Researchers have uncovered significant implications from a specific gut bacterium linked to improved growth in Bangladeshi children who were given a specialized therapeutic food aimed at fostering healthy gut microbes. This particular strain of bacteria found in the children’s gut microbiomes contained a newly identified gene that is capable of producing and processing essential molecules that regulate numerous vital functions, including appetite, immune responses, nerve function, and the abilities of harmful bacteria to cause disease.
To combat childhood malnutrition that impacts 200 million children worldwide, a team from Washington University School of Medicine in St. Louis developed a therapeutic food that feeds beneficial gut microbes, thereby enhancing children’s growth and overall health. To get to the bottom of how this food therapy works, the research team, led by physician-scientist Jeffrey I. Gordon, MD, concentrated on the reactions of the children’s gut microbiomes to this therapy.
In their recent research, the scientists discovered broad-reaching effects of a gut bacterium associated with enhanced growth in Bangladeshi children who consumed the therapeutic food called MDCF-2, designed to support healthy gut microbes. This strain of bacteria identified within the children’s gut microbial communities had a previously unrecognized gene that could create and process crucial molecules that govern many important functions, from appetite to immune system responses to the functioning of the nervous system and the pathogenic bacteria’s ability to cause illness.
The findings were published on October 25 in the journal Science.
“By implementing new therapies aimed at childhood malnutrition and repairing gut microbiomes, we have a unique chance to delve into the functionalities of our microbial allies,” said Gordon, the Dr. Robert J. Glaser Distinguished University Professor and director of the Edison Family Center for Genome Sciences & Systems Biology at WashU Medicine. “We’re uncovering how gut microbes influence many aspects of our physiology. This research illustrates that gut microbes act as master biochemists with metabolic abilities we were previously unaware of.”
Gaining a deeper understanding of how gut microbes influence our health could pave the way for new strategies to enhance human health and steer the development of treatments for a range of diseases beyond just malnutrition, the researchers believe.
In two randomized controlled trials of the therapeutic food among malnourished Bangladeshi children, researchers cataloged a group of microbes whose populations and functions were linked to the improved growth of participants. One notable organism was a bacterium known as Faecalibacterium prausnitzii.
The paper’s co-first authors, Jiye Cheng, PhD, an assistant professor of pathology & immunology, and Sid Venkatesh, PhD, a former postdoctoral researcher in Gordon’s lab now at the University of Washington, studied mice that were raised in sterile conditions and then exposed to specific microbial communities derived from the Bangladeshi children’s microbiomes. They discovered that the levels of two compounds, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), were significantly lower in the guts of mice colonized with a specific strain of F. prausnitzii compared to those without it. This was particularly interesting since OEA and PEA are known lipid signaling molecules crucial for regulating inflammation, metabolism, and appetite.
Gordon’s team utilized various bioinformatic and biochemical techniques to identify an enzyme named fatty acid amide hydrolase (FAAH), produced by this bacterial strain, responsible for breaking down OEA and PEA. The human version of FAAH is well-known for degrading specific types of neurotransmitters called endocannabinoids, thereby regulating physiological functions throughout the human body. This human enzyme is a target for several experimental drugs due to its roles in chronic pain, anxiety, and mood disorders, among other neurological conditions.
Cheng and Venkatesh pointed out that the identification of the F. prausnitzii FAAH enzyme marks the first instance of a microbial enzyme of its kind, showing how microbes can influence the levels of key molecules known as N-acylethanolamides, including OEA and PEA, in the gut.
Analysis of stool samples from malnourished children gathered during the therapeutic food trial indicated that the treatment reduced OEA levels while increasing the abundance of F. prausnitzii and promoting its enzyme’s activity. These findings suggest that this gut bacterial enzyme could lower intestinal OEA levels–a compound that suppresses appetite–which is beneficial for children facing malnutrition.
Aside from offering new perspectives on the positive impacts of the therapeutic food, the paper highlights that the bacterial enzyme has a far broader range of functions than the human FAAH. These include a unique ability to create lipid-modified amino acids and various novel molecules that regulate human cell receptors sensing external conditions and modulate immune responses within the gut.
The bacterial enzyme not only synthesizes vital regulators of cell function but also regulates other lipid-based signaling molecules such as neurotransmitters involved in neuron communication and quorum-sensing molecules used by harmful bacteria to orchestrate infections and hinder immune responses.
“The structures of the human FAAH and the bacterial FAAH enzyme differ significantly; investigational drugs designed to inhibit the human enzyme do not impact the bacterial version,” Gordon noted. “This creates opportunities for developing new therapeutics that selectively target the activity and outputs of the bacterial enzyme. This is a classic example of how microbes have evolved functionalities not encoded in our human genomes, yet still play crucial roles in our body’s normal operations. We’ve now identified that we possess two distinct forms of this enzyme located in two different areas – our human cells and our gut microbiome.”
Gordon, along with his colleague Michael Barratt, PhD, a professor of pathology & immunology and co-author of the paper, underscored that identifying this gut bacterial enzyme opens doors for exploring the beneficial outcomes of the therapeutic food treatment. Barratt also mentioned that beyond breaking down components of a typical diet, such enzymes may offer insights into the variances in individual responses to certain orally administered medications.
“It’s remarkable how much functionality the microbial version of this enzyme has,” stated Gordon. “In our upcoming research, we’re eager to investigate whether similar enzymes found in the genomes of other bacteria could complement FAAH or engage in entirely different functions. These organisms are exceptional chemists, and we are just beginning to understand their capabilities.”
Cheng, Venkatesh, Barratt, and Gordon are listed as inventors on a patent application submitted by Washington University in St. Louis that covers therapeutic uses of F. prausnitzii FAAH.
