Pain Modulating

Dr. Strandwitz

Co-Founder and CEO, Holobiome

Dr. Strandwitz is a microbiome scientist turned entrepreneur. He’s the inventor of many of the key technologies powering Holobiome, and is an expert in the field of the human microbiome, with a special focus on the gut-brain-axis. He was supported by one of the first grants in the Human Microbiome Project, and received his PhD in Biology in 2016 at Northeastern University. His graduate work was focused on unraveling the complexities of the human microbiome, resulting in publications in top journals like Nature Microbiology and Microbiome. He is now CEO at Holobiome, a platform biotech company that’s mapping how our microbes impact our biology and developing solutions from that knowledge in the form of drugs and consumer products. He’s raised millions in venture financing, secured multiple corporate partnerships (including Kenvue, Johnson and Johnson, and a major neuro pharma), and won grants the Translational Space Institute for Space Health (TRISH), the National Institute of Neurological Disease and Stroke, the National Institute of Digestive and Kidney Disorders, among others. He’s also a Termeer Fellow, a mentorship network started by the legendary CEO of Genzyme, Henri Termeer.

Holobiome:

The human gut microbiome – the trillion of microbes that live in us – is our most promising source of cures. However, because most bacteria that exist within the human gut microbiome has yet to even be cultured, we lack the knowledge and tools to unlock its potential. Holobiome is building a microbiology-first platform to solve that problem, with three core pillars – an international fecal biobank, a pipeline to build a collection of all known human gut bacteria (the Holobiome Microbiome Vault), and a means to make the microbiome screenable for target activity. We use this knowledge to generate drugs and consumer-facing probiotics, which we commercialize with large partners (B2B). Our initial focus is around mapping the gut-brain-axis, with lead programs in depression and pain.

Intro:

We hypothesize that the human gut microbiome is a major driver of the variability of pain responses seen in people. If true, and we can understand this link better, we can then develop human-derived analgesic bacteria as novel pain therapeutics. As such, the goal of this project was to explore broadly if human gut bacteria can alter known biological drivers of pain.

Chronic pain is a global health crisis, affecting 20-30% of adults worldwide. It comes with a significant decline in the quality of life of the individual and a major cost to the medical system, and it is worsened by ineffective or high-risk treatments, including those that contribute to the opioid epidemic. As such, development of effective and safe chronic pain management measures is a public health priority.

One promising potential source of novel pain treatments is the human gut microbiome. Decades of research have shown that the gut microbiome is an essential component to host physiology, ranging from driving immunity to altering behavior. Recent advancements have also linked changes in the gut microbiome structure and function to modulation of pain endpoints (PMID: 31551115, PMID: 37278059). In rodents, changing the microbiome with antibiotics, diet, or probiotic interventions have been shown to impact visceral pain (PMID: 25088912, PMID: 35727704), chemotherapy induced pain (PMID: 31889131), and neuropathy (PMID: 33895287). In humans, fecal microbiome transplant has also been found to improve pain in people with irritable bowel syndrome (PMID: 32681922) and taking antibiotics and poor diet has been linked to an increased risk of pain disorders like fibromyalgia and osteoarthritis (PMID: 38260960, PMID: 36278278, PMID: 31387605). Taken together, these converging lines of evidence strongly suggest the microbiome is linked to pain. However, to translate this potential into precision microbiome solutions, we need to better understand the mechanisms driving these effects.

Figure 1

Outline of the Holobiome <> CSB pain program.

Results and key findings

Leveraging the diversity contained in the Holobiome Microbiome Vault, we screened over 250 unique species of human gut bacteria for activity against 20 major pain drug targets involved in pain using in vitro and ex vivo models (Figure 1). To our knowledge, this is the most diverse panel of gut bacteria screened for activity against any set of targets, let alone for pain. Remarkably, we found strains that influenced a wide range of pain pathways, such as cytokines, endocannabinoid signaling, and COX-related pathways, in either favorable (analgesic) and unfavorable (algesic) directions (Figure 2). Using our in-house human gut simulator – which allows us to grow the complete gut microbiome communities from humans — we then found that not only did the pain-target response vary amongst microbiomes sourced from different people, but detrimental pain-target phenotypes could be ameliorated by intervening with our putative analgesic strains (Figure 3). Finally, we used bacterial and mammalian datasets to develop a predictive AI/ML pipeline to identify mechanisms driving these effects.

Figure 2:

Human-derived bacteria can alter pain target profiled in human immune cells. One of the assays used in this program was an exposure assay, where inflammation was induced in human peripheral blood mononuclear cells via exposure of lipopolysaccharide. Once inflammation was induced, we then exposed to these inflamed cells to our bacteria at normalized concentrations. We found bacteria that could suppress this inflammatory response, as measured by reduced release of one of our inflammatory targets.

Figure 3:

In a human gut simulator, analgesic isolates can reverse inflammatory phenotypes of complex fecal-derived donor communities. We built a gut simulator in house, which allows us to grow the microbiome from our diverse donor bank in our laboratory. Here we found (A) different donor microbiomes can elicit different profiles on major pain targets, and (B) we could improve this phenotype in these donor communities by spiking in our putative analgesic bacteria.

Outlook

Collectively, this work yielded insights on the human microbiome-pain axis at a strain-level resolution and led to the identification of several promising analgesic strains. These strains are being studied in additional in vitro and in vivo models, with the goal to develop them as novel pain therapeutics.

Learn more

Research by: Corundum Systems Biology

Pain Modulating

Pain Modulating

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