TOPLINE

Patients with intestinal sulfide overproduction (ISO) showed widespread changes in small bowel gene expression affecting mitochondrial function, redox balance, and immune signaling, while those with intestinal methanogen overgrowth (IMO) and small intestinal bacterial overgrowth (SIBO) showed far fewer such changes. Rats gavaged with hydrogen sulfide (H₂S)-producing bacteria exhibited gene expression changes comparable to those observed in patients with ISO, supporting a link between microbial H₂S and host cellular stress responses.

METHODOLOGY

• Although ISO, IMO, and SIBO are associated with distinct microbial signatures, their effects on host gene expression within the small bowel have remained unclear.
• In an exploratory analysis of a prospective clinical research study, researchers analyzed 85 patients (mean age, 59 years; 58% women) who underwent upper gastrointestinal endoscopy or antegrade double-balloon endoscopy and provided breath samples, duodenal aspirates, and biopsy specimens to examine gene expression patterns associated with ISO, IMO, and SIBO within the small bowel.
• ISO was defined based on fasting breath H₂S levels of at least 1.5 parts per million (ppm), IMO was defined based on breath methane levels of at least 10 ppm, and SIBO was defined by elevated bacterial counts in duodenal aspirate cultures; of 85 patients, 46 met criteria for ISO, 22 for IMO, and 21 for SIBO.
• RNA sequencing was performed on duodenal biopsy samples and was used to identify differentially expressed genes across ISO, IMO, and SIBO.
• Separately, male rats were gavaged with H₂S-producing bacteria to assess whether changes in gene expression linked to ISO were seen in an animal model.

TAKEAWAY

• Among patients with ISO, 643 differentially expressed genes were identified, with overall small bowel gene expression patterns differing significantly from those without ISO (P = .008).
• Differentially expressed genes in patients with ISO were associated with changes in pathways involved in redox balance, mitochondrial respiration, and immune signaling; effects were detectable at the study's lowest H₂S threshold of 1.5 ppm.
• Rats gavaged with Fusobacterium varium, a known H₂S-producing bacterium, showed 1244 differentially expressed genes, including changes in pathways related to mitochondrial respiration, redox balance, water homeostasis, gut motility, and visceral hypersensitivity, mirroring several of the molecular changes observed in patients with ISO; rats gavaged with a non-H₂S-producing strain showed no such pattern.
• In contrast, patients with IMO and those with SIBO showed no overall differences in transcriptomic profiles, and changes in gene expression in both groups were less pronounced than those seen in the ISO group.

IN PRACTICE

"Overall, these data identify ISO as an H₂S-associated transcriptomic phenotype with relevance to diarrhea-predominant IBS [irritable bowel syndrome] mechanisms, while emphasizing the need for larger, mechanistic studies integrating small bowel microbiome profiling, breath tests, and host -omics to validate these pathways and clarify their therapeutic implications," the authors wrote.

SOURCE

The study was led by Juliana de Freitas Germano, Medically Associated Science and Technology Program at Cedars-Sinai in Los Angeles. It was published online in mSystems.

LIMITATIONS

The relatively small sample sizes, particularly in the IMO and SIBO groups, may have limited the ability to detect additional gene-expression changes. The analysis did not fully clarify how key microbes associated with IMO and SIBO may have affected the transcriptomic findings observed in ISO. The study lacked small-bowel shotgun microbiome sequencing data, limiting the ability to directly link specific microbial communities with host gene-expression patterns.

DISCLOSURES

The study was supported by the Scott Gray Foundation, the Steve Perry Foundation, the Monica Lester Charitable Trust, and the Elias, Genevieve, and Georgianna Atol Charitable Trust. Some authors reported receiving grant support from, serving as consultants or speakers for, or holding equity in multiple companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.