“Diet and lifestyle can impact outcomes for patients with hematologic disorders – and this has been an overlooked area to date! We’re hoping to change that, through this research.”

Dr. Ami Bhatt, Associate Professor of Medicine and of Genetics, Stanford University and V Scholar grant recipient, funded in partnership by SagerStrong Foundation and VFoundation

2022 UPDATE FROM THE BHATT LAB:

Precisely shaping the intestinal microbiome to improve cancer therapy outcomes

February 21, 2022 – “There are trillions of bacteria, viruses and fungi inside each and every human. We call this the microbiome. Scientists have found that the microbiome can change how cancer grows and how people respond to cancer therapies. Our lab wants to make the lives of cancer patients better by improving their microbiomes. The usual ways to change the microbiome are through diet, antibiotics, and by eating live bacteria in food. An example of a food with live bacteria is active culture yogurt. We are doing an experiment to see if a special type of fiber can improve the human microbiome. This fiber is digested by specific bacteria in the gut. When it is digested, it is turned into molecules that control the human immune system. We are giving cancer patients this fiber to see if we can increase these immune system-controlling molecules. If this works, we will prevent the immune system from doing harm in cancer patients. We hope to help patients like those who get blood and marrow transplants for treatment of leukemia or lymphoma. Once we understand how these fibers and our microbes change the immune system, we can figure out precise ways to use this knowledge to make the immune system work better. For example, we may be able to make exciting new cancer therapies, like immunotherapy, work better

Stanford Cancer Institute | Stanford,CA
Cancer Type:Blood Hodgkin Disease,Leukemia (ALL),Leukemia (AML),Leukemia (CLL),Leukemia (CML),Leukemia (CMML),Myelodysplastic Syndrome,Non-Hodgkin Lymphoma

Milestones achieved during this grant include:

1) Completion of our first prospective clinical trial of prebiotics for modifying the gut microbiome of HCT patients, and co-development (with substantial assistance from our collaborator Crystal Mackall) and application of a CyTOF method for measurement of T-regs and iNKT cells in the peripheral bloo

2) For Aim 2 – We directly measured the concentration of butyrate and several additional short chain fatty acids in stool samples and have compared this to the relative abundance of T-reg cells measured using CyTOF in the peripheral blood. This was an advance from our originally planned experiment to compare the abundance of butyrate-producing genes to peripheral T-regs.

3) The post-doc from my lab who led this work has benefitted greatly from this support, as well – she has now transitioned to an independent faculty position as an Assistant Professor at UNC, Chapel Hill. This work and experience also enabled her to compete successfully for an Amy Strelzer Manasevit Fellowship and she just submitted a NIH K23 as well. Thus, this grant has benefitted not only me, but also my trainees.

4.) Completed clinical trial. 50 participants in the study. This is part of an ongoing, phase 3 randomized controlled national trial – 300 subjects will be enrolled in the microbiome portion of this national, randomized controlled trial of Tac/MTX vs. post-HCT Cyclophosphamide for GVHD prophylaxis. The trial is currently enrolling at tens of sites around the USA and has enrolled >150 subjects to the microbiome portion of the study.

2020 UPDATE FROM THE BHATT LAB:

February 25, 2020 – Summary Update: In the past year, our lab learned how to better measure and understand the microbiome. The microbiome is the trillions of bacteria, viruses and fungi inside each and every human. Based on our recent research, we know that the microbiome can change over time in cancer patients. Other people’s research shows that the microbiome can make some people respond better to cancer treatment than others. Our lab wants to make the lives of cancer patients better by improving their microbiomes. We are doing an experiment to see if a special type of fiber can improve the human microbiome. This fiber is digested by specific bacteria in the gut. When it is digested, it is turned into molecules that control the human immune system – in the last year, we figured out how to measure these molecules. We gave cancer patients this fiber to see if we can increase these immune system-controlling molecules. In the last year, we developed better methods to measure the microbiome and also got the help of another scientist to measure a particular type of immune cell that we think is important in this process. Once we understand how these fibers and our microbes change the immune system, we can figure out precise ways to use this knowledge to make the immune system work better. For example, we may be able to make exciting new cancer therapies, like immunotherapy, work better.

Clinical trial: We have completed the first prospective interventional trial of prebiotics to modify the microbiome of HCT patients. This has formed the basis of others in our field doing similar studies with different prebiotic compounds. We are discussing (though still have not finalized) a prebiotic intervention arm for the upcoming UK ALL prospective trial. These discussions are ongoing with Adele Fielding, who is the UK ALL PI. We had previously discussed using a proprietary prebiotic from a US based pharmaceutical company, but this opportunity just fell through – so we are now evaluating other compounds that we may use.

Actual description and write up from Dr. Ami Bhatt – on full grant project:

Introduction: Humans co-exist with trillions of microorganisms (microbiome). When the delicate balance between the microbiome and people is disturbed, illness ensues. Our lab aims to bring innovative and cutting-edge molecular biological, microbiological, clinical informatics and bioinformatics skills to understand the impact (positive and negative) of the microbiome on patient outcomes, especially as it pertains to individuals with cancer. As a group that sees the role for novel approaches to improving patient care, we are committed to leveraging advances in genomics and translational biology to manipulate the microbiome safely and effectively in this vulnerable patient population.

Patient-centered genetic research: Patient participation is a critical part of our research success and our efforts to make impact in this realm of research. In addition to collecting comprehensive clinical information about hundreds of cancer patients treated at Stanford, the lab also has a rich resource of biospecimens from these individuals. Beginning with efforts in 2015 in the blood and marrow transplantation (BMT) Unit at Stanford Hospital, the lab has collected >1000 samples for >400 patients. The stool collection combined with curiosity and clever ideas of our lab members has already potentiated the development of many testable hypotheses regarding microbial biomarkers of disease and drug response, which are actively being investigated.

Genome plasticity: Projects in the laboratory range from those that focus solely on the bacterial side of the host-microbe interface, to those that enumerate and characterize host responses at the cellular, genomic and genetic level. Evaluating “real patient samples” also allows us to investigate the strengths and pitfalls of existing sequencing methodologies. For example, a current project in the lab studies the plasticity of bacterial genomes within human microbiomes over clinical time courses. The bacteria that live in our gut have genomes that behave differently than those in animals; they swap genes, duplicate genes, and generally “shuffle the deck” in ways that challenge our existing sequencing technologies.  By applying new sequencing approaches, the lab hopes to solve these challenges through single molecule barcoding and extra-long read sequencing.

Clinical Interventions: While detailed hypothesis testing in vitro and characterization of genome plasticity over clinical time courses is of great interest, the ultimate translational intention of our group is to identify safe and effective methods for microbiome manipulation and subsequent improvement of health. This has led the lab to pursue projects focusing on fecal microbiota transplantation. When we lose the complex bacterial communities that are found in healthy guts, we become susceptible to infection. Ironically, this can be caused by the antibiotics used to treat bacterial infections in the first place.  The lab explores the use of other treatments, including bacterial transplants and prebiotics, for preventing and treating bacterial infections in the gut. Our first phase 1 clinical trial in patients at Stanford has just finished enrolling. In this study, we have investigated the tolerability of a prebiotic in BMT and we plan to study the effects of prebiotics on the community of commensal bacteria in this vulnerable patient population.

The microbiome-host interface: Fundamentally, alterations in the microbiome are likely to impact host health by directly or indirectly impacting host cell biology. Through interdisciplinary collaborations with other laboratories at Stanford (including the Pritchard, Snyder, Montgomery and Kundaje labs in Genetics as well as the Negrin lab in Medicine), we hopes to define specific microbe-host interactions critical for host adaptation, immunity and beyond. For example, using Big Data and sophisticated computational approaches, genes that are potentially critical for host adaptation of microbes have been identified and are being characterized. The hope is to define genes that are required for host-adaptation and thus may be responsible for health-altering effects. Additionally, we study how the intestinal immune cell composition and microbial signatures can be used as a potential diagnostic tools for post-BMT care in the setting of inflammation, and they seek to investigate how microbial metabolites affect human hosts at the level of gene regulation. The production of microbial metabolites greatly depends on diet, gut microbial composition, and microbial gene expression. By studying a panel of abundant microbial metabolites, the lab hopes to mechanistically understand how these compounds impact the structure and folding of the genome (chromatin landscape) and how this may lead to the turning on and off of specific genes.