AI models help redefine the core microbiome for personalized therapies

Researchers from Rutgers University-New Brunswick, together with international collaborators, have introduced a new method for identifying the crucial set of gut microbes that are common in humans and essential for health.

The researchers, whose study was published in Cell, said the discovery offers innovative opportunities for precision nutrition and personalized therapies aimed at managing chronic diseases linked to imbalances in the gut microbiome, including diabetes, inflammatory bowel disease and cancer.

The core microbiome refers to a set of microbes in the digestive tract that play a crucial role in maintaining functions such as digestion, immune defense and mental health. When the core microbiome is reduced or lost, it can lead to a condition known as dysbiosis: an imbalance between beneficial and harmful microbes in the gut. Dysbiosis has been linked to numerous chronic diseases, including inflammatory bowel disease, metabolic disorders, neurological disorders, chronic kidney disease and certain cancers.

Many studies have shown that the transfer of beneficial fecal microbiota from a healthy colon to a diseased colon can alleviate these conditions, strongly suggesting that a core microbiome is crucial for maintaining our health.

The essential structure of the core microbiome – two distinct groups of bacteria, the so-called foundation guild and the pathobiont guild – engage in dynamic and stable interactions that are crucial for supporting human health. Using artificial intelligence models, the ‘two competing guilds’ approach classifies cases from controls from different populations, unaffected by ethnicity, geography or disease types, and predicts personalized responses to immunotherapy in four different diseases.

The field has yet to reach a consensus on what exactly constitutes the core microbiome or how to accurately identify these key microbial players.

Conventional methods for microbiome analysis often define the core microbiome using commonly shared taxonomic units, such as species or genera, within a human population. However, these taxa may have limited resolution. For example, within a single species there can be both beneficial and harmful species. The well-known intestinal bacteria species E. coli includes mainly benign strains, but E. coli O157 can cause serious foodborne illness.

This new study overcomes these limitations by using high-quality genomes assembled directly from metagenomic sequencing datasets. Each genome is tagged with a universal, unique identifier that allows its ecological behavior to be tracked. This genome-specific approach not only provides high resolution for analysis, avoiding the mixing of signal with noise, but also includes genomes of novel, unclassifiable bacteria that are not limited by incomplete databases.

“Our research identifies the bacteria in the gut that stay connected no matter what challenges the body faces, such as dietary changes or illness,” said Liping Zhao, the Eveleigh-Fenton Chair of Applied Microbiology and professor in the Department of Biochemistry and Microbiology at the Rutgers School of Environmental and Biological Sciences. “By focusing on these resilient and interconnected bacteria, we have developed a new method to identify the microbes most critical to maintaining our health.”

This approach led to the identification of two distinct and opposing groups of core bacteria of the gut: the beneficial foundation guild and the necessary but potentially harmful pathobiont guild.

The foundation guild is crucial for structuring and stabilizing the entire gut microbiome. These bacteria break down dietary fiber and produce short-chain fatty acids (SCFAs), such as butyrate, which are crucial for intestinal health by supporting the intestinal barrier, reducing inflammation and serving as an energy source for intestinal cells. SCFAs are also critical for suppressing harmful bacteria.

In contrast, the Pathobiont Guild, while necessary in small amounts for immune training and vigilance, can drive disease progression when it becomes ecologically dominant.

The seesaw-like balance between these two guilds is crucial. When the foundation guild dominates, intestinal health is maintained. However, when the balance tips in favor of the pathobiont guild, dysbiosis occurs, potentially leading to inflammation that can worsen several chronic conditions.

“Our model not only helps us identify these core bacterial guilds, but also shows how they can be nurtured to maintain their dominance,” Zhao said. “This opens up new possibilities for personalized nutrition and targeted therapies that can restore balance to the gut microbiome.”

By targeting the fiber breakdown genes of the foundation guild, personalized nutritional recommendations can be made to support the ecological dominance of these important microbes.

The two competing guilds model provides both a new method and a new standard for identifying members of the core microbiome. By requiring that the members of the core microbiome are not only communally shared within a population, but also stably connected despite dramatic changes in their environment, the model sets a new benchmark for microbiome research, according to Zhao.

Zhao and his team plan to conduct a series of studies to further refine personalized therapies aimed at restoring and maintaining the ecological dominance of the foundation guild in patients with severe dysbiosis. By applying the two competing guild model in clinical settings, they aim to translate their research into practical treatments that can significantly improve patient outcomes in conditions previously considered irreversible.