Addressing Newborn and Infant Gut Health Through Bacteriophage-Mediated Microbiome Engineering (Round 15)

Opportunity:

A growing body of evidence suggests that healthy gut function early in life plays a significant role in adult wellbeing. Chronic malnutrition and chronic or repeated gut infection have been implicated in the development of environmental enteropathy,^[i] which in turn has been implicated in the development of stunting.^[1],^[2] This condition, generally characterized by a reduced linear growth rate, is disproportionally prevalent in developing countries, and is associated with numerous pathologies including lack of response to oral vaccines, cognitive impairment, metabolic diseases, and trans-generational perinatal morbidity.^[1],^[3],^[4]

It is further becoming increasingly clear that the gut microbiome in newborns and infants plays a significant role in gut health and therefore child development. The role of the gut microbiome is supported, for example, by studies that have identified large discrepancies between the microbiomes of children experiencing different life events, such as breastfeeding vs. formula feeding, cesarean vs. vaginal birth, and environmental exposure to pathogens, including those that cause diarrhea.^[5] Furthermore, the mechanisms by which the microbiome may affect gut health include immune signaling, toxin release, nutrient use, and modulation of the physical nature of the gut wall (including mucosal barrier function and wall integrity).^[5],^[6]

While efforts to address the exogenous factors affecting gut function (e.g. sanitation, the promotion of exclusive breast feeding, and the administration of probiotic nutrients) are underway, it is difficult to perform hypothesis-based, rational, robust and specific perturbation of the gut microbiome by these means. The use of antibiotics, while successful in treating the progression of many acute pathogenic bacterial infections, can lead to antibiotic resistance, is challenging to deliver to low-resource settings, and often kills probiotic gut microbes as well. We are therefore looking for an innovative new way of manipulating and evaluating the gut microbiome in newborns and infants, with a particular focus on reducing environmental enteropathy in low-resource settings.

The Challenge:

Precise engineering of the gut microbiome requires understanding of host-microbiome interactions, including population dynamics, mechanistic insight into nutrient use and signaling, the progression of disease, and the stability of such a complex ecosystem with respect to disruption. Such studies can be enabled by the development of a tool that would allow the specific perturbation of native microbiome communities in newborns and infants. These challenges are even more critical when considering treatment, which requires specific yet robust (e.g. resistant to resistance) perturbations to the system while at the same time having limited or no negative impact on the host.

Bacteriophage-based strategies may address many of the challenges above, as they are pathogen-specific and do not directly interact with eukaryotic cells. Furthermore, there may be ways to mitigate the development of bacterial resistance to introduced bacteriophage to the extent that an intervention could be plausible. Yet the majority of research aimed at developing bacteriophage therapeutics ceased with the advent of modern antibiotics. The Bill & Melinda Gates Foundation sees this call as an opportunity to leverage decades worth of progress in biotechnology, including high-throughput sequencing, gene synthesis, advanced omics, and systems biology, to develop a novel bacteriophage-based tool to probe, modify, and ultimately foster healthy gut function through a healthy gut microbiome – one that is complementary to nutritional and chemotherapeutic approaches.

What we are looking for:

The goal of this topic is to support all stages of development of bacteriophage-mediated strategies for microbiome engineering in children under two years of age, as a means to reduce the number of cases of environmental enteropathy in low-resource settings. An example of a more early-stage proposal would be the use of bacteriophages to develop a dynamic model for the bacterial determinants of gut health. This could include, for example, targeted killing of specific bacterial strains or classes of strains within the gut, titrating the treatment efficacy from moderate reduction to complete elimination of targeted strains, and the concomitant monitoring and modeling of how the microbial community responds to such disruption. An example of a more applied proposal would be that of testing a bacteriophage intervention in a relevant model, where the treatment would be developed based on a mechanistic model that considers pharmacokinetics, delivery characteristics, microbiome dynamics, signaling, inflammation, etc.

Examples of what we will consider funding.

• Systems-level approaches that address many of the criteria below are of particular interest.
• Selection and/or engineering of pathogen-specific bacteriophage or bacteriophage cocktails;
• Strategies to mitigate the evolution of resistance of microbial pathogens to introduced bacteriophage;
• Modulation/optimization of the persistence and/or efficacy of bacteriophages in the newborn and/or infant gut;
• Studies aimed at using bacteriophage to understand the mechanistic and/or dynamic principles underlying microbiome-host health and pathology, especially under acute disruption;
• Development of relevant animal models for bacteriophage modeling and efficacy studies;
• Development of bacteriophage preparations that reduce or eliminate endotoxin exposure to the gut, from both the bacteriophage preparation itself and resulting from bacterial lysis;
• Studies investigating timing, formulation, and/or route of administration of bacteriophage therapies.

Proposals must do all of the following:

• Convey a clear and testable hypothesis for how the innovation will measurably improve gut function, mitigate environmental enteropathy, or inform/enable future strategies to do so;
• Outline a clear measurement and evaluation plan for each component;
• Be relevant to the newborn or infant (less than two years old) gut;
• Be relevant to the developing world, especially on the basis of cost. This includes cost of preparation, delivery, stability, administration, etc.;
• Strategies involving the use of engineered bacteriophage or gene therapy must include a discussion on overcoming regulatory hurdles.

We will not consider funding for:

• Ideas that are not directly relevant to developing countries;
• Ideas without a clearly articulated and testable hypothesis and metrics;
• Literature reviews or market studies;
• Incremental improvements over existing technologies;
• Ideas that address diseases not directly relevant to environmental enteropathy;
• Studies only on bioethics and/or regulatory issues. Applicants interested in these areas should consider partnering with others;
• Applications only proposing a screen or selection;
• Strategies that do not involve bacteriophage;
• Strategies aimed at killing pathogens without consideration of (1) microbiome dynamics, (2) the evolution of resistance, and (3) gut function consequences;
• Broad-spectrum antibacterial strategies;
• Ideas for which a relevant indicator of success cannot be demonstrated within the scope of the GCE Phase 1 award ($100,000 over 18 months);
• Solely infrastructure or capacity-building initiatives;
• Basic research without clear relevance to the goals of this topic.

References:

^{[1] [a],[b]} From the MAL-ED Network Investigators. The MAL-ED Project: A multinational and multidisciplinary approach to understand the relationship between enteric pathogens, malnutrition, gut physiology, growth, cognitive development and immune responses in infants/children in resource poor environments. Clin Infect Dis 59, S193–206 (2014).

^[2] Korpe, P. S. & Petri, W. A. Environmental enteropathy: Critical implications of a poorly understood condition. Trends in Molecular Medicine 18, 328–336 (2012).

^[3] Prendergast, A. J. & Humphrey, J. H. The stunting syndrome in developing countries. Paediatr. Int. Child Health 34, 250–265 (2014).

^[4] Haque, R. et al. Oral polio vaccine response in breast fed infants with malnutrition and diarrhea. Vaccine 32, 478–482 (2014).

^{[5] [a],[b]} Groer, M. W. et al. Development of the preterm infant gut microbiome: a research priority. Microbiome 2, 38 (2014).

^{[6] [a],[b]} Ahmed, T. et al. An evolving perspective about the origins of childhood undernutrition and nutritional interventions that includes the gut microbiome. Ann. N. Y. Acad. Sci. 1332, 22–38 (2014).

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^[i]Intestinal inflammation, reduction in epithelial surface area and absorptive capacity, and blunting of intestinal villi due to fecal-oral contamination. Often asymptomatic.^[6]