Gut microbiome diversity protects against harmful pathogens through nutrient competition, latest research suggests

19 Feb 2024 --- Diverse communities of resident bacteria can protect the human gut from harmful pathogens by consuming nutrients that these disease-causing microorganisms need, suggest researchers at the University of Oxford, UK. They note that their findings could help develop new strategies to optimize gut health, though more research is required.

In their study, the authors note that colonization resistance is a collective property of microbiome communities — meaning that a single strain is only protective when combined with others. They determined that protective bacterial communities block pathogen growth through nutrient blocking — consuming the same nutrients the pathogen needs.

Nutrition Insight discusses the research with co-first author Frances Spragge from the Departments of Biology and Biochemistry at the University of Oxford. 

“We directly show for the first time that microbiome diversity in the mammalian gut is protective against harmful pathogens — previous studies have highlighted the association between diversity and health, but here we show the mechanistic basis.” 

“We show that, based on this mechanism, we can predict which communities will be protective,” highlights Spragge. “We would like to explore whether our predictions hold for other non-Enterobacteriaceae pathogens. This is something we are beginning to work on in the lab.”  

Targeted nutrition and probiotics 
Spragge adds that the research provides a potential basis for designing probiotic communities against a target pathogen using bacterial genomes. 

“By modifying the microbiome, these communities would help prevent infections and reduce the need for antibiotics. However, while our results from test tube experiments and in mice are promising, these ideas have not yet been applied to a clinical setting.”

“We envisage that it may be possible to create supplements for people containing gut bacteria that help to prevent pathogen growth. Another interesting consideration is diet, as our work suggests a link between gut nutrients and colonization resistance, which suggests that diet may be an important factor in disease risk, but more work is needed.” 

However, she cautions that these ideas have yet to be applied to a clinical setting, so it is too early to say. The researchers view this as an exciting area for future work.  

Decoding colonization resistance  
The study, published in Science, aims to understand better how the gut microbiome protects the gut against invading pathogens and whether certain bacterial species have a more important role than others. 

“The human gut microbiome is integral to our health, but it is highly complex and therefore can be challenging to study,” details Spragge. She adds that the team used a bottom-up approach to decode colonization resistance. 

The team tested 100 human gut symbionts — bacteria strains — individually and in combinations to determine their ability to limit the growth of two harmful bacterial pathogens — Klebsiella pneumoniae and Salmonella enterica. To assess pathogen growth, the team created luminescent strains of these organisms. 

“We combined human gut bacteria into many different synthetic communities of varying diversity and composition and challenged them with pathogens,” adds Spragge. “This allowed us to work out the general principles of colonization resistance that held for all the protective communities.” 

The research provides a potential basis for designing probiotic communities against a target pathogen using bacterial genomes.While even the “best-performing species” provided limited protection against pathogens, the researchers found that when they combined them into diverse communities of up to 50 species, pathogen growth was “greatly limited.”  

Co-author Kevin Foster explains: “These results demonstrate that colonization resistance is a collective property of microbiome communities — in other words, a single strain is protective only when combined with others.” 

Spragge adds: “We carried out all experiments on two important pathogen species in parallel and obtained similar results with both species, which helped to validate our approach and strengthen the study’s conclusions.”

The researchers observed the same results when germ-free mice were colonized with a subset of these communities and challenged with a pathogen. 

Nutrient blocking 
The research notes that ecological diversity is crucial for colonization resistance but also highlights that community composition is essential. 

According to the authors: “Both in vitro and in vivo, we found that colonization resistance rested upon certain species being present, even though these species offer little protection on their own.” 

They suggest that nutrient blocking is key in this process, emphasizing that the “overlap in nutrient-utilization profiles between the community and the pathogen is key.” 

Through genome analysis, the researchers found that the most protective communities comprised species with highly similar protein compositions to the pathogens. 

“Although increased microbiome diversity increases the probability of protection against these pathogens, the overlap in nutrient utilization profiles between the community and the pathogen is essential. Certain species with a crucial role in community protection show a high degree of metabolic overlap with the pathogen, and therefore similar nutrient demands,” explains Spragge.

Spragge hopes the study will inspire others to research the gut microbiome further, to better understand its impact on human health.Using this nutrient blocking principle, the researchers predicted bacteria communities offering weak and robust protection against a new pathogen — an antimicrobial-resistant E. coli strain. In experimental testing, the communities with the highest nutrient overlap with this strain were up to 100-fold more effective at reducing the pathogen’s abundance than those predicted to give weak protection. 

Inspiring future research  
Spragge hopes the study will inspire others to research the gut microbiome further — its importance to human health is “only beginning to be appreciated.” 

“It has been known for decades that a major benefit of the microbiome is its ability to protect us against harmful, pathogenic bacteria. Many mechanisms have previously been proposed to explain how the microbiome confers this protection, known as colonization resistance, but here we show that the key mechanism is competition  over nutrients.” 

“I would also like to see the study promote the cause of antibiotic stewardship as we become more aware of the negative, unintended consequences of taking antibiotics for our microbiomes and, therefore, our health. Many pathogens are developing antibiotic resistance, and stewardship of antibiotics is a crucial part of addressing this problem.” 

She hopes the research can provide a basis for developing targeted probiotic communities against harmful microbes. “These would also be important in the fight against antibiotic resistance as we search for alternatives to antibiotics.” 

Meanwhile, scientists developed a new tool to match microbes to the metabolites they produce, in an effort to support new research to better understand the functional roles of microbiomes across ecosystems. 

By Jolanda van Hal