New long COVID study suggests tiny packets released by gut bacteria may help drive gut problems, immune activation, and brain-related symptoms in some people with long COVID.
This study focused on extracellular vesicles. In simple terms, these are tiny packages released by bacteria and other cells. They can carry different materials and may send signals from the gut to other parts of the body.
The team used stool samples from 103 people: 12 pandemic controls and 91 people with long COVID. Samples were taken 3 to 6 months and or 12 months after infection.
They grouped people by neurological symptom burden. This included brain fog, memory and concentration issues, but also sleep problems, anxiety, depression, and post-exertional malaise.
First, they checked whether the gut microbiome differed between long COVID and controls. It did. And among people with long COVID, those with more neurological symptoms also had different gut bacteria patterns.
An important point: this was not just a simple case of “lower diversity = worse.” In some women with worse neurological symptoms, diversity was actually higher. So the issue may be which microbes are present, not just how many.
Next, they transplanted gut microbes from long COVID donors into germ-free mice. Mice given microbes from donors with neurological symptoms showed more signs of gut barrier damage and more immune cell activation in the brain.
The behavior changes in those mice were less clear than the tissue findings. The gut and brain inflammation signals looked stronger than the movement and behavior results.
Then the researchers isolated the bacterial vesicles themselves from human stool and tested them directly. This matters because they were no longer testing the whole microbiome, just the tiny packets released by it.
In human gut cell models, vesicles from long COVID samples increased inflammatory signals. In a standard gut barrier model, vesicles from the neurological symptom group weakened the barrier the most.
A weaker gut barrier means the lining of the gut may become more “leaky,” so unwanted bacterial products can pass through more easily and may increase immune activity.
In immune cells called macrophages, long COVID vesicles also increased inflammatory signals. The strongest effects usually came from vesicles from people with neurological symptoms.
The researchers also tested the vesicles on human microglia, which are immune cells in the brain. Long COVID vesicles pushed these cells toward an inflammatory state.
They found big shifts in gene activity in the microglia, including pathways linked to immune signaling, inflammation, cell movement, and responses seen in infection.
One repeated signal across the study was BAFF, an immune molecule linked to B cell activity and chronic immune stimulation. It showed up in gut cells, immune cells, brain immune cells, colon tissue, and blood in mice.
That does not prove BAFF is the key driver. The study did not block BAFF to show that the problem goes away. So BAFF may be a useful clue, but it is not proven as the main cause.
The team then gave purified bacterial vesicles by mouth to normal mice for 6 weeks. Even without transferring the full microbiome, the vesicles alone were enough to produce several concerning changes.
Those mice showed signs of gut barrier damage, higher blood markers linked to bacterial leakage and immune activation, and more activation of astrocytes and microglia in the brain.
Astrocytes and microglia are support and immune cells in the brain. When they become overactive, that may be a sign of brain inflammation or stress.
The vesicle-treated mice also showed behavior changes, especially increased movement. But the memory and anxiety-style tests were less definitive, so those parts should be interpreted carefully.
Another interesting finding was that long COVID vesicles also changed the gut microbiome of the mice. So these vesicles may not just come from dysbiosis. They may also help keep it going.
Overall, this study suggests a possible chain: COVID may alter gut bacteria, those bacteria may release harmful vesicles, the vesicles may weaken the gut barrier and activate the immune system, and that may then affect the brain.
This is a strong mechanistic study, but it is still a preprint, so it has not yet been peer reviewed. It also does not prove this happens in every person with long COVID, or identify the exact bacterial cargo responsible.
So the main takeaway is not that this paper proves the full cause of long COVID. It suggests a credible gut-brain pathway that may help explain symptoms in at least a subgroup of patients.
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