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Age-specific antidepressant-gut microbiome interplay in anti-tumor immunity.

Award Number: K01CA316937
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/02/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Age-specific antidepressant-gut microbiome interplay in anti-tumor immunity. - Project Summary/Abstract Research: Early onset colorectal cancer (CRC) incidence rates have significantly increased over the past two decades, but the underlying mechanisms are poorly understood. Antidepressants, like selective serotonin reuptake inhibitors (SSRIs), are among the largest increases in prescription medications during pregnancy over the past decades. Recent work by our lab and others have elucidated the gut as a major source of the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). However, it remains unknown how maternal antidepressant use affects neonatal gut 5-HT, immune regulation, and CRC susceptibility in adulthood. I have demonstrated that neonatal gut bacteria increase production of 5-HT while inhibiting breakdown 5-HT, leading to significantly higher levels of 5-HT in the neonatal gut which in turn shapes T cell response to promote immune tolerance in early life. I have established a maternal SSRI mouse model; my preliminary data show that postnatal exposure to maternal SSRI significantly elevates gut 5-HT levels and changes the gut microbiome composition in neonatal mice. Using a mouse CRC model, I found that continuous SSRI exposure starting from nursing reduced tumor size in male mice, but not in female mice; this was associated with an increase of tumor infiltrating T cells producing interferon-gamma and Perforin and a decrease of tumor infiltrating B cells in SSRI-exposed male mice. Therefore, I hypothesize that exposure to antidepressants (SSRIs) shapes immune cell development and anti-tumor immunity in an age and sex-dependent manner. To test my hypothesis, I will: 1) use AOM/DSS and MC38 mouse models of CRC to characterize age/sex-specific effects of SSRIs on anti-tumor immunity and 2) use Htr3afloxCD4cre or Htr2afloxMblcre mice and 13C-labeled 5-HT to investigate the mechanisms by which early life SSRI exposure alters anti-tumor immunity. Career goals: My long-term career goal is to lead an independent research laboratory investigating how diet and the gut microbiome shape development of immunity and gut disease in infants, with the goal to uncover significant early life factors that could be leveraged to lower cancer. Career development: I will meet weekly with my mentor Dr. Melody Zeng and bi-weekly with my co-mentors (Drs. Taha Merghoub, Gregory Sonnenberg, and Chun-Jun Guo) to discuss my research progress and career development. Additionally, I will participate in at least 2 scientific conferences and attend workshops to polish my presentation, grant writing, mentoring, and job search and interviewing skills. Environment: I will primarily work in the laboratory of Dr. Zeng, a research space adequately equipped to conduct my proposed experiments with additional technical support from my co-mentors. Moreover, the Tri-Institutional consortium (WCM, MSKCC, and Rockefeller) is home to an outstanding immunology and microbiology community, providing me with a diverse group of colleagues and collaborators; this unique environment has resources for research and career development, including immunology and cancer core facilities.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $177,004 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Research Manpower	000	1	9/2/2026	NEW	$177,004
														Subtotal = $177,004

Grand Total All Awards = $177,004

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Age-specific antidepressant-gut microbiome interplay in anti-tumor immunity.

Award Number: K01CA316937

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/02/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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