Illustration of several SARS-CoV-2 virus particles in blue on a red background
Credit: phonlamaiphoto / Adobe Stock

Gut bacteria may influence the degree of immunity conferred by COVID-19 vaccines, Japanese researchers have discovered.

Microbes in the digestive tract that broke down the sugar fucose led to a reduced T-cell response to the Pfizer mRNA vaccine BNT162b2, the team reports in the journal Communications Biology.

Further investigation indicated that these gut microbes may impact the immune system through the genes that encode AP-1 transcription factors.

“Not everyone who gets the same vaccine receives an equal level of protection, but we still don’t really understand why people respond so differently,” said senior researcher Hiroki Ishikawa, PhD, who heads the Immune Signal Unit of Okinawa Institute of Science and Technology.

“If we can get to the bottom of what causes this variation, we could predict how an individual might respond to a vaccine, and perhaps find new strategies to promote the immune response.”

The team used a systems biology approach based on multiomics analyses of blood and stool samples in 96 healthy individuals.

Results from the 95 participants who received two doses of the Pfizer vaccine BNT162b2 at a three- to four-week interval were analyzed, with one participant excluded who did not receive a second dose due to severe side effects after the first.

The researchers note that the vaccine induces a remarkable increase in the expression of genes relating to innate immunity one day after the first dose and one to seven days after the second dose.

They therefore collected blood samples at multiple time points, analyzing baseline responses before vaccination and innate immune responses on the second day after the first and second vaccine doses and also on day eight after the second dose.

Long-term adaptive immune responses were also assessed on day 41 after the second dose.

In addition, the team collected stool samples from all participants once during the study to investigate their gut microbiomes.

Results showed that vaccine-induced adaptive immune responses were associated with specific immune and gut microbial parameters.

Baseline expression of the AP-1 genes FOSFOSB, and ATF3 and the gut microbial fucose/rhamnose degradation pathway were both inversely correlated with vaccine-induced T-cell responses.

Furthermore, the gut microbial fucose/rhamnose degradation pathway positively correlated with mRNA expression of AP-1, as well as a gene encoding an enzyme producing prostaglandin E2 (PGE2), which promotes AP-1 expression.

“The mechanism is not yet proven, but we propose that fucose digestion leads to increased baseline expression of FOS and ATF3 in blood immune cells, which in turn weakens the response to the COVID-19 vaccine,” said Masato Hirota, first author and PhD student also at the Immune Signal Unit of Okinawa Institute of Science and Technology.

“It’s clear that the gut bacteria have an important impact on the overall health of the immune system.”

Also of Interest