... Interactions of Biotechnology with Human Physiology and Function Along the Gut-Brain Axis...

... effects on our health. Recent research has revealed that their sphere of influence extends well beyond their long-recognized role in digestion and nutrient absorption to include interactions with the immune system, the brain, and other systems. New biotechnologies are tapping into ... with commensal microbes along the gut-brain axis, opening exciting opportunities to prevent and treat neurological and other disorders, discover new therapeutic modalities, and improve health throughout the lifespan....

... The National Academies of Sciences, Engineering, and Medicine hosted a workshop on Interactions of Biotechnology with Human Physiology and Function on December 15-16, 2022. The workshop was organized under the auspices of the National Academies’ Standing Committee on Biotechnology ... and National Security Needs....

... Presenters and attendees from government, academia, and industry gathered for discussions and presentations addressing recent research into the connections and mediators along the gut-brain axis, key challenges and limitations in this research, ... transdisciplinary technologies being pursued for potential applications, and a vision for future developments in this field. This Proceedings of a Workshop—in Brief provides the rapporteurs’ high-level overview of the ...

... Workshop Chair Elliot Chaikof (Harvard Medical School) set the stage with introductory remarks. The microbes that dwell on and within the human body are known to have profound effects on human physiology,...

... Chaikof described how coevolution between humans and our gut microbes has spanned our entire history as a species, yet the conditions in which people live today are dramatically different from those of ... the relatively recent past. Cultural and technological developments in the past few centuries, including our...

... physical environments, diets, and behaviors, he said, have implications for health and the human body’s interactions with the microbes with which people have co-evolved. One challenge in dissecting these interactions, he added, is the ... -overlooked vast source of genetic variation stemming from microbes both within and among humans, including a diversity in gene expression and metabolic pathways....

... While this unique point in human history poses challenges, understanding more about microbiome activity and interactions along the gut-brain axis also reveals tremendous opportunities. Chaikof noted an emerging body of research suggests that we may be able ...

... To explore and realize these opportunities, Chaikof said, will require not just deep expertise in one field but bringing together facts and theory across multiple disciplines to create a common knowledge base—something that can only be achieved with a balanced workforce of specialists ... generalists with the support necessary to foster innovation and problem-solving. By convening experts from a wide range of areas to examine the emerging opportunities in this space, this workshop provided a forum ... envisioning the path toward a greater understanding of the gut-brain axis to enhance fundamental knowledge and spur technological advances....

... In the first session, speakers examined how gut microbiota influence the immune and nervous systems and drive molecular and sensory inputs that contribute to behavior. Speakers offered examples of opportunities to modulate the two-way transmission of signals along the gut- ... axis with electronic devices, bacteria-based therapeutics, and other approaches....

... Sriram Chandrasekaran (University of Michigan) discussed how genome-scale metabolic models can help to inform precision medicine approaches by deciphering ... between microbiome metabolites and the epigenome. He described how metabolites produced by bodily processes, including by the activity of our microbiome, result in changes in gene ... .1 The complexity of the molecular signals mediating the crosstalk between metabolism and the epigenome makes it challenging to untangle these pathways, but researchers have found that combining engineering models with machine learning can ... . Using this approach, Chandrasekaran and colleagues have discovered new metabolic-epigenetic interactions and developed ways to integrate across biological scales, bridging from macroscale inputs such as diet and environment to molecular-level changes within ... how different nutrients alter cells’ sensitivity to certain drugs, illustrating that metabolites can, in effect, determine a drug’s potency.2 Chandrasekaran noted that the work highlights how linking siloed biological data across different scales of space and time can help researchers predict ... behavior and inform new approaches for precision medicine....

... One way to influence the signals between the nervous system and the immune system is through electronic impulses. Kevin Tracey (Feinstein Institutes for Medical Research and Northwell Health) shared his work in ... medicine, with a focus on vagus nerve stimulation. Tracey described how the vagus nerve is a structure composed of two paired nerves (left and right) which are commonly referred to in the singular, and together collectively comprising approximately 160,000 nerve fibers that transmit ... between the body and the brain. It has long been known to play a key role in the systems that maintain homeostasis such as heart rate, respiration rate, and insulin ... . Over the past two decades, Tracey and colleagues have uncovered its role in the immune system and inflammatory processes,3 using a variety of experimental approaches aided by machine learning. They used this information to develop vagus nerve...

