TECHNOLOGY AREA(S): Bio Medical
OBJECTIVE: Develop and validate an ingestible telemetric device for the non-invasive in vivo measurement of bacterial metabolite production within the human gastrointestinal (GI) tract.
DESCRIPTION: Military personnel and civilians are commonly exposed to physiologic stressors that challenge health, cognitive function, and physical performance. The adverse impact of these stressors may be mediated in part through effects on the microorganisms residing in the human gut, collectively known as the gut microbiome. The metabolic output of the gut microbiome, in part, determines the net benefit or decrement of the gut microbiome to host health. Therefore, understanding how stressors, host physiology and the gut microbiome interact is critical to developing targeted strategies for optimizing human health and performance. Diet is the primary non-pharmacologic factor shaping the composition and metabolic output of the adult human gut microbiota (1), and thereby provides a tool for manipulating the health-promoting properties of the gut microbiome. Within the varied diets of most healthy humans, non-digestible carbohydrates (NDCs) provide the primary food source for many gut microbes. Fermentation of NDCs produces several metabolites known to directly or indirectly influence human physiology including carbon dioxide, hydrogen and methane gases, and short-chain fatty acids (2). Proteins also provide fermentative substrate to gut microbes. However, in contrast to byproducts of NDC fermentation, many metabolites of protein fermentation are thought to be toxic to human cells. Relevant compounds include hydrogen sulfide gas, branched-chain fatty acids, cresols, amines, indoles, N-nitroso compounds, and ammonia (2, 3). Additionally, many nutrients from diverse food sources including fruits, vegetables, cocoa, tea, coffee, and wine are metabolized by gut microbes into bioavailable, health-modulating bioactive compounds. The inability to directly sample and quantify gut microbiota metabolism in situ represents a significant technology gap which has limited advancement in the understanding of relationships between the gut microbiota and human health. Current methods for quantifying gut microbiota metabolic activity rely on measuring metabolite concentrations in blood, urine and feces (2, 3). However, it is widely recognized that these measures are confounded by differences in absorption, transport, and metabolism, and therefore may not reflect actual production in situ. Moreover, differences in bacterial composition and substrate availability in separate regions of the human GI tract create different metabolite profiles throughout the GI tract. Due to the inaccessibility of the human GI tract to non-invasive tools, measuring these metabolite gradients is largely impossible at present, which complicates efforts to elucidate the relevance of these compounds to human health. Ingestible telemetric capsules may provide an innovative, non-invasive method for measuring microbial activity within the human GI tract. Currently, capsules for measuring environmental characteristics within the human GI tract (e.g., pressure, pH, temperature) exist and are commercially available (4). Recently, ingestible capsules for measuring gas production within the GI tract have been prototyped and tested in animals (5). This project should extend these technologies, or develop new technology, to provide innovative and novel tools for the in vivo quantification of bacterial metabolite production within the human GI tract. The minimal deliverable of this effort is a minimally-invasive device or an ingestible sensor capable of measuring gas concentrations within the human GI tract. Note that this minimal requirement necessitates that the device be approved for human use. However, the objective of the effort should be to develop an ingestible telemetric sensor capable of non-invasively measuring a panel of the aforementioned gut microbiota metabolites in vivo within the human GI tract. Developing such a device is, firstly, integral to empirically establishing a healthy baseline to which environment- or disease-mediated perturbations can be compared to ultimately advance understanding of the gut microbiomes role in health and disease, and secondly, to identify biomarkers of organ injury and/or disease. Further, this device would facilitate monitoring the efficacy of clinical, personalized interventions aiming to improve health by targeting activity within the gut microbiome. This may include monitoring and treating chronic disease states such as gastrointestinal diseases and obesity, and building resiliency in the gut microbiome to acute stressors that challenge gut health (e.g., infection, environmental and physical extremes). Finally, research enabled by this technology could pursue determining the utility of using this device, or a modification of this device, for clinical diagnostic purposes.
PHASE I: Identify technological barriers and determine the technical feasibility of developing ingestible sensors for monitoring bacterial metabolite production in the human GI tract. Should technical feasibility be established, develop an innovative plan for building the device. Desired characteristics include: small size, low power requirement, ingestible and/or facilitates ambulatory use, approved for human use, capable of measuring multiple compounds (e.g., hydrogen sulfide, hydrogen, and methane gases, short-chain and branched-chain fatty acids, ammonia, amines, cresols, phenols, indoles), capable of measuring the GI environment (e.g., pH, temperature, pressure), and telemetric. Proposed work should include research into the feasibility of developing the capability and describing the overall concept. The offeror shall identify innovative technologies being considered, technical risks of the approach selected, costs, benefits, schedule associated with development and demonstration of the prototype, and define success criteria.
PHASE II: Develop, test and validate the recommended solution in Phase I, providing a device for the minimally-invasive or non-invasive in vivo measurement of bacterial metabolite production within the human GI tract. The minimum required deliverable is a prototype of the solution recommended in Phase I, and initiation of the human use approval process. In addition, the offeror shall deliver a report describing the design and operation of the device, detailing the equipment lifecycle, and including a projection of costs to manufacture, train users, maintain systems, and replenish disposable supplies. The objective of Phase II should be to obtain approval for human use in research and development, and to deliver the device itself, any electronic software required to use the device, instructions on using the device, and a report demonstrating the validity of the device. The device should be delivered/made available to the U.S. Army Medical Research and Materiel Command and other research entities within the DoD. Initial application of the device will include human use research aiming to advance understanding of gut microbiome-human health interactions. A draft commercialization plan should also be provided to inform Phase III requirements, and the offeror should consult the FDA during Phase II if the offeror intends to develop the device as a diagnostic tool.
PHASE III: Refine and execute the commercialization plan included in the Phase II of the proposal. Phase III may include initiation of collaborative research studies with government organizations, and/or academic and industry partners. These studies should confirm the validity of the manufactured device, and leverage the device to study gut microbiome-diet-host physiology interactions. Initial research applications will include establishing a healthy baseline of gut microbiota activity, and upon establishing a healthy baseline, monitoring the efficacy of interventions aiming to improve health by targeting the gut microbiome. This research may include using the device to develop monitoring and treatment strategies for acute gastrointestinal injury or illness, and chronic disease states (e.g., gastrointestinal diseases, obesity). Additional applications include developing personalized interventions for building resiliency in the gut microbiome to acute military-relevant stressors that challenge gut health (e.g., infection, environmental and physical extremes). Further, research enabled by this technology could be used to identify biomarkers of organ injury and/or disease. Research conducted with the device could therefore inform continued development of the device, or a modification of the device, for clinical diagnostic purposes. Commercial marketing of this device for any diagnostic or health monitoring applications may require medical device classification by the FDA. Pursuit of FDA classification is the responsibility of the contractor, and contractors are advised to begin this process as early as practical (possibly in Phase I or II), and to establish a plan for obtaining FDA approval during Phase III.
1: Scott KP, Gratz SW, Sheridan PO, Flint HJ, Duncan SH. The influence of diet on the gut microbiota. Pharmacol Res 2013;69:52-60.
2: Verbeke KA, Boobis AR, Chiodini A, Edwards CA, Franck A, Kleerebezem M, Nauta A, Raes J, van Tol EA, Tuohy KM. Towards microbial fermentation metabolites as markers for health benefits of prebiotics. Nutr Res Rev 2015;28:42-66. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501371/
3: Yao CK, Muir JG, Gibson PR. Review article: Insights into colonic protein fermentation, its modulation and potential health implications. Aliment Pharmacol Ther 2016;43:181-96 http://onlinelibrary.wiley.com/doi/10.1111/apt.13456/abstract;jsessionid=3444A05869A87B30A6F3CBD1EC6361C8.f03t01
4: Pan G, Wang L. Swallowable wireless capsule endoscopy: Progress and technical challenges. Gastroenterol Res Pract 2012;2012:841691. http://www.hindawi.com/journals/grp/2012/841691/
5: Kalantar-Zadeh K, Yao CK, Berean KJ, Ha N, Ou JZ, Ward SA, Pillai N, Hill J, Cottrell JJ, Dunshea FR, et al. Intestinal gas capsules: A proof-of-concept demonstration. Gastroenterology 2016;150:37-9. http://www.sciencedirect.com/science/article/pii/S0016508515015139
KEYWORDS: Gut Microbiome, Alimentary Canal, Gastrointestinal Tract, Fermentation, Metabolome, Nutrition, Telemetry, Ingestible Sensors