To thwart pathogens, researchers are giving beneficial microbes what they really want
UC San Diego researchers have developed a new method that allows precise modification of any microbiome with prebiotics, helping beneficial organisms outcompete dangerous pathogens
University of California San Diego researchers have developed a new tool for understanding and modifying any microbiome, including the human microbiome. The approach, called Microbial Interaction and Niche Determination (MIND), accurately predicts how microbes compete within complex communities and identifies their specific nutrient preferences. The findings, published on April 17 in Cell, have the potential to accelerate the translation of microbiome science from the lab to the clinic, paving the way for highly targeted microbiome therapies, for example, as an alternative to traditional antibiotics.
Until now, establishing a causal link between a specific microbe and certain disease has remained elusive, hampering the development of microbiome-based therapies. Microbiome science has traditionally resembled a census: researchers could observe which bacteria were present in the gut or other environments, but they lacked the means to predict how they interact or change the abundance of specific microbes.
“ Microbiome research in general has been very descriptive and we were not able to manipulate microbiomes because we did not understand how they're assembled, how they're maintained and the dynamics within them,” said senior author Karsten Zengler, PhD, professor of pediatrics at UC San Diego School of Medicine, adjunct professor of bioengineering at the Shu Chien-Gene Lay Department of Bioengineering and a member of the Center for Microbiome Innovation at Jacobs School of Engineering.
The MIND approach shifts the field from simply describing microbiomes to actively and precisely controlling them. According to Zengler, controlling a microbiome requires knowing what the bacteria want and which other microbes they are competing against to get it.
MIND deciphers this by analyzing how microbes allocate their finite resources to translating messenger RNA (mRNA) into functional proteins, a cell’s most energy-intensive process. By measuring which specific proteins a microbe is actively making at any given time using a technique called ribosome profiling, the tool reveals which exact nutrients it prefers and how it allocates its energy.
If two different types of bacteria prefer the same nutrients, MIND flags them as competitors.
By applying this approach to thousands of microbes, the researchers can map out complex competitive interactions and predict how communities will respond when species are added or removed.
Armed with this interaction map, the researchers tested these predictions by introducing specific nutrients (prebiotics) like sugars and amino acids to selectively feed and boost certain microbes, allowing them to outcompete others and reshape the microbial community in several environments:
Synthetic Microbial Communities: In a 16-member microbial community, MIND accurately predicted competitive interactions and identified which specific microbes would benefit from the addition of particular substrates.
Soil Microbiomes: MIND accurately predicted which nutrients would boost beneficial bacteria and naturally crowd out their competitors.
Human Microbiomes: The tool identified the preferred nutrients of beneficial infant gut bacteria like Bifidobacterium, guiding precise prebiotic (nutrients like sugars and amino acids) and probiotic (microbe) interventions that selectively promoted target bacteria while suppressing competitors.
Live Mouse Model: MIND predicted that a beneficial gut bacterium, Faecalibaculum rodentium, would thrive in the presence of lactose. Supplementing mice with lactose selectively enriched this bacterium, demonstrating that the method works safely and precisely in a living animal.
“ Showing that we can do this not only in a flask, but also in a living organism was astonishing,” said Zengler. He believes the findings have major implications for treating infectious diseases by enabling rapid, cost-effective and precise prebiotic interventions.
For example, many healthy adults naturally carry potentially dangerous bacteria like Clostridioides difficile or Staphylococcus aureus without ever getting sick because beneficial microbes keep them in check. Using MIND to identify these natural competitors could allow clinicians to administer prebiotics that lower pathogen levels just enough to prevent an infection. This offers an additional approach beyond the use of broad-spectrum antibiotics, which can also destroy beneficial bacteria and drive antibiotic resistance.
“The benefit of this approach is that you take advantage of competitive interactions between bacteria that have evolved over millions of years, so there's likely no resistance popping up with this,” said Zengler.
He notes that selectively feeding prebiotics to beneficial bacteria is often superior to introducing live probiotic bacteria, because many strains cannot be successfully stabilized or mass-produced, and frequently fail to integrate into existing microbiome communities.
And because MIND relies on manipulating naturally occurring microbes rather than developing new drugs, these therapies would be more cost-effective, face fewer regulatory hurdles and could reach the clinic more quickly.
“Right now, we have small clinical safety trials going on where people take specific nutrients we identified as prebiotics to prevent dysbiosis, an imbalance in the microbiome caused by pathogenic bacteria,” Zengler said.
Beyond human health, the MIND approach has a multitude of other applications, including fighting climate change by promoting microbes that enhance carbon storage in soil and improving pathogen resilience in plants.
“ This really opens up many possibilities in microbiome research,” said Zengler, who is also faculty director of the Soil Center at UC San Diego Scripps Institution of Oceanography. “Instead of just describing how important the microbiome is, we can actively tinker with microbiome composition for improved outcomes.”
Additional co-authors on the study include: Oriane Moyne, Grant J. Norton, Mahmoud Al-Bassam, Chloe Lieng, Deepan Thiruppathy, Manish Kumar, Eli Haddad, Yuhan Weng, Manuela Raffatellu and Livia S. Zaramela, all at UC San Diego.
The study was funded, in part, by U.S. Department of Energy (awards DE-SC0021234, DE-SC0022137 and DE-AC02-480 05CH11231), the UC San Diego (UCSD) Center for Microbiome Innovation, the UC San Diego Larsson-Rosenquist Foundation Mother-Milk-Infant Center of Research Excellence and the National Institutes of Health (T32 DK007202, 485 F31AI186410-01 and R21AI186034).
Moyne, Al-Bassam and Zengler are inventors on a related patent application. The authors declare no other competing interests.
Journal
Cell
Method of Research
Experimental study
Article Publication Date
17-Apr-2026
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