Microbial and Metabolite Signatures of Stress Reactivity in Ulcerative Colitis Patients in Clinical Remission Predict Clinical Flare Risk

Inflamm Bowel Dis. 2024 Mar 1;30(3):336-346. doi: 10.1093/ibd/izad185.


Jonathan P Jacobs 1 2 3 4Jenny S Sauk 1 2 3Aaron I Ahdoot 2Fengting Liang 2William Katzka 2Hyo Jin Ryu 5Ariela Khandadash 1Venu Lagishetty 2Jennifer S Labus 1 2 3Bruce D Naliboff 1 3Emeran A Mayer 1 2 3


Author information

1G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California Los Angeles, Los Angeles, CA, USA.

2Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

3Goodman-Luskin Microbiome Center, University of California Los Angeles, Los Angeles, CA, USA.

4Division of Gastroenterology, Hepatology and Parenteral Nutrition, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.

5A.T. Still University School of Osteopathic Medicine in Arizona, Mesa, AZ, USA.


Background: Stress reactivity (SR) is associated with increased risk of flares in ulcerative colitis (UC) patients. Because both preclinical and clinical data support that stress can influence gut microbiome composition and function, we investigated whether microbiome profiles of SR exist in UC.

Methods: Ninety-one UC subjects in clinical and biochemical remission were classified into high and low SR groups by questionnaires. Baseline and longitudinal characterization of the intestinal microbiome was performed by 16S rRNA gene sequencing and fecal and plasma global untargeted metabolomics. Microbe, fecal metabolite, and plasma metabolite abundances were analyzed separately to create random forest classifiers for high SR and biomarker-derived SR scores.

Results: High SR reactivity was characterized by altered abundance of fecal microbes, primarily in the Ruminococcaceae and Lachnospiraceae families; fecal metabolites including reduced levels of monoacylglycerols (endocannabinoid-related) and bile acids; and plasma metabolites including increased 4-ethyl phenyl sulfate, 1-arachidonoylglycerol (endocannabinoid), and sphingomyelin. Classifiers generated from baseline microbe, fecal metabolite, and plasma metabolite abundance distinguished high vs low SR with area under the receiver operating characteristic curve of 0.81, 0.83, and 0.91, respectively. Stress reactivity scores derived from these classifiers were significantly associated with flare risk during 6 to 24 months of follow-up, with odds ratios of 3.8, 4.1, and 4.9. Clinical flare and intestinal inflammation did not alter fecal microbial abundances but attenuated fecal and plasma metabolite differences between high and low SR.

Conclusions: High SR in UC is characterized by microbial signatures that predict clinical flare risk, suggesting that the microbiome may contribute to stress-induced UC flares.

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