients; and they affect the immune system and other aspects of our health. Researchers are learning more about the many bioactive compounds that microbes modify and create, and how they impact human health.
Scientists are also studying how the immune system deals with this microbiome, and learns to tolerate it. The human body has to sequester the gut microbiome, and the gut lining or epithelium is a crucial barrier; humans also make molecules like antibodies, proteins, and mucus that can control gut microbes and reduce the chance of infection by pathogens.
Research has now shown that the immune system is so attuned to the gut microbiome, it can interact with certain gut microbes in specific ways. This work was conducted in a mouse model, but likely applies to the human microbiome as well.
In this study, which was reported in Nature, the investigators analyzed the proteins in portions of the gut epithelium from mice that did not carry any gut microbiome, so-called germ-free mice. The proteins from these cells were compared to the proteins from the same cells, but from regular mice. In mice with normal gut microbiomes, there were much higher levels of a protein called APOL9 compared to germ-free mice. This protein is generated primarily by gut epithelial cells.
Next, the investigators looked for the bacteria that could bind to APOL9. This work, which used an advanced type of cell-sorting, showed that both APOL9 and the human version: APOL2, attaches very tightly and specifically to a type of gut bacteria known as Bacteroidales, which are common gut microbes.
APOL9 was found to identify the bacteria using a certain type of fat on the surface of Bacteroides, called ceramide-1-phosphate (Cer1P). When Cer1P was no longer present (on specially engineered bacteria), APOL9 was unable to attach to the bacteria. This work may be the first to reveal that specific microbes can be targeted by host cells theough the bacterial cell's lipid signatures.
APOL9 also does not harm bacteria once attached. Instead, the bacteria releases little sacs that are they taken up by the immune system; they contain bacterial molecules called OMVs that appear to boost the immune system. The researchers found that they enhance certain immune signals and immune readiness. This also leads to a more balanced gut microbiome.
In a mouse model, the removal of APOL9 weakened the immune response against a Salmonella infection, and the infection was more widespread. But when the researchers added bacterial OMV molecules like those found in the sacs, the immune response in the mice became more robust.
"The specific interaction between APOL9 and Cer1P highlights a finely tuned molecular dialogue forged through long-term coevolution between the host and its microbiota. In the future, we plan to explore the role of human APOL2 and investigate whether modulating this pathway can strengthen the intestinal immune barrier," said senior study author Professor Youcun Qian of the Chinese Academy of Sciences, among other appointments.
Sources: Chinese Academy of Sciences, Nature