Exploratory research in mSystems finds broader small-bowel gene-expression changes in ISO than in methanogen overgrowth or culture-defined bacterial overgrowth, with each condition showing a distinct profile, supporting the biological rationale for distinguishing them

A new peer-reviewed study in mSystems, a journal of the American Society for Microbiology, finds that intestinal sulfide overproduction (ISO) is associated with a distinct gene-expression signature in the small bowel, one that looks markedly different from two related conditions commonly grouped with ISO.

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ISO, small intestinal bacterial overgrowth (SIBO), and intestinal methanogen overgrowth (IMO) are microbial imbalances closely tied to irritable bowel syndrome (IBS), which affects an estimated 6.1% of U.S. adults yet remains widely underdiagnosed. In this study, researchers classified ISO and IMO from fasting breath samples, measuring hydrogen sulfide and methane, respectively, and classified SIBO using duodenal aspirate culture. Until now, no study had compared how gene activity in patