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Research Projects

Dynamics of microbial populations are critical for human health. Auto-inflammatory disease, colitis, sepsis and obesity are all dysbiotic conditions that depend on the interactions between microbes (pathogenic and beneficial), the host, and the surrounding environment. As the traditional drug-based treatment to cure these conditions is ineffective due to selection for resistance and disruption of the healthy balance in the resident intestinal flora, it is necessary to determine targeted therapies that effectively cure these diseases while minimizing side effects. The goal of my research program is to develop new therapies that, by exploiting the ecological and evolutionary processes underlying these microbes’ dynamics, cure or prevent intestinal diseases. We achieve this by combining our expertise at the interface between engineering, systems biology and microbiology, with that in immunology, medicine and infectious disease from our collaborators. 

The list of current, externally-funded project udergoing in the lab is below:

Project 1: Microbiome engineering for the decolonization of drug-resistant ESKAPE pathogens. Infections caused by drug-resistant gram-negative ESKAPE pathogens pose significant challenges in hospital settings. These bacteria are unresponsive to standard antibiotics, resulting in complex infections, extended hospitalizations, and poor patient outcomes. To address this issue, there's growing interest in using microbiome-based interventions to remove these pathogens from the intestine, reducing infection risks and transmission. However, the specific microbes and their functions for this purpose remain unknown. My team uses a two-part strategy to solve this issue. Firstly, we develop and leverage advanced dynamical systems modeling and machine learning algorithms to analyze microbiome-metabolome data over time, identifying influential microbe and metabolite groups impacting gram-negative ESKAPE pathogen dynamics. Secondly, drawing from our synthetic microbiology expertise, we engineer probiotic strains that are designed to effectively combat drug-resistant gram-negative ESKAPE pathogens through the production of new Class II microcins. These live bacteriotherapeutic products (LBPs) are assessed for their capacity to eliminate and mitigate diseases caused by drug-resistant Klebsiella, Pseudomonas, Acinetobacter, and Enterobacter. Our research paves the way for innovative microbial therapies to combat colonization and infection by drug-resistant gram-negative ESKAPE pathogens, potentially advancing to human trials. Additionally, our work will provide valuable insights into the interactions between gut commensal microbes and pathogens. This project is supported by a DOD grant (Bucci PI). An additional NIH R01 proposal (Bucci PI) focused on Class IIb microcins mechanism of action has been submitted to the NIH in October 2024 and is currently pending. 

Project 2: Targeted Microbiome Therapeutics and Dietary Interventions for Intestinal Barrier Promotion to Minimize GI-ARS. Exposure to total body irradiation (TBI) produced by nuclear accidents, premeditated nuclear, or terrorist attacks causes gastrointestinal (GI) acute radiation syndrome (GI-ARS), a state of severe intestinal mucosal barrier damage, loss of tissue integrity, and translocation of the luminal content. Measures to counteract the effect of such detrimental exposure are critical for the survival and well-being of those impacted.  The gastrointestinal microbiome (bacteria and metabolites) plays a crucial role in the maintenance of tissue homeostasis. Multiple studies have implicated specific microbiome clades as responsible for promoting intestinal barrier function and consequent resistance against infections and inflammatory conditions. The central hypothesis of this project is that targeted microbiome supplementation with specific subsets of intestinal bacteria or probiotics engineered to produce barrier function-promoting metabolites and their enhancement via precise dietary intervention actively improves barrier homeostasis in the intestinal epithelium, creating an environment that reduces GI-ARS. In Aim 1, we develop novel live biotherapeutic products that minimize GI-ARS by promoting barrier function through the potent induction of functional epithelial surface P-glycoprotein expression. In Aim 2, we develop genetically engineered strain of the probiotic E. coli Nissle 1917 that minimizes GI-ARS by promoting barrier function through the potent constitutive production of the colonic barrier-remodeling succinate. Lastly, in Aim 3 we evaluate the effect of prebiotics-enriched diets in promoting GI-ARS limitation by barrier-enhancing intestinal bacteria. Cumulatively, this work has the potential to generate novel microbiome therapeutic agents that, by specifically targeting intestinal barrier function, minimize GI-ARS and increase survival after total body irradiation. This project is supported by an NIH U01 grant (Bucci PI). 

