Scientists at the Keio University School of Medicine in Tokyo and the Broad Institute of MIT and Harvard say they have isolated eighteen bacterial strains from stool from healthy people that could potentially be a more effective treatment for antibiotic-resistant gut infections. The team found that these strains suppress the growth of Enterobacteriaceae and alleviate inflammation in the guts of mice by competing with the harmful bacteria for carbohydrates and preventing them from colonizing the intestine.
The study, “Commensal consortia decolonize Enterobacteriaceae via ecological control,” appears in Nature and could lead to the development of a microbial transplant for patients that manages antibiotic-resistant bacteria in a more targeted way and with fewer side effects than current treatments, according to the researchers.
“Despite two decades of microbiome research, we are just beginning to understand how to define health-promoting features of the gut microbiome,” said Marie-Madlen Pust, PhD, a computational postdoctoral researcher at Broad and co-first author on the paper. “Part of the challenge is that each person’s microbiome is unique. This collaborative effort allowed us to functionally characterize the different mechanisms of action these bacteria use to reduce pathogen load and gut inflammation.”
“Microbiome studies can often consist of analyzing collections of genetic sequences, without understanding what each gene does or why certain microbes are beneficial,” added Ramnik Xavier, MD, PhD, co-senior author on the study and a core institute member at Broad. “Trying to uncover that function is the next frontier, and this is a nice first step towards figuring out how microbial metabolites influence health and inflammation.”
Bacterial balances
Pust is in the lab of Xavier, who is co-director of its Infectious Disease and Microbiome Program. Xavier is the Kurt J. Isselbacher Professor of Medicine at Harvard Medical School, director of the Center for Computational and Integrative Biology at Massachusetts General Hospital (MGH), and co-director of the Center for Microbiome Informatics and Therapeutics at MIT.
Antibiotic-resistant Enterobacteriaceae such as E. coli and Klebsiella bacteria are common in hospitals, where they can proliferate in the gut of patients and cause dangerous systemic infections that are difficult to treat. Some research suggests that Enterobacteriaceae also perpetuates inflammation in the intestine and infection by other microbes.
Kenya Honda, MD, Xavier, and colleagues wanted to understand which specific bacteria in fecal microbiota transplants could help protect the intestinal microbiome against Enterobacteriaceae. Honda’s team isolated about forty strains of bacteria from each stool sample from five healthy donors and used them to treat mice infected with E. coli or Klebsiella. They tested different combinations of strains and identified a group of eighteen strains that suppressed the Enterobacteriaceae the most.
The Keio University researchers found that in Klebsiella-infected mice treated with the eighteen beneficial strains, Klebsiella altered the expression of genes involved in carbohydrate uptake and metabolism. This included downregulating gluconate kinase and transporter genes, indicating increased competition among the gut microbes for nutrients.
Xavier’s team wanted to study samples from patients with and without gut inflammation. In partnership with the Broad’s Metabolomics Platform, led by senior director and study co-author Clary Clish, PhD, they analyzed samples from pediatric patients with ulcerative colitis, looking for the presence of alternate gluconate pathway genes of gut microbes and fecal gluconate levels. They found higher levels of gluconate linked to more gluconate-consuming Enterobacteriaceae in samples from pediatric patients with ongoing inflammation, indicated by high levels of the protein calprotectin.
Together, the findings suggest that Enterobacteriaceae processes gluconate as a key nutrient and contributes to inflammation in patients. But when a gut microbiome includes the 18 helpful strains, they likely compete with Enterobacteriaceae for gluconate and other nutrient sources, limiting the proliferation of the harmful bacteria.
The eighteen strains also did not disrupt the growth of other healthy bacteria in animals with gut microbes from patients with Crohn’s disease and ulcerative colitis, further underscoring their therapeutic promise.
Although more work will be needed to shed light on the precise mechanisms underlying how different bacteria compete with each other, the findings suggest that microbial therapeutics could be used to tweak the ecology of the gut and suppress harmful bacterial infections with fewer negative side effects than typical antibiotic treatments.
In the meantime, the team aims to uncover the identity and function of unknown metabolites that contribute to gut health and inflammation.
