Why do some people develop a fever after a vaccination while others barely notice they've had one? Why do our immune systems sometimes react very differently to what appears to be the same challenge?

We usually think of these differences in terms of genetics, age or general health. But an intriguing new study published in Science suggests that part of the explanation may lie in the trillions of microorganisms living inside our intestines.

Researchers discovered that certain gut bacteria produce molecules capable of influencing how strongly the immune system responds to vaccination. The findings raise a fascinating possibility: our gut microbiome may help establish the baseline sensitivity of our immune system, influencing how readily it responds to a potential threat.

This doesn't mean that particular bacteria are necessarily weakening or strengthening immunity. Rather, it suggests that the microbial environment inside our intestines may help determine how our immune system is regulated.

Your Gut Is One of Your Most Important Immune Organs

Although we often associate the immune system with white blood cells circulating through the bloodstream, a substantial amount of immune activity takes place within the gastrointestinal tract.

This makes perfect sense when you consider what the intestines are exposed to. Every day, the gut encounters food components, environmental substances and enormous numbers of microorganisms. Some are harmless, some are beneficial, and others have the potential to cause disease.

The immune system must therefore perform a remarkable balancing act. It needs to tolerate ordinary dietary components and the microorganisms that normally live alongside us, while remaining capable of recognising and responding to genuine threats.

Much of this activity takes place within the gut-associated lymphoid tissue, or GALT, which contains specialised immune cells involved in monitoring the intestinal environment.

The intestinal lining also plays an important role. Epithelial cells form a physical barrier between the contents of the gut and the tissues beneath it, while mucus, antimicrobial compounds and immune molecules help regulate interactions with intestinal microorganisms.

These defences are not simply designed to eliminate bacteria. They help maintain a controlled relationship between the immune system and the microbial community.

Importantly, that relationship involves constant biochemical communication.

How Gut Bacteria Communicate With Immune Cells

Our immune cells possess specialised receptors capable of recognising molecular structures associated with microorganisms. These are known as pattern-recognition receptors, and one particularly important family is the Toll-like receptors, or TLRs.

Different Toll-like receptors recognise different microbial components. For example, TLR4 can recognise certain forms of bacterial lipopolysaccharide, while TLR5 recognises flagellin, a protein used to construct the whip-like structures that allow many bacteria to move.

When these receptors detect microbial molecules, they can activate intracellular signalling pathways that influence inflammatory responses.

One important pathway involves the transcription factor NF-κB, which helps regulate the expression of genes involved in immune activation. Depending on the cell and surrounding environment, these signals can contribute to the production of inflammatory cytokines such as interleukin-6 and tumour necrosis factor-alpha.

These signalling systems are essential for defending the body against infection. However, their activity must be carefully regulated. An immune response that is too weak may fail to control a pathogen, while excessive or persistent activation can contribute to tissue damage and chronic inflammation.

The intestinal microbiome exists in close proximity to these signalling systems, meaning that the molecules produced by gut bacteria may influence the immune environment even when no obvious infection is present.

The Fascinating New Research on Fever

The new Science study investigated 171 healthy adults receiving mRNA vaccines against SARS-CoV-2.

Researchers collected stool samples, measured immune markers and monitored participants' temperatures before and after vaccination. They wanted to understand why some individuals developed stronger fever responses than others.

Interestingly, people who subsequently experienced greater fever responses tended to have differences in their intestinal microbiomes before vaccination.

In particular, the researchers identified increased activity of genes involved in bacterial movement, including those responsible for producing flagellin. Certain bacteria belonging to the Lachnospiraceae family were associated with this pattern.

Participants with stronger fever responses also showed evidence of greater low-grade intestinal inflammation before receiving their vaccines.

This suggested that the microbiome might be influencing the immune system's baseline inflammatory state, potentially affecting how strongly it responded to vaccination.

But the researchers went further than simply identifying an association.

They transferred intestinal microbial communities from human participants into mice raised without their own microbiomes. Animals receiving microbiomes from people who had experienced stronger fever responses developed more pronounced inflammatory reactions following vaccination.

Importantly, this effect was partly dependent upon the animals' ability to recognise bacterial flagellin, providing experimental evidence that microbial signalling through pathways involving TLR5 contributed to the response.

The researchers also used human intestinal organoids, laboratory-grown structures that reproduce some features of intestinal tissue, to investigate how these microbial communities influenced inflammatory activity.

Together, the findings suggest that the intestinal microbiome can contribute to the immune environment in which a subsequent inflammatory challenge occurs.

There is an important distinction here. A stronger fever does not necessarily mean better protection against infection, just as a milder fever does not mean that vaccination has failed. Fever is one manifestation of immune activation, not a reliable measurement of overall immune competence.

The Other Side of the Conversation: How Bacteria Help Regulate Inflammation

Microbial influences on immunity are not exclusively inflammatory. Some bacterial metabolites can also participate in pathways involved in immune regulation and the maintenance of intestinal barrier function.

A particularly interesting group of compounds are the short-chain fatty acids, including acetate, propionate and butyrate.