... 1 Campit, S. E., A. Meliki, N. A. Youngson, and S. Chandrasekaran. 2020. Nutrient sensing by histone marks: Reading the metabolic histone code using tracing, omics, and modeling. BioEssays 42(9):2000083....

... 2 Shen, F., L. Boccuto, R. Pauly, S. Srikanth, and S. Chandrasekaran. 2019. Genome-scale network model of metabolism and histone acetylation reveals metabolic dependencies of histone deacetylase inhibitors. Genome Biology 20(1):49....

... disorders, supported by a growing body of evidence that microbes modulate behaviors. Through work examining the relationship between maternal obesity and autism spectrum disorders (ASD), Costa-Mattioli and colleagues discovered that the bacterium Lactobacillus reuteri is instrumental in the ... gut can influence behavior by altering the production of molecules in cells. These chemical signals can then be transmitted through the vagus nerve and ultimately alter pathways in the brain. Costa-Mattioli described how in animal studies and small clinical trials in humans, L. reuteri has been found ...

... A deeper understanding of the gut microbiome leads to the possibility of manipulating these microbes to influence their roles to the advantage of the host. In the second ...

... on the development of the nervous system in early life, their impact on chemosensory signaling, their place in the gene–environment interface, and the ways in which these roles influence microbial fitness and evolution.6 Applying microbiome research to inform new therapeutic approaches, Hsaio’ ... team has used molecular approaches to identify bacterial species and molecules that predict protection against seizures in people with epilepsy, and is exploring how these might be exploited to enhance the protective effects of a ketogenic diet....

... tested dietary interventions that increase short chain fatty acids, finding that a high-fiber, Mediterranean-style diet limited neuroinflammation and attenuated motor deficits in animal models. Further studies pointed to microglia activation states as a likely mediator of this effect. Together, ... noted that this body of work suggests that dysbiosis in the gut microbiome could contribute to Parkinson’s disease and that a high-fiber diet may limit neuroinflammation through its impacts on microglia....

... SIGNALING FROM GUT TO BRAIN...

... The gut-brain axis has multiple mechanisms for detecting and transducing signals, including neuronal signaling, metabolite production, and interactions with the immune system. To start the workshop’s second day,...

... 4 Koopman, F. A., S. S. Chavan, S. Miljko, S. Grazio, S. Sokolovic, P. R. Schuurman, A. D. Mehta, Y. A. Levine, M. Faltys, R. Zitnik, K. J. Tracey, and P. P. Tak. 2016. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proceedings of the ...

... 5 Sgritta, M., S. W. Dooling, S. A. Buffington, E. N. Momin, M. B. Francis, R. A. Britton, and M. Costa-Mattioli. 2019. Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder. Neuron 101(...

... 6 Fung, T. C., H. E. Vuong, C. D. G. Luna, G. N. Pronovost, A. A. Aleksandrova, N. G. Riley, A. Vavilina, J. McGinn, T. Rendon, L. R. Forrest, and E. Y. Hsiao. 2019. Intestinal serotonin and fluoxetine exposure modulate bacterial colonization in the gut. Nature Microbiology 4(12):2064-2073....

..., C. E. Schretter, S. Rocha, V. Gradinaru, M. F. Chesselet, A. Keshavarzian, K. M. Shannon, R. Krajmalnik-Brown, P. Wittung-Stafshede, R. Knight, and S. K. Mazmanian. 2016. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167(6):1469-1480....

... speakers highlighted recent findings, emerging tools, and conceptual frameworks for understanding and leveraging these signaling mechanisms to improve health....

