Scientists discover metabolic capacities of gut bacterial enzymes linked to growth in malnourished children

Researchers have identified a gut bacterial enzyme with metabolic capacities linked to better growth in Bangladeshi children receiving therapeutic food to nurture healthy gut microbes. The microbiota-targeted therapeutic food (MDCF-2) nourishes the collections of beneficial gut microbes and improves children’s growth and other health measures. 

MDCF-2 was developed by a team from the Washington University School of Medicine (WashU Medicine) in St. Louis, US, based on an earlier clinical trial. The team linked the presence of a bacteria strain in the gut of malnourished children to age-appropriate growth. 

Researchers from the same university have now determined that a bacterium strain in children’s gut microbiome taking MDCF-2 possesses a “previously unknown gene” capable of producing and metabolizing key molecules that play a role in important functions, such as appetite, immune responses, neuronal function and the ability of pathogenic bacteria to produce diseases. 

“As we apply new therapies to treat childhood malnutrition by repairing their gut microbiomes, we have an opportunity to study the inner workings of our microbial partners,” details lead researcher Jeffrey Gordon, Dr. Robert J. Glaser University professor and director of the Edison Family Center for Genome Sciences & Systems Biology at WashU Medicine. 

“We are discovering how the gut microbes affect different aspects of our physiology. This study shows that gut microbes are master biochemists that possess metabolic capabilities that we have been unaware of.”

Unveiling metabolic capabilities

The study, published in Science, investigates how MDCF-2 works by analyzing children’s gut microbiomes’ responses to food therapy. They explain that the study’s discovery reveals a role for microbes in regulating essential molecules in the gut. 

In two randomized-controlled clinical trials with malnourished Bangladeshi children taking MDCF-2, the researchers linked the improved growth of participants to a higher presence and functions of several microbes, including the bacterium Faecalibacterium prausnitzii.

The researchers colonized mice born under sterile conditions, with microbial communities cultured from the Bangladeshi children’s microbiomes. In mice colonized with a specific F. prausnitzii strain, they found much lower levels of oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) molecules than in animals without this strain. 

MDCF-2 helped to improve the appetite of malnourished children by suppressing OEA levels, an appetite-suppressing compound.OEA and PEA are naturally occurring lipid signaling molecules that regulate inflammation, metabolism and appetite. For example, Gencor’s PEA offer, marketed as Levagen+, shows promise in joint health, sleep, recovery, cognition, stress management and skin health. 

The team used bioinformatics and biochemical tools to identify the fatty acid amide hydrolase (FAAH) enzyme produced by the bacterial strain responsible for degrading OEA and PEA. 

After analyzing the fecal samples of malnourished children in the clinical trial on MDCF-2, the researchers found that the food treatment led to decreased OEA levels. At the same time, F. prausnitzii’s abundance and expression of its enzyme increased. They note that the gut bacterial enzyme could reduce the appetite-suppressing compound OEA in the intestines. 

For example, CV Sciences includes OEA in its ReShape +PlusHlth supplement to support metabolism and achieve weight management goals. 

Human health impact

The researchers note that a better understanding of gut microbes’ effects on the body could lead to new strategies to maintain human health and help develop therapeutics for various diseases beyond malnutrition. 

They highlight that while the human version of the FAAH enzyme is widely known for its ability to break down the neurotransmitters endocannabinoids, their discovery is the “first example of a microbial enzyme of this type.” The human version of FAAH is researched in investigational drugs as it plays a role in chronic pain, anxiety and mood. 

Moreover, the research indicates that the bacterial enzyme has a “dramatically wider range of capabilities” than human FAAH. The paper describes its ability to synthesize lipid-modified amino acids. It includes novel molecules that function as modulators of human receptors in sensing cells’ external environment and help regulate the gut’s immune responses. 

Structures of bacterial FAAH are on the left, and the human version is on the right (Image credit: Jiye Cheng).In addition, the bacterial enzyme can control levels of other lipid-containing signaling molecules, such as neurotransmitters and molecules that pathogenic bacteria use to coordinate infection and disrupt host immune responses.

“The structures of the human and bacterial FAAH enzyme are very distinct. The investigational drugs that inhibit the human enzyme were found not to affect the bacterial enzyme,” explains Gordon. “This opens the door to developing new therapeutics to selectively manipulate the activity and products produced by the bacterial enzyme.” 

“This is an example of how microbes have evolved functions that aren’t encoded in our own human genomes but are still important for the normal functions of our human bodies. We now know that we have two different versions of this enzyme in two different locations — our human cells and our gut microbiome.”

Follow-up research

The team notes that further research is key to determining the biological significance of the F. prausnitzii FAAH enzyme in generating a “broad range of possible products” in the human gut. This includes developing small-molecule regulators of its activities and evaluating the actions of compounds with similar functions and properties.

The discovery of the bacterial enzyme also offers new opportunities to investigate the benefits of therapeutic food treatment. The Bill & Melinda Gates Foundation recently sounded the alarm on rising childhood malnutrition predictions due to climate change. By 2050, stunting is projected to affect 40 million children, and wasting will affect 28 million children. 

In addition, beyond processing diet components, such enzymes could help explain differences in how individuals respond to orally administered drugs. 

“It’s astonishing how much the microbial version of this enzyme can do,” underscores Gordon. “In our future studies, we’re interested in investigating whether cousins of this enzyme that might be encoded in the genomes of other bacteria could complement FAAH or perform entirely different activities. These organisms are master chemists, and we’re just beginning to explore what they can do.”