# Role of intestinal luminal and epigenetic factors to mediate intestinal metabolic remodeling after gastric bypass surgery

> **NIH NIH K08** · BOSTON CHILDREN'S HOSPITAL · 2020 · $169,440

## Abstract

PROJECT SUMMARY
 The rising incidence of type 2 diabetes (T2D) highlights a growing need to understand mechanisms behind
highly-effective therapies such as Roux-en-Y gastric bypass surgery (RYGB) in order to develop better, more
widely-applicable treatments. The long-term goal is to understand the role of luminal factors to mediate the
effect of intestinal re-routing upon energy metabolism, including T2D. The overall objective of this application is
to test for tissue-level epigenetic changes in the intestine after RYGB, as a potential mechanism for Roux limb
(RL) remodeling that we have shown to relate to T2D remission in humans. The central hypothesis is that RL
metabolic reprogramming is driven by segment-specific epigenetic modifications which are plastic and require
continuous luminal stimulation. The rationale for this project is that a greater understanding of intestinal gene
expression regulatory networks after RYGB will shed light on ways to mimic RYGB’s effects with less invasive
alternative therapies. The central hypothesis will be tested in two specific aims: (1) to test the role of an
unexpected luminal nutrient load to influence RL epigenetic and transcriptomic signatures for key genes
associated with metabolically-significant RL remodeling; and (2) to test the dependency of RL epigenetic
signatures and metabolic substrate utilization upon in vivo factors using intestinal epithelial organoids (IEOs).
In aim 1, gene expression (RNA-seq) and chromatin remodeling (ATAC-seq) will be studied in RL versus
bypassed intestinal limb (biliopancreatic limb) or versus sleeve gastrectomy, and these methods will also be
employed to test the plasticity of RL remodeling during caloric restriction and refeeding. In aim 2, IEOs will be
used to ask whether epigenetic (ATAC-seq) and metabolic reprogramming (RNA-seq; Seahorse XF Analysis)
change in the absence of in vivo factors. The candidate for this career development award, Dr. Margaret
Stefater, is a pediatric endocrinologist with an MD/PhD and expertise in the integrated physiology of energy
balance, especially after bariatric surgery. In order to achieve scientific independence for the candidate, a
comprehensive career development plan has been developed to gain additional experience in the areas of (1)
epigenetics and gene regulatory networks, (2) bioinformatics, and (3) use of intestinal organoids as a model of
intestinal biology. This will be accomplished through coursework and seminars, under the mentorship of
experts in the fields of bariatric surgery (Nicholas Stylopoulos) and intestinal biology (David Breault). The
proposed research in this application is innovative, in the applicant’s opinion, because it represents a
substantial departure from the status quo by using state-of-the-art sequencing and bioinformatics techniques to
address how RYGB’s core surgical elements (e.g., biliary exclusion, accelerated nutrient delivery) influence
epigenetic regulation of gene expression. Ultimately, t...

## Key facts

- **NIH application ID:** 10039735
- **Project number:** 1K08DK125878-01
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Margaret Stefater-Richards
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $169,440
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10039735

## Citation

> US National Institutes of Health, RePORTER application 10039735, Role of intestinal luminal and epigenetic factors to mediate intestinal metabolic remodeling after gastric bypass surgery (1K08DK125878-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10039735. Licensed CC0.

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