... Mark Lyte (Iowa State University) discussed neurochemicals as an evolutionarily conserved mechanism for communication between microbiota and their hosts. Neurochemicals are ubiquitous, found not only in organisms with complex nervous systems but also in plants and microbes. He described ... there is mounting evidence that commensal bacteria are not passively relying on their hosts as a source of nutrition and energy, but rather are active players in the host’s health, by both producing and responding to neurochemicals.8 This mechanism can be exploited to ... probiotics to influence the gut-brain axis, but to advance this work will require traditional microbiology studies to better understand microbes’ capacity to make and use neurochemicals and will require addressing key challenges in bioinformatics to enhance predictive capabilities, ...

... Melody Zeng (Cornell University) highlighted insights into the role of the microbiome in immune and neuronal development during pregnancy, birth, and early life. The maternal microbiome has been found to influence susceptibility to infections, asthma, obesity, and neurodevelopmental disorders in ... .9 Zeng and colleagues have traced the activity of gut microbiota-specific immunoglobulin G (IgG) antibodies as a mediator in the gut-placenta axis.10 They also ...

... Michael Fischbach (Stanford University) described how new research platforms can accelerate advances in microbiome research, and he discussed a model developed by his lab. To overcome the drawbacks of fecal transplant-based studies, which offer the benefit of a microbial ... -based approach but lack specificity, and single organism-based approaches, which offer specificity but fail to capture the community context, Fischbach and colleagues developed a complex ... gut microbiome.11 This collection of microbes reproducibly and reliably colonizes germ-free mice and can be used to trace how individual microbial species modulate the immune system by profiling T-cell specificity to each strain. Using this model ... with immune cells in a one-to-one fashion, demonstrating the model’s utility in uncovering how microbial communities interact with immune cells and identifying the genes that define such relationships. The researchers are making the model freely accessible for others to use and adapt, Fischbach ...

... about the neurological processes involved. Studies of cellular behavior,12,13 spread of a monosynaptic rabies virus from the gut to the brain,14 and activity of microbes in regulating eating behavior15 have elucidated how the body quickly sorts nutrients and informs the brain so that behavior can ...

... 8 Lyte, M. and D. R. Brown. 2018. Evidence for PMAT- and OCT-like biogenic amine transporters in a probiotic strain of Lactobacillus: Implications for interkingdom communication within the microbiota-gut-...

... 9 McDonald, B. and K. D. McCoy. 2019. Maternal microbiota in pregnancy and early life. Science 365(6457):984-985....

... 10 Sanidad, K. Z., M. Amir, A. Ananthanarayanan, A. Singaraju, N. B. Shiland, H. S. Hong, N. Kamada, N. Inohara, G. Núñez, and M. Y. Zeng. 2022. Maternal gut microbiome-induced IgG regulates neonatal gut microbiome and immunity. Science Immunology 7(72):3816....

... 11 Cheng, A. G., P. Y. Ho, A. Aranda-Díaz, S. Jain, F. B. Yu, X. Meng, M. Wang, M. Iakiviak, K. Nagashima, A. Zhao, P. Murugkar, A. Patil, K. Atabakhsh, A. Weakley, J. Yan, A. R. ... , S. Higginbottom, A. Dimas, A. L. Shiver, A. Deutschbauer, N. Neff, J. L. Sonnenburg, K. C. Huang, and M. A. Fischbach. 2022. Design, construction, and in vivo augmentation of a complex gut microbiome. Cell 185(19):3617-3636....

... 12 Kaelberer, M. M., K. L. Buchanan, M. E. Klein, B. B. Barth, M. M. Montoya, X. Shen, and D. V. Bohórquez. A gut-brain neural circuit for nutrient sensory transduction. Science 361(6408):5236....

... 13 Buchanan, K. L., L. E. Rupprecht, M. M. Kaelberer, A. Sahasrabudhe, M. Klein, J. Villalobos, W.W. Liu, A. Yang, J. Gelman, S. Park, P. Anikeeva, and D. V. Bohórquez 2022. The preference for sugar over sweetener depends on a gut sensor cell. Nature Neuroscience. 25:191-200....

... 14 Bohórquez, D. V., R. A. Shahid, A. Erdmann, A. M. Kreger, Y. Wang, N. Calakos, F. Wang, and R. A. Liddle. 2015. Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells. Journal of Clinical Investigation 125(2):782-786....

