# Anti-inflammatory microbiome-substrate-host interactions

> **NIH NIH R56** · TEXAS A&M AGRILIFE RESEARCH · 2022 · $632,593

## Abstract

SUMMARY
 Inter-individual variability in host-microbiome interactions contributing to inconsistent results in human
clinical studies, presents a major hurdle in determining efficacy and intake recommendations for dietary
polyphenols. Gallotannins and other gallated phenolics are present in fruits, spices, and teas, and represent a
significant portion of human polyphenol intake. Gallotannins are non-absorbable polymerized gallates that are
hydrolyzed and metabolized by the colonic microbiota to gallic acid (GA) and pyrogallol (PG) as primary microbial
metabolites. Gut microbial metabolism is a poorly defined determinant of polyphenol pharmacokinetics (PK) and
is characterized by inter-individual variability. Preliminary data indicate that: (i) Lactobacillus plantarum (L.
plantarum) converts gallotannins to free, absorbable GA and PG; (ii) sulfated and methylated metabolites of GA
and PG are readily detected in plasma, urine, and feces of healthy humans after consumption of gallotannins;
(iii) PG and its metabolites exhibit potent anti-inflammatory activities both in vitro and in vivo and in human clinical
pilot studies; and (iv) metabolism of tannins/gallates is associated with decreased endotoxin and increased short-
chain fatty acid (SCFA) production. Central Hypothesis: Inter-individual differential microbial metabolism of GTs
into GA and PG is a significant determinant of their anti-inflammatory efficacy in intestinal inflammation. Three
integrated specific aims will be pursued as follows: Aim 1 Elucidate GT metabolism in genetic Lp variants and
anti-inflammatory signatures in intestinal organoids in vitro using engineered L. plantarum (Lp) strains, including
wildtype (LpWT), gallotannase (LpTAN) and gallate decarboxylase (LpDCX-) knockouts, and a double-knockout
(LpTAN-/DCX-). Aim 2 Evaluate GT-metabolite signatures within isolated intestinal microbial environments in
vivo by applying targeted and unbiased LC-MSn-metabolomics, meta-genomic, and transcriptomic profiling as
well as pharmacokinetics in a gnotobiotic mouse model treated with Lp-variants and GTs. Aim 3 Assess
pharmacokinetic GT-metabolite signatures and their anti-inflammatory signatures within human intestinal
microbial environment as well as microbial adaptation to GTs via targeted meta-genomic, -transcriptomic, and
metabolomic analysis in human feces (ulcerative colitis (UC) and controls) +/- LpWT, in mini-bioreactor arrays
and in an Mdr1a KO mouse model +/- LpWT stably associated with UC and healthy human fecal microbiota.
The host-microbiome-metabolite nexus represents a critical missing link in human clinical trials. Completion of
Aims 1-3 will provide a better understanding of causal relationships in the cross-talk between dietary polyphenol
intake, and L. plantarum as a probiotic component of the microbiome.

## Key facts

- **NIH application ID:** 10695400
- **Project number:** 1R56AT011587-01A1
- **Recipient organization:** TEXAS A&M AGRILIFE RESEARCH
- **Principal Investigator:** Margaret E. Conner
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $632,593
- **Award type:** 1
- **Project period:** 2022-09-26 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10695400

## Citation

> US National Institutes of Health, RePORTER application 10695400, Anti-inflammatory microbiome-substrate-host interactions (1R56AT011587-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10695400. Licensed CC0.

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