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Antibiotics-associated microbiota and functional changes in immune-mediated enterocolitis.

Award Number: K08AI193408
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Antibiotics-associated microbiota and functional changes in immune-mediated enterocolitis. - Project Summary/Abstract: This K08 proposal outlines a five-year research and training plan that will propel Dr. Fan’s career as an independent physician scientist and expert in microbiome manipulations in immunotherapy enterocolitis (IMEC). Immune checkpoint inhibitors have revolutionized cancer treatment by leveraging our own immune system against tumor cells. Unfortunately, off-target effects, including inflammation of the gastrointestinal tract, like IMEC, can occur. Antibiotic exposure leads to dysbiosis which disrupts the careful interplay between beneficial and harmful bacteria. Antibiotics, specifically those with anaerobic spectrum increase the incidence of moderate-severe IMEC. In cancer patients, antibiotic exposure often leads to gut microbiome domination with vancomycin-resistant Enterococcus faecium (Efm), and exposure to anaerobic spectrum antibiotics can also target beneficial members of the Bacteroides spp., which play a critical role in carbohydrate degradation. Indeed, Bacteroides spp. have a diverse repertoire of carbohydrate degrading enzymes with gene groups predicted to code for Carbohydrate-Active enZyme (CAZyme) families, designated polysaccharide utilization loci (PUL), which coordinate complex carbohydrate degradation. Our preliminary patient data show an expansion of B. xylanisolvens in IMEC patients who responded to fecal microbiota transplantation (FMT). Moreover, CAZyme genes (encoding GH16 and GH3) increase after FMT in responders, which can be attributed to B. xylanisolvens. Further, these enzymes degrade the prebiotic product, beta-glucan. On the other hand, clade A Efm has been associated with hospitalized and critically ill patients who have received massive amounts of antibiotics and isolates belonging to this clade have been shown to worsen colitis, in genetically susceptible il10-/- mice. Antibiotic exposure and the gene abundance of a “resistant allele” of pbp5, coding for penicillin-binding protein 5 (PBP-5) and mediating ampicillin resistance in Efm is typical of clade A. Our data suggests that enterococci are more abundant in patients with IMEC and enterococcal abundance decreases in responders after FMT. This balance of good and bad bacteria may be critical to IMEC development. Developing microbiome targeted opportunities to mitigate disease severity and activity is promising. Based on preliminary data from our upfront FMT cohort, we find that two specific bacteria that are associated with antibiotic exposure may play a role in mediating severity in IMEC. Specifically, we aim to investigate the contributions of the following in the development and severity of IMEC: 1) carbohydrate degradation of B. xylanisolvens and prebiotic, beta-glucan and 2) antibiotic exposure and clade A Efm predominance. This K08 award will facilitate the mentorship and career development of Dr. Fan with world experts to help elucidate the role of these two bacteria in IMEC development. With mentors from Houston Methodist and the Texas Medical Center, led by Dr. Cesar A Arias, MD, PhD., discoveries from this award will set the basis for an R01 on the mechanisms of both Efm gut colonization and the functional role of carbohydrate degradation by B. xylanisolvens in IMEC.


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 = $184,030 )
2026	2026	THE METHODIST HOSPITAL RESEARCH INSTITUTE	6565 FANNIN ST STE D200	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	1	6/1/2026	NEW	$184,030
														Subtotal = $184,030

Grand Total All Awards = $184,030

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Antibiotics-associated microbiota and functional changes in immune-mediated enterocolitis.

Award Number: K08AI193408

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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