... M., J. D. Aitken, F. A. Carvalho, T. C. Cullender, S. Mwangi, S. Srinivasan, S. V. Sitaraman, R. Knight, R. E. Ley, A. T. Gewirtz. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328(5975):228-231....

... infection. In the future, Bohórquez suggested it will be useful to study how commensal bacteria might influence behavior in ways that encourage people to eat foods that would benefit the microbes, but not necessarily their human host....

... Gates Foundation) discussed how her organization is investing in microbiome research as part of a broader effort to improve the health of women and children globally. In the near term, the foundation aims to build a body of work that elucidates the role of the maternal microbiome in fetal and ... development and informs products and mechanisms of action needed to impact clinical outcomes in vulnerable populations. Looking forward, she said it will be valuable to study immune ... through pregnancy, interactions between the vaginal and gut microbiomes, and impact of the gut microbiome on placental development....

... Advances in understanding how the nervous system maintains homeostasis suggest that devices or drugs targeting the central nervous system and peripheral neural circuits can be exploited to learn about, and potentially modify, the underlying pathology of some diseases. In the second session ... the workshop’s second day, speakers examined opportunities and challenges in this space....

... for leveraging electrical activity in the digestive system as a tool to tap into the gut-brain axis. He described a series of lab-based, portable, and wearable devices he developed to measure electrical activity in the digestive system. These devices shed light on the features and causes of ... disorders and can even be used to entrain digestive system components in a target direction, representing a potential novel therapeutic modality.16 Coleman and ... axis, with particular focus on a brain structure known as the anterior insula, through simultaneous electrophysiologic monitoring of the stomach and brain.17...

... Hubert Lim (University of Minnesota) described ultrasound-based methods for influencing neuronal signaling and immune response. He described how the field is in a new era of brain-machine interfacing and neural prosthetics, from implanted devices such as ... cord and vagal nerve stimulators to external devices such as transcranial magnetic stimulation and transcutaneous electrical nerve stimulation (TENS) devices, each of which has benefits and drawbacks. Within this technology landscape, ultrasound ... has emerged as a promising way to achieve targeted modulation of the brain and peripheral nerves.18 Lim noted that ultrasound has the potential to be used as a noninvasive tool to probe or modulate the function of other cell ... and end-organs in the body, including the liver, gut, pancreas, and celiac plexus for applications in a range of health conditions. In particular, Lim’s group studied the application of ultrasound to the spleen, an ... instrumental in interfacing between the nervous system and immune system.19 Studies in animals and humans suggest this approach can help suppress a hyperactive innate immune response, pointing to possible clinical applications for diseases like ... arthritis and COVID-19....

... Stewart Campbell (Axial Therapeutics) discussed his company’s development of small molecule drug candidates that target the microbiome. One benefit of this approach, he said, is that drugs can affect neurological outcomes without needing to cross the...

... 16 Perley, A., M. Roustaei, M. Aguilar-Rivera, D. C. Kunkel, T. K. Hsiai, T. P. Coleman, and P. Abiri. 2021. Miniaturized wireless gastric pacing via inductive power transfer with non-invasive monitoring using cutaneous electrogastrography. ...

... 17 Balasubramani, P. P., A. Walke, G. Grennan, A. Perley, S. Purpura, D. Ramanathan, T. P. Coleman, and J. Mishra. 2022. Simultaneous gut-brain electrophysiology shows cognition and satiety specific coupling. Sensors 22(23):9242....

.... Wallace, S. Kaanumalle, J. Graf, W. Rigby, T. J. Kao, J. Roberts, C. Bhushan, S. Joel, T. R. Coleman, S. Zanos, K. J. Tracey, J. Ashe, S. S. Chavan, and C. Puleo. 2019. Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation. Nature Communications 10:952....

..., R. S., Kim, Y., Mueller, J., Auger, J. L., Schuldt, N. J., Kaiser, C. R. W., Heiller, A. P., Dutta, R., Guo, H., Alford, J. K., Binstadt, B. A., and Lim, H. H. 2019. Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis. Nature communications 10(1):951....

