Addressing Newborn and Infant Gut Health Through Bacteriophage-Mediated Microbiome Engineering (Round 16)

The Opportunity

A growing body of evidence suggests that healthy gut function early in life plays a significant role in adult wellbeing. Enteropathogen burden, for example, has been implicated in the development of Environmental Enteric Dysfunction (EED, also known as 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 young children 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 acute pathogenic bacterial infections progression, can lead to antibiotic resistance, are challenging to deliver in low-resource settings, and often kills commensal 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 enteric dysfunction 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-based tools to study the effects the gut microbiome has on the development of environmental enteric dysfunction in children in low income settings.

Topic areas underrepresented in the previous funding round and therefore of particular interest:

• The pharmacokinetics and pharmacodynamics of phage therapies – how complete is pathogen elimination and over what timescale?
• The combination of empirical “subtractive” experiments in model systems, omics, and computational modeling to help understand the implications of acute microbial community disruption, the presence of new and high-titer bacteriophage, the release of endotoxins, etc. This could include modeling studies on:
  • The response of the microbial community (e.g. through metagenomics);
  • The immunogenic response of the host (e.g. through transcriptomics);
  • Chemical signaling within the microbial community and between the microbial community and the host (e.g. through metabolomics).

Examples of what we will consider funding:

• Systems-level approaches that address many of the criteria below are of particular interest.
• Studies aimed at using bacteriophage to understand the mechanistic and/or dynamic principles underlying microbiome-host health and pathology, especially under acute disruption;
• 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;
• 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;
• Proposals that identify regulatory risks for bacteriophage-based tools or therapies, and propose specific technical solutions for mitigating those risks;
• Selection and/or engineering of pathogen-specific bacteriophage or bacteriophage cocktails.

Proposals must do all of the following:

• Strategies involving the use of temperate bacteriophage must include a discussion on the mitigation of lysogen immunity to superinfection and generalized transduction;
• Convey a clear and testable hypothesis for how the innovation will measurably improve gut function, mitigate environmental enteric dysfunction 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.

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;
• Proposals, or portions of proposals, for scale-up of existing preparations or business development;
• 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.

A more expository vision for what this topic is meant to accomplish is given here.

^{[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. em>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]