A gut microbial enzyme that impacts host signaling in undernourished children
October 25, 2024
Before joining the Seattle-based Institute for Systems Biology (ISB) last Fall, Dr. Siddarth Venkatesh was a postdoctoral fellow in Dr. Jeffrey Gordon’s laboratory at Washington University in St. Louis, where he studied the role of the gut microbiome in driving the pathogenesis of childhood undernutrition. In 2019, Sid and his co-first authors (Jeanette Gehrig and Hao-Wei Chang) reported the development of a microbiota-directed complementary food (MDCF) that promoted the abundances of growth-associated bacterial strains. The MDCF also improved plasma levels of mediators of musculoskeletal and CNS development, metabolic regulation, and immune function compared to a ready-to-use supplementary food (RUSF) in undernourished Bangladeshi children. Subsequently, a longer study demonstrated that the MDCF produced improved rates of weight gain compared to the RUSF, even though the latter had greater caloric density than the MDCF (Sid was not involved in that study). This week, Science published Sid’s final project in the Gordon Lab which identifies a microbial fatty amide hydrolase (FAAH) that catalyzes the hydrolysis and synthesis of a broad range of N-acyl amides in the gut lumen that may play a key role in general nutritional health and the treatment of undernourishment.
Dr. Venkatesh joined the Institute for Systems Biology faculty in 2023.
With his co-first author, Dr. Jiye Cheng, Sid sought to determine whether the MDCF intervention could induce chemical changes in the metabolic environment of the gut through MDCF-targeted microbes. Using a “bedside-to-bench” approach of giving gnotobiotic (i.e., germ-free) mice defined bacterial strains isolated from the fecal samples of healthy and undernourished children, with or without a specific growth-associated strain, Faecalibacterium prausnitzii (F. prausnitzii), the study revealed a mechanism through which this microbial enzyme regulates gut luminal levels of signaling molecules that modulate appetite, inflammation, and pain. For example, the observed reduction in fecal levels of a gut satiety factor in MDCF-treated undernourished children that harbor the FAAH-containing F. prausnitzii strain might indicate a beneficial effect of MDCF treatment through remediation of the low appetite common in undernourished children. Characterization of this strain-specific enzyme revealed that it can regulate the levels of a diverse pool of bioactive compounds such as N-acylated conjugates of amino acids, dopamine, and GABA that could potentially be manipulated to improve health outcomes and thus may be pursued as candidate metabolites for more precise and effective therapies.
Now at ISB, Sid is an active member of the mim_c community and is an Affiliate Assistant Professor in the UW Department of Microbiology. He and his new team aim to elucidate mechanisms by which microbial metabolites impact human physiology and health, and to define general principles of metabolite recognition in the gut.
By Monica Tschang
Graphical Summary: Discovery and characterization of a Faecalibacterium prausnitzii (F. prausnitzii) fatty acid amide hydrolase (FAAH) that regulates gut luminal levels of N-acylethanolamines. An FAAH with broad amidase and biosynthetic activities was identified in a strain of the gut bacterium F. prausnitzii isolated from a healthy Bangladeshi child. In fecal samples from undernourished Bangladeshi children treated with a microbiota-directed complementary food (MDCF), F. prausnitzii FAAH expression was inversely correlated with levels of a gut satiety factor, oleoylethanolamide (OEA), an NAE substrate for the enzyme in vitro. Treatment with a ready-to-use supplementary food (control diet) had no effect on gut luminal levels of OEA.
