Profiling the human gut microbiome for potential analgesic bacterial therapies - The human gut microbiome is an essential component of host physiology: it modulates immune activity,
influences the balance of neurotransmitters both peripherally and centrally, and produces a vast and variable
array of small-molecule metabolites which enter circulation to impact distal body sites. It is highly heritable,
implying a symbiosis that has developed over evolutionary timescales, but is also susceptible to the influence of
diet and other factors such as antibiotic use. Notably, disruptions in microbiome composition are associated with
a number of disorders characterized by chronic pain and inflammation, such as rheumatoid arthritis and
fibromyalgia. Given the microbiome’s immunomodulatory and metabolic capacities, and its role as a pseudo-
endogenous component of human biology, human gut-derived bacteria are a promising potential source of novel,
safe, and non-addictive therapeutics for pain management. However, the mechanisms underlying the “gut–pain
axis” are still being elucidated, and key functional drivers of the observed connections have yet to be identified.
As such, to advance the development of microbiome-derived biotherapeutics for pain management, the goals of
this project are: to identify human-gut-native bacteria capable of engaging established pain targets in vitro, to
validate their activity and analgesic/anti-inflammatory potential in vivo, and to develop a computational tool to
predict microbial-genetic drivers of response, which can guide future mechanism validation and therapeutic
development. Because the vast majority of human gut bacteria are strictly anaerobic, they cannot be cultivated
using typical laboratory equipment and techniques. This has historically presented a roadblock in mechanistic
explorations of the gut microbiome’s therapeutic potential, resulting in a focus on “culture-independent” methods
such as metagenomics—approaches that produce a wealth of correlative data, but little by way of causal
validation. Holobiome is uniquely suited to meet this complex challenge, having overcome the difficulties inherent
in anaerobic cultivation to build an in-house strain library of nearly ten thousand bacterial isolates from a variety
of donors which contains representatives of nearly every major human gut-bacterial taxon cultured to date. This
resource, along with an assembled team bringing extensive experience in microbiology, mammalian cell culture
and assay development, and computational genomics, will allow a diverse library of human gut bacteria to be
individually screened for their capacity to modulate cytokine response, cyclooxygenase expression, TRP channel
activity, and other targets with high therapeutic potential for pain. This approach is expected to provide concrete
insights on the mechanisms by which the gut microbiome influences nociception and the inflammatory response,
with implications for the development of novel non-opioid analgesics. Findings of this research may also have
translational potential for the treatment of autoimmune disorders, cancer, and neurodegenerative diseases such
as Alzheimer’s Disease, which has both autoimmune components and demonstrated links to the microbiome.
