The work of Dr. Brittany Needham’s laboratory has been one of the first to demonstrate a direct causative relationship between gut biosynthesis of a specific bacterial metabolite and altered brain activity and behavior. We have established a template that can be expanded to study additional bacterial molecules correlated with a range of host phenotypes and delve further into the chemical signaling that occurs within us.
Manipulating microbial communities and their byproducts is a rich and tractable opportunity for therapeutics. Dr. Needham first became interested in bacterial-host interactions studying the evolutionary strategies employed by bacterial pathogens that disguise their exterior and subvert mammalian immune detection. Surface-structure modifying enzymes were harnessed to design and characterize an extensive library of altered bacterial lipopolysaccharides (PNAS, 2013). Exploiting the enzymatic machinery in this way yielded a broad range of immunogenic properties for a bacterial product that is typically an overly robust and toxic immunogen. Upon manipulation, several resulting lipopolysaccharide products were distinguished as appropriate immune stimulants for vaccine adjuvant use.
The research focus now includes the study of bacterial byproducts of commensal gut microbes. For instance, the levels of one gut-derived metabolite, 4-ethylphenyl sulfate (4EPS), were found to be highly elevated in a mouse model of atypical neurodevelopment. The Needham group identified novel biosynthetic genes from the gut microbiome for 4EPS production and bioengineered gut bacteria to selectively produce 4EPS in mice (Nature, 2021). 4EPS was detected in the brain and was associated with changes in brain activity and increased anxiety-like behaviors. Transcriptional and functional profiles oligodendrocytes were implicated in mediating these effects, with 4EPS exposure leading to reduced myelination of neuronal axons and disorganized myelin. In a separate study by the lab, it was discovered that 4EPS is ~7-fold higher in plasma samples from children with ASD compared to controls (Bio. Psych. 2020). This led to a clinical trial (Nature Med., 2021), where the group reported that a GI-restricted adsorbent reduces circulating levels of 4EPS and other phenolic molecules, and is associated with improvements in anxiety and irritability.
Work on Electroactive microbiota and effects on the brain, behavior, and immunity
In the collective human gut microbiome, almost a hundred species of supposed electroactive bacteria are found, some of which can even be enriched from growth directly on an electrode. However, how or if electrical signaling by the gut microbiota influences the host remains completely unknown. This is an entirely new avenue of research, specifically exploring electroactive gut bacteria and knockouts in controlled, gnotobiotic paradigms.
Boktor J, Adame MD, Rose DR, Schumann CM, Murray KD, Bauman MD, Careaga M, Mazmanian SK, Ashwood P, Needham BD. Global Metabolic Profiles in a Non-human Primate model of Maternal Immune Activation: implications for neurodevelopmental disorders. Molecular Psychiatry. (In press 2022).
Needham BD, Funabashi M, Adame MD, Wang Z, Boktor JC, Haney J, Wu WL, Ladinsky MS, Rabut C, Hwang S, Guo Y, Zhu Q, Griffiths JA, Knight R, Shapiro MG, Bjorkman PJ, Geschwind DH, Holschneider DP, Fischbach MA, Mazmanian SK. A gut bacterial metabolite modulates brain activity and anxiety-like behavior in mice. Nature. (2022).
Needham BD, Adame MD, Serena G, Rose DR, Preston GM, Conrad MC, Campbell AS, Donabedian DH, Fasano A, Ashwood P, Mazmanian SK. Plasma and Fecal Metabolites in Autism Spectrum Disorder. Bio. Psychiatry. (2020).
Campbell AS*, Needham BD*, Meyer CR*, Tan J, Conrad M, Preston GM, Donabadian DH, Bolognani F, Rao S, Heussler H, Griffith R, Guastella A, Mazmanian SK. Open-label clinical trial targeting gut-derived metabolites shows safety and improved behaviors in Autism Spectrum Disorder. Nat. Medicine. (2022). *co-first authors.