... implementation compared to other emerging microbiome-based therapeutic modalities since they fit into existing pathways for pharmaceutical developers and regulators. As an example, Campbell described the development of a small molecule drug targeting a microbiome metabolite, 4-ethylphenyl sulfate, that ... dysregulated in ASD as a means of addressing irritability, a manifestation of ASD that poses particular challenges for patients and families.20 Animal studies and early phase trials showed that ingestion of the experimental agent results in a host of changes in microbial ... as well as reductions in irritability and anxiety,21 and it is currently being tested in a phase two trial....

... In open discussion, speakers explored challenges to advancing basic research at the intersection of the microbiome, brain, and immune system along with considerations for translating research insights into practical applications....

... specific in order to avoid side effects or unintended consequences; how interventions might be tailored to a person’s background or genetics; and what factors affect the timing and persistence of effects, which could impact how experimental findings are interpreted and how therapies are used in ... . For example, Hsiao noted it will be important to understand which interventions may have more short-term effects (such as a probiotic that does not lead to colonization of the gut microbiome) and which may ...

... Speakers also discussed different ways therapies could be developed and used. Hsiao noted that researchers are examining the use of both endogenous and engineered microbes. Mazmanian commented on the distinction between prophylactic and therapeutic applications and added that it will be useful to ... examine the microbiome’s influence on how the body accesses and responds to drugs, which could help explain why some people respond to certain drugs or experience certain side effects while others do not. Building ... this point, Hsiao suggested that the effects of the microbiome could be incorporated into screening approaches used for pharmacology and even the regulation of environmental chemicals....

... Given the complexity of the microbiome and its connections across multiple organs and systems, Hsiao said researchers need to focus more on integrated, multi-system modeling and less on reductionist, trial- and-error approaches. ... , noting that microbiome-based therapeutics may require a framework of thinking that goes beyond particular molecules hitting particular receptors and triggering a discrete, finite effect. He commented that metagenomic methods are a cost-effective approach for a more integrated view, but a lack of ...

... Drivers and Roadblocks for Translational Science...

... Throughout the discussions, some speakers pointed to a tension between the drive to develop medical innovations and the importance of understanding the biological mechanisms through which they work. Costa-Mattioli stressed the value of uncovering mechanisms to the greatest extent possible; for ...

..., S. J. Hwang, Y. Guo, Q. Zhu, J. A. Griffiths, R. Knight, P. J. Bjorkman, M. G. Shapiro, D. H. Geschwind, D. P. Holschneider, M. A. Fischbach, and S. K. Mazmanian. 2022. A gut-derived metabolite alters brain activity and anxiety behaviour in mice. Nature 602:647-653....

..., J. Tan, M. Conrad, G. M. Preston, F. Bolognani, S. G. Rao, H. Heussler, R. Griffith, A. J. Guastella, A. C. Janes, B. Frederick, D. H. Donabedian, and S. K. Mazmanian. 2022. Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: An open-label ...

... benefits and reliability, for example, from a 10-20 percent improvement in outcomes to a 60-70 percent improvement. He added it can also lower the barrier to ...

... that an intervention works before researchers can fully describe the mechanism involved. Tracey noted that patient advocacy drives innovation and adoption of new therapeutic modalities, particularly with therapies for which mechanisms are not yet known. Given the urgent need for effective ... and societal challenges such as medical debt, he suggested that researchers should not let a lack of mechanistic knowledge hamper advances that could ... that in his view a lack of mechanistic knowledge shouldn’t impede clinical application of a microbiome-based therapeutic if it is shown to be safe and there are people suffering from ailments that could be addressed. On the other hand, adequately ensuring safety can be a challenge when, as Chaikof ... biotechnologies are racing ahead of the regulatory oversight structures such that they are being adopted directly by consumers before elucidation and communication of potential benefits and risks....