Project 3: Microbiome in TB treatment response and disease resolution. Treatment of TB is defined by two factors: the requirement for combination chemotherapy and the extended duration of therapy. For antibiotic-sensitive disease, the shortest duration of therapy that will cure >95% of treated subjects is 2 months of INH/RIF/PZA/ETH, followed by 4 months of INH/RIF. However, abundant clinical trial evidence indicates that most treated subjects will be cured with shorter durations of treatment, yet we lack any clinical or laboratory biomarkers that can identify these candidates for treatment shortening. The overriding hypothesis of this project is that interindividual differences in microbiome composition and function, either pretreatment, or induced by antimycobacterials during treatment, are associated with, and predictive of, different rates of pathogen clearance and resolution of inflammatory markers of active Tuberculosis. To test this hypothesis, as integral part of the TRI-I Tuberculosis Research Unit also comprehending Weill Cornell, Memorial Sloan-Kettering, Rockefeller University and Rutgers University, my laboratory conducts human and animal studies aimed at expanding this concept to 1) validate microbiome-derived biomarkers of TB treatment success 2) understand the contribution of microbiome perturbation to the inflammatory state of TB infection and its resolution and 3) yield mechanistic insight into the interaction of microbiome driven immunomodulation and TB disease. This project is supported by an NIH U19 grant (Bucci PI for Project #3). 

Project 4: Microbiome manipulation to minimize Environmental Enteric Dysfunction in expecting mothers. Environmental Enteric Dysfunction (EED) is an inflammatory disorder of the intestinal tract that affects people in countries with very low socioeconomic status and poor sanitation. EED is associated with stunting, wasting, reduced response to vaccines, and other poor clinical outcomes, especially in children. When pregnant mothers are affected by EED, outcomes are especially poor for newborns as it leads to shorter gestation periods (prematurity), low birth weight, and overall poorer health. The Bucci laboratory is the only US-funded academic laboratory tasked to provide analytical support for the Experimental Medicine Platform funded by the Bill & Melinda Gates Foundation to combat EED via targeted microbiome intervention. For this project, the Bucci laboratory's overarching goal is the development of a suite of computational methods and machine learning tools enabling the systematic identification and optimization of microbiome-based targets for interventional strategies to treat EED. The project is structured under two main parallel aims. The first aim is centered on developing testing and applying new computational infrastructures to simultaneously forecast the intestinal microbiome dynamics and the host immune system in EED patients to find causal links between the gut microbiome and host immune phenotypes in EED. These models are optimally calibrated on longitudinal microbiome and host phenotyping data, which represents a significant advancement from current machine-learning approaches that can only infer associations. The second aim is centered on developing new theory and related software infrastructure to produce novel human-interpretable deep-learning methods that learn ‘focused regions’ in the microbiome and metabolome (alone and in combination), and in the temporal dimension from human interventional trials, that are highly predictive of intervention-induced resolution of EED. This project is supported by a B&MGF grant (Bucci PI).

Project 5:  Microbiome and MDROs in Nursing Home populations. 1.4 million are currently cared for in a US nursing home (NH), the majority (88%) of whom are over the age of 65. This population of elders is particularly vulnerable to infectious (often multi-drug resistant) diseases, with an estimated 3.8 million infections per year and 400,000 NH resident deaths annually. Despite the acknowledged role of the intestinal microbiome in mediating infectious diseases and an explosion in gut microbiome literature, data on gut microbiota and multidrug-resistant organisms (MDRO) colonization in nursing home elders are still quite limited. In this project, I co-lead efforts with Dr. John Haran (Emergency Medicine at UMMS) to: (1) investigate how microbiome dynamics predict the risk of MDROs colonization and infection in the Nursing Home population and (2) discover rational bacteriotherepeutic strategies that would protect from MDROs and C. difficile infections via the stimulation of specific host immune pathways. This project is supported by an NIH R01 grant (Bucci MPI).

Project 6. Sponsored Research Agreement - Modeling immune-microbiome dynamics to discover immune-modulatory consortia in the context of autoimmune disease and cancer. Identifying the maximal immune-modulatory subset from a pool of bacterial strains that in conjunction produce a desired host immune phenotype is an experimentally intractable problem. My laboratory tackles this problem by leveraging mathematical modeling of microbiome and host-microbiome dynamics. Specifically, in addition to resolving the ecological dynamics of the microbial system to be optimized by using metagenomics-constrained dynamical systems models, we leverage end-point colonization measurements and simultaneous immune-system profiling to decouple the contribution of each strain of interest to the measured immune signature. The two parametrized models are combined to predict the immune induction of every possible and ecologically stable microbial combination. To demonstrate the power of this approach my laboratory has been collaborating with Kenya Honda (Riken, JP) and Vedanta Biosciences for the past eight years and applied our methodology to identify subsets of bacteria that would lead to potent (a) CD4+FOXP3+-Treg (regulatory T-cells) induction for repressing auto-immune conditions, or (b) CD8+ induction in the context of immune-oncology applications.  This project is supported by an SRA from Vedanta Biosciences (Bucci PI).