These are produced when intestinal microorganisms ferment certain dietary fibres and other carbohydrates that escape digestion in the small intestine.

Butyrate provides an important energy source for cells lining the colon and can influence intestinal barrier function. Short-chain fatty acids can also interact with receptors such as FFAR2 and FFAR3 and influence the activity of histone deacetylases, enzymes involved in regulating gene expression.

Through these mechanisms, they can affect immune-cell differentiation, inflammatory signalling and the activity of regulatory T cells.

Regulatory T cells are especially interesting because they help prevent inappropriate immune responses and maintain tolerance towards harmless substances.

This illustrates an important principle: the microbiome is not simply turning inflammation up or down. Different microbial compounds interact with different pathways, potentially influencing how the immune system responds to particular circumstances.

The effects are also context-dependent. A signalling molecule that contributes to normal immune defence under one set of conditions may have different consequences when the intestinal barrier is disrupted or inflammatory disease is already present.

Can Diet Influence Our Immune Sensitivity Through the Microbiome?

This is where nutritional medicine becomes particularly interesting.

Diet helps shape the intestinal microbial environment, influencing which organisms thrive and which metabolic compounds they produce.

In the new vaccination study, researchers observed associations between self-reported dietary patterns and microbiome characteristics linked to fever responses. Experimental dietary changes also influenced microbial flagellin activity and vaccine-related inflammatory responses in mice.

However, these findings do not establish that changing someone's diet will reduce vaccine-related fever in humans. That question requires controlled dietary intervention studies.

We do have human evidence showing that diet can influence aspects of the microbiome–immune relationship.

In a study published in Cell in 2021, researchers compared the effects of a diet rich in fermented foods with a diet containing increased quantities of plant-derived fibre.

Thirty-six healthy adults completed the study, with eighteen participants in each group.

The fermented-food group experienced an increase in microbial diversity alongside reductions in several measured inflammatory markers.

The higher-fibre group showed changes in microbial metabolic capacity, but immune responses varied considerably between individuals, and the study's primary immune outcome did not significantly improve.

This is a particularly useful finding because it demonstrates that changing the diet can influence microbial activity without producing an identical immune response in everyone.

It also reminds us that microbial diversity, although frequently discussed as a marker of gut health, is not a complete measure of microbial function or immune health.

The study was relatively small, and changes in inflammatory markers cannot automatically be interpreted as reductions in infections, autoimmune disease or other clinical outcomes.

Nevertheless, it provides an intriguing example of how dietary interventions may influence the relationship between intestinal microorganisms and immune regulation.

What Does This Mean for Everyday Nutrition?

We are not yet at the point where microbiome testing can reliably tell someone how reactive their immune system is, or where particular probiotics can be recommended to adjust immune sensitivity in otherwise healthy individuals.

However, the research supports the broader value of maintaining a varied, nutritionally adequate diet that provides substrates for microbial metabolism.

Vegetables, fruits, legumes, whole grains, nuts and seeds supply different types of dietary fibre and plant compounds that interact with the intestinal microbial community.

Fermented foods such as live yoghurt, kefir, sauerkraut and kimchi may also contribute microorganisms and fermentation products, although their effects differ between products and individuals.

Rather than attempting to stimulate or suppress the immune system indiscriminately, a more useful goal is to support normal immune regulation through good overall nutrition, appropriate sleep, physical activity and the management of underlying health conditions.

For people with inflammatory or immune-mediated diseases, nutritional strategies need to be considered in the context of their individual condition and treatment.

The Bigger Picture

One of the most fascinating aspects of this research is that our immune system may be responding to microbial signals long before we encounter an infection or receive a vaccination.

The bacteria living inside our intestines are continually producing compounds that interact with the intestinal barrier, immune cells and signalling pathways involved in inflammation.

Some of these interactions help maintain tolerance and regulate immune activity. Others may influence how readily inflammatory responses are triggered.

The new research suggests that differences in microbial flagellin production may help explain why individuals experience different inflammatory reactions to the same immune challenge.

There is still much to learn about how these mechanisms operate in everyday human health and whether dietary interventions can reliably modify them.

But the emerging picture is fascinating: our immune system isn't simply responding to the outside world. It is also being influenced by the microbial world living inside us.

References

Huus, K.E. et al. (2026) ‘The human gut microbiome primes fever after vaccination’, Science, 394(6820), eaea7733. https://doi.org/10.1126/science.aea7733

Mann, E.R., Lam, Y.K. and Uhlig, H.H. (2024) ‘Short-chain fatty acids: linking diet, the microbiome and immunity’, Nature Reviews Immunology, 24, pp. 577–595. https://doi.org/10.1038/s41577-024-01014-8

Mukhopadhya, I. and Louis, P. (2025) ‘Gut microbiota-derived short-chain fatty acids and their role in human health and disease’, Nature Reviews Microbiology, 23, pp. 635–651. https://doi.org/10.1038/s41579-025-01183-w

Wastyk, H.C. et al. (2021) ‘Gut-microbiota-targeted diets modulate human immune status’, Cell, 184(16), pp. 4137–4153.e14. https://doi.org/10.1016/j.cell.2021.06.019