... Tracey noted that clinical trials can help to fully understand risks and benefits, but they are costly. In the life sciences, venture capitalists are accustomed to investing in technologies that may take a decade or more ... help patients,” these investment decisions are driven by expectations regarding how many people may use the product, how much they will pay for it, and how long it will take to penetrate the market, he said. As an example, the misalignment of incentives is why TENS devices have not been well studied ... companies are not likely to make a high enough return on investment to support clinical trials for this inexpensive and widely available technology. Given this incentive structure, he said, one potential solution might be greater data sharing among researchers across ... and mechanisms to enable more efficiency in, and prioritization of, clinical trials. To extract more value from the clinical trials that do occur, he suggested researchers and investors pay greater ... to clinical trials that fail; for example, by assessing whether there is a subset of patients who do derive benefits and focusing further assessments of that population. Drawing lessons from COVID-19 vaccine trials, Lim added that a general cultural shift toward ... . Tracey added that building nonprofit research groups that join multiple health systems or sponsors could also help to increase trial enrollment and speed studies. Chandrasekaran noted that sharing of genomic data could also help....

... From a practical standpoint, Mazmanian noted that while the securing of intellectual property (IP) and the ability to make a profit play a role in investment decisions for technologies in this space and getting therapies to market, manufacturing could ... pose as a barrier. Jorge Santiago-Ortiz (Apertura Gene Therapy) stressed the importance of addressing product development and scalability, including manufacturing capabilities, early in the process to avoid insurmountable barriers later....

... expressed their hope that research findings can translate into effective clinical interventions for various conditions. To achieve this, Mazmanian and Costa-Mattioli stressed the need to resolve regulatory questions with the U.S. Food and Drug Administration to create a path to approval for ... that are safe and effective. In moving forward with basic research and translational efforts simultaneously, Hsiao and Chandrasekaran said it will be important to account for the complexity of the microbiome, which means not giving up after the first failed attempt, ... to characterize mechanisms and molecules, and experimenting with combinatorial approaches that may...

.... Tracey expressed hope that neuromodulation could reduce the need for pharmaceutical interventions for a variety of conditions, increasing safety and driving costs down. To get there, he said it will be important to better align incentives and increase data sharing based on a drive to address ...

... from effective interdisciplinary teams. Some participants said this requires people from diverse fields to be willing to work across disciplines and break out of the traditional academic career structure, which may require rethinking the higher-level organization of institutes within universities ... a field, but also to create incentives to foster team science. Under current structures, he said, the work required to sustain one’s own laboratory and advance one’s own career can disincentivize large multi-lab interdisciplinary teams and studies for which credit is more dispersed. Chandrasekaran ... training the next generation of researchers to have basic knowledge of key terminology across fields will help researchers speak the same language and collaborate more effectively....

... To envision a path forward for the research insights and biotechnologies presented at the workshop, speakers discussed how various research strategies and funding models might influence the innovation ... to support or pose barriers to advancements and applications....

... Bonvillian (Massachusetts Institute of Technology) offered remarks on models for accelerating convergence to advance opportunities for insight and intervention at the gut-brain axis. Placing convergence alongside molecular biology and genomics—which he described as two previous ... “revolutions” in biology—Bonvillian said this approach merges science and engineering to build a new knowledge base while developing new tools and new therapies. Bonvillian noted that the merger of talent bases of biology, engineering, and physical sciences could create new fields of scientific ... language across fields, lack of interdisciplinary training to enable biologists to take advantage of emerging toolsets, entrenched siloing in funding and institutional operations despite efforts to increase cross-disciplinary collaboration, and limitations and barriers inherent to peer review models. ... suggested that the Advanced Research Projects Agency for Health (ARPA-H) initiative could overcome some of these challenges and become a new mechanism for enabling convergence research....

... included a willingness to “pick winners” by identifying a small number of technologies to invest in; the establishment of guaranteed contracts; and a variety of other measures to assist with practicalities that often bog down technology development and deployment—including certification; ... ; regulatory compliance; and supply chain, scale-up, and distribution....

... Of course, he noted, that program was undertaken in response to a unique set of circumstances, and one key advantage was that several vaccine platforms were already “in range” for translation into rapid vaccine development when the pandemic ... in every field, Bonvillian emphasized that the mechanism of guaranteed contracts is something that could be leveraged in various contexts and could result in a cost savings for the government if the technology is poised to benefit (and reduce health care costs for) a large group of people. ... raised the point that without sufficient checks and balances, guaranteed contracts could result in a...

... command economy. In response, Lim noted that models such as the Defense Advanced Research Projects Agency (DARPA) provide sufficient funding to enable ...

... another difference with COVID-19 vaccines is that the risk-benefit assessment for clinical trials was calculated against the backdrop of a global pandemic and large numbers of people were willing to volunteer to participate. He suggested that future clinical trials could move forward more quickly by ...

... Barriers and Opportunities for Translational Science...

... Throughout the workshop, speakers noted that a challenge in many translational research efforts is the difficulty of moving between animal models and humans. For example, Zeng noted that the short gestation period of mice makes them useful for studies of the microbiome during pregnancy and early ... , creating a challenge for translational studies. Bohórquez noted another challenge is the heterogeneity of gut microbiota, both between individuals and throughout the long course of the human digestive tract, which adds complexity to translating laboratory studies to practical applications intended ...

... Speakers also highlighted opportunities to translate basic science and emerging biotechnologies relevant for the gut-brain axis to other areas of the body. For example, Coleman said the electrophysiologic devices his ... modulation is being tested on various parts of the body; the key challenge is developing ways to target the intervention to specific structures and then measure the effects in a manner that is sufficiently localized. For small molecule drug development, Campbell said the microbial metabolites ...

... To facilitate transformative technology in the coming years, Coleman and Lim pointed to a need for synergistic, multimodal approaches, such as developing ways to measure microbiome activity and physiology simultaneously or ... datasets, many of which exist in separate silos, to enable a predictive, personalized approach to drug development. Costa-Mattioli noted that DARPA and other funders have explored creative models for providing more lasting funding streams to push truly innovative work that may require a longer ...

... Scale-Up and Manufacturing Considerations...

... The ability to scale up and manufacture biomedical products is crucial to their ultimate success, yet Chaikof pointed out that there is very little attention afforded to this ... in science education and academia. Lim and Bonvillian pointed to DARPA as a good model for funding the intermediary work necessary to bridge academic research to implementation. In particular, ... said that ARPA-H and other organizations could help to facilitate scale-up by cultivating collaborative communities of thinkers (which informs the selection of ... to prioritize for investment) and by creating roadmaps to chart a path forward and anticipate challenges early in the process....

...-based products raises some special considerations. Ridaura speculated that microbial products derived from foods are likely easier to manufacture and scale up, but thinking beyond individual...

... specify that such products should be made in facilities with a Good Manufacturing Practice (GMP) designation, but this is not happening in practice and will be logistically difficult to implement while keeping costs low enough to be suitable for widespread use in under-resourced regions. Lyte added ... , as living organisms, microbes will continue to divide and evolve as they are grown in a fermenter, and studies have shown that probiotics often have very different properties depending on how they are manufactured. He said it will be important to go ... simply documenting a product’s genus and species and establish functional assays to ensure products will behave as intended when given to patients....

... effective cross-disciplinary collaboration, speakers reflected on how their organizational structure influences the way they work as individuals and in teams. Zeng, working in a traditional university structure, said that she wants her work to ultimately find applications—not end in the form of ... challenging in academia. Lim commented that moving from academia to industry can be refreshing because the structure of having investor expectations and milestones to meet forces a more practical viewpoint and can speed progress. Costa-Mattioli said that while his company is still new, it is ... in a new way outside of the traditional government funding structure. While most of the researchers came to the company from careers in academia (and, accordingly, with a mental model in which rewards are earned based on individual achievements), he said the goal is to keep the focus on the ...

... Science education and training structures also influence the capacity for effective team science. Bonvillian said being educated in silos creates a barrier to convergence ... suggested a focus on developing “T-shaped learners”, who have a depth of knowledge in one field but broad exposure to concepts, terminology, and tools in other fields. Lim agreed, adding that nudging people to learn about other fields without sacrificing depth of knowledge in their own field ... require a culture shift and incentives that are aligned with team science, which may require a rethinking of metrics for success used in academia....

... Chaikof closed the workshop with reflections on the opportunities and challenges raised by the technologies highlighted at the workshop (summarized in Table 1). Elucidating the intricate interactions along the gut-brain ... opens new opportunities to understand food and microbes as medicines, with exciting potential to develop new treatments for debilitating disorders and to improve health throughout the lifespan. Work in this field has advanced the ability to track and influence how our bodies interact with microbes ... send and receive signals and modulate pathways affecting functioning from the level of cells to the level of human behavior. Workshop discussions also surfaced possible areas for ... investments; including understanding mechanisms to refine therapeutic approaches, new tools to modulate signaling along the axis, streamlining regulatory pathways to make these tools ... available, and integrating data and building bridges across fields and between academia and industry....

... decades of work will culminate in transformative medical advances, likening biotechnologies in this area to gene therapies, RNA-based medicines, and cell-based cancer therapies in that, only a few years ago, these innovations were still unproven but have now become reality in clinics around the ...

... (Chandrasekaran)...

... Integrates biological data from across scales of space and time to predict cellular behavior...

... Understanding metabolite-epigenome crosstalk remains a complex problem...

... Basic research approach ready for refinement and use...

... electrophysiologic monitoring and modulation devices...

... Monitoring to study and diagnose gastrointestinal disorders and the coupling of gut and brain; modulation as novel treatment modality...

... New opportunities to observe digestive processes and signaling; accessible alternative to brain-monitoring technologies; potential minimally invasive therapeutic option...

... Technology is still early-phase; limited exploration of research and clinical applications to date...

... Modulate immune-neural axis and potentially multiple end-organ targets to treat a range of conditions...

... Can modulate neural and non-neural cells; limited exploration of research and clinical applications to date...

... Targeted stimulation of vagus nerve to treat a range of inflammation-related and other conditions...

... Commercially available but limited use for some conditions and mixed evidence on efficacy; ongoing clinical trials to validate efficacy for other conditions...

... Potential new therapies for conditions such as autism and epilepsy that have limited treatment options currently; could reduce barriers to treatment and increase access to effective therapeutic approaches; ...

... Important to pinpoint mechanisms at work to improve reliability and efficacy...

... Pre-clinical cell and animal studies; small clinical trials...

... Drugs to treat neurological and other conditions...

... influence neurological outcomes without crossing the blood-brain barrier; fits with established drug development pathways for pharmaceutical industry and regulators...

... Requires well-elucidated pathways and mechanisms of action...

... NOTE: This table summarizes examples of technologies shared by workshop participants and should not be interpreted as consensus conclusions or recommendations of the National Academies....

... DISCLAIMER This Proceedings of a Workshop—in Brief was prepared by Anne Johnson, Kanya Long, and Andrew Bremer as a factual summary of what occurred at the workshop. The statements made are those of the rapporteurs or individual workshop participants ... do not necessarily represent the views of all workshop participants; the planning committee; or the National Academies of Sciences, Engineering, and Medicine....

... WORKSHOP PLANNING COMMITTEE Elliot L. Chaikof (Chair), Harvard Medical School; Yasmine Belkaid, National Institute of Allergy and Infectious Diseases; Todd P. Coleman, Stanford University; Mauro Costa-Mattioli, Altos Labs; and ...

... institutional standards for quality and objectivity, this Proceedings of a Workshop—in Brief was reviewed by Elliot L. Chaikof, Harvard Medical School; Hubert Lim, University of Minnesota, Twin Cities; and Harris Wang, Columbia University. Lauren Everett, National Academies of Sciences, Engineering, ...

... SPONSORS The Standing Committee on Biotechnology Capabilities and National Security Needs, under which this workshop was organized, is supported by the U.S. government....

... additional information regarding the workshop, visit https://www.nationalacademies.org/our-work/interactions-of-biotechnology-with-human-physiology-and-function-a-workshop....

... SUGGESTED CITATION National Academies of Sciences, Engineering, and Medicine. 2023. Interactions of Biotechnology with Human Physiology and Function Along the Gut-Brain Axis: Proceedings of a Workshop—in Brief. Washington, DC: The National Academies Press. https://doi.org/10.17226/27014....