# Modulation of the Intestinal Microbiome in Obesity by a High Protein Diet

> **NIH VA IK2** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2021 · —

## Abstract

ABSTRACT
A high protein diet has been shown in preclinical rodent models and clinical trials to be an effective obesity
treatment that is associated with greater loss of body weight and fat mass and increased satiety compared to
isocaloric standard protein diets. However, the mechanisms of this response have not been fully elucidated. I
recently demonstrated in a rodent model that a high protein diet induces shifts in the intestinal microbiome
including a bloom of Akkermansia muciniphila, a microbe reported to have an anti-obesity effect. Based on
these preliminary studies, I hypothesize that a high protein diet induces alterations in the intestinal microbiome
that mediate its clinical efficacy for obesity. To test this, I will study 216 overweight and obese Veterans (BMI
27-40) who will be randomized 1:1 to isocaloric high protein (30%) or normal protein (15%) 1500 calorie diets
for 16 weeks utilizing existing clinical infrastructure at the West Los Angeles VA Medical Center established for
a recently completed clinical trial of a high protein diet. In Aim 1, the effect of a high protein diet on the
composition and function of the intestinal microbiome will be assessed by 16S rRNA sequencing, shotgun
metagenomics, and metabolomics. I predict that following a high protein diet, there will be a major shift in the
composition of the intestinal microbiome to favor colonization with Akkermansia and other microbes that
promote fat loss compared to the normal protein diet. I anticipate that this change in microbial composition will
be associated with alterations in the metagenome – including reduced abundance of bacterial genes involved
in carbohydrate utilization – and the metabolome. A total of 11 fecal samples will be collected during the study
period to determine the kinetics of microbial changes. In Aim 2, fecal microbial, metagenomic, and
metabolomic predictors of response to a high protein diet will be identified. Response will be measured by
weight loss, reduced body fat, decreased hepatic steatosis, altered lipid profiles, reduced hemoglobin A1c,
decreased high sensitivity C-reactive protein, and increased satiety. Predictors will be generated using the
baseline microbiome data as well as samples collected at each time point during treatment. I will also evaluate
whether specific microbes, genes, and metabolites are associated with circulating levels of hormones affecting
satiety (leptin, ghrelin glucagon, glucagon-like peptide-1, peptide YY, and pancreatic polypeptide). In Aim 3,
germ-free mice will be colonized with fresh frozen feces obtained at baseline or after 16 weeks of dietary
intervention to establish a causal relationship between alteration of the microbiome on a high protein diet and
susceptibility to obesity. These humanized gnotobiotic mice will be placed on a Western diet to induce obesity
and compared for weight gain, body fat accumulation, insulin sensitivity, and satiety/hunger hormone levels. In
parallel, mice with pre-exist...

## Key facts

- **NIH application ID:** 10292890
- **Project number:** 5IK2CX001717-04
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** Jonathan Patrick Jacobs
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10292890

## Citation

> US National Institutes of Health, RePORTER application 10292890, Modulation of the Intestinal Microbiome in Obesity by a High Protein Diet (5IK2CX001717-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10292890. Licensed CC0.

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