In today’s world, infectious diseases continue to pose a major threat to public health. The Global Burden of Disease study estimated that in 2019, approximately 25% of all deaths worldwide were due to infections. This staggering statistic highlights the critical need for new strategies to prevent and manage severe infections.

Emerging evidence suggests that the key to reducing susceptibility to infections may lie within the trillions of microbes that inhabit our gut – the gut microbiome. In two large-scale population studies recently published in The Lancet Microbe, researchers found that the composition of an individual’s gut bacteria was closely tied to their risk of being hospitalized for an infectious disease.

The studies, led by a team at Amsterdam UMC in the Netherlands, analyzed the gut microbiomes of over 10,000 participants from two independent cohorts – one in the Netherlands and one in Finland. The researchers then followed these participants for 5-7 years, tracking who was hospitalized or died due to an infectious disease during that time.

Their findings were striking. Participants with higher relative abundances of certain gut bacteria, specifically those that produce the short-chain fatty acid butyrate, had a significantly reduced risk of severe infections requiring hospitalization. This protective effect held true even after accounting for factors like age, ethnicity, lifestyle, antibiotic use, and underlying health conditions.

“This is the largest study to date examining the relationship between the gut microbiome and susceptibility to infections in the general population,” said corresponding author Dr. W. Joost Wiersinga of Amsterdam UMC. “And the fact that we were able to replicate our findings across two distinct cohorts from different countries really adds to the strength and generalizability of the results.”

The Gut-Infection Connection

The connection between the gut microbiome and infection risk is not entirely surprising. Researchers have long observed that patients hospitalized with severe infections often display significant disruptions to their gut microbial communities, even before receiving antibiotics or other treatments.

“Patients with infections frequently show loss of beneficial anaerobic bacteria and overgrowth of potentially pathogenic microbes in the gut,” explained Dr. Wiersinga. “But the big question has been whether these microbiome alterations are just a consequence of the infection, or if they actually contribute to increased susceptibility in the first place.”

Animal studies have provided key insights into this question. In mice and other models, disrupting the gut microbiome – for example, by treating with antibiotics – has been shown to blunt immune responses and increase the severity of various viral, bacterial, and fungal infections. Conversely, boosting levels of beneficial anaerobic bacteria like butyrate producers can enhance antimicrobial defenses and protect against systemic infections.

The new population-based studies in humans suggest these same principles apply in the real world. Participants with higher abundances of butyrate-producing bacteria at the start of the study were substantially less likely to be hospitalized for an infectious disease over the following years.

“The protective effects of butyrate-producing bacteria likely stem from their ability to modulate both local gut immunity and systemic inflammatory responses,” said Dr. Teemu Niiranen, a co-author from the University of Turku in Finland. “Butyrate has been shown to stimulate the production of antimicrobial peptides, enhance the gut’s barrier function, and dampen excessive inflammation that can drive tissue damage during infections.”

A Microbial Signature of Infection Risk

Beyond just the abundance of butyrate producers, the new studies also revealed distinct microbial signatures associated with increased infection susceptibility. Participants who were later hospitalized for infections had higher relative levels of certain bacteria like Veillonella, which can act as opportunistic pathogens, as well as lower levels of strict anaerobic genera like Butyrivibrio.

“The fact that we saw these same microbial differences between outcome groups in both the Dutch and Finnish cohorts is really striking,” noted Dr. Niiranen. “It suggests there may be a core gut microbiome profile that predisposes individuals to severe infections, regardless of geography or other factors.”

Interestingly, the researchers were able to leverage these microbial signatures to develop a personalized risk score for infection-related hospitalizations. When applied to the Finnish cohort, participants deemed high-risk based on their gut bacteria at baseline had a 39% increased likelihood of being hospitalized for an infection compared to low-risk individuals.

“This highlights the potential for using the gut microbiome as a predictive biomarker to identify people at elevated risk of serious infections,” said Dr. Rob Knight, a microbiome expert at the University of California San Diego who was involved in the study. “With further validation, a microbiome-based risk assessment could help target prevention strategies to the individuals who need them most.”

Rethinking Antibiotic Use

The new findings also raise important questions about the widespread use of antibiotics and its potential impact on infection susceptibility. Antibiotics are known to disrupt the gut microbiome, often leading to a depletion of beneficial anaerobic bacteria like butyrate producers.

Previous research by the Amsterdam UMC team and others has shown that loss of these anaerobic gut microbes is associated with increased risk of infections in high-risk patient populations, such as those recovering from strokes or undergoing stem cell transplants.

“Now we’re seeing that the detrimental effects of microbiome disruption on infection risk may extend to the general population as well,” said Dr. Wiersinga. “This really underscores the need to reevaluate our use of antibiotics, particularly those with potent anti-anaerobic activity, and consider the long-term consequences on the gut ecosystem and susceptibility to severe infections.”

In fact, a recent study led by Dr. Wiersinga’s team found that administering broad-spectrum antibiotics to critically ill patients in the emergency department was associated with worse clinical outcomes, including increased risk of mortality. Such findings add to the growing body of evidence highlighting the unintended harms of indiscriminate antibiotic use.

The Road Ahead

While the new studies provide compelling evidence linking the gut microbiome to infection risk, the researchers are quick to note that more work is needed to establish causality and translate these findings into clinical practice.

“Our observational data show a clear association, but we can’t say for certain whether the microbiome changes are truly driving increased infection susceptibility or just acting as a marker of underlying dysregulation,” cautioned Dr. Wiersinga. “Interventional studies that deliberately manipulate the gut microbiome will be crucial to determine if modulating these microbial communities can actually reduce the burden of severe infections.”

Several research groups are already exploring potential microbiome-based therapies, such as administering beneficial bacteria or targeted delivery of metabolites like butyrate. If proven effective, such approaches could represent a paradigm shift in how we think about infection prevention and management.

“Ultimately, our goal is to harness the power of the gut microbiome to bolster the body’s natural defenses against pathogens,” said Dr. Knight. “By understanding the complex interplay between our microbial inhabitants and the immune system, we may be able to develop innovative ways to enhance resistance to severe infections and improve public health outcomes.”

With infectious diseases continuing to pose a major global threat, the findings from these large population studies offer new hope. The gut microbiome may hold the key to unlocking more effective strategies for infection prevention – a prospect that could have far-reaching implications for human health worldwide.

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GUT HEALTH | INFECTIOUS DISEASES | MEDICINE | PREVENTION | PUBLIC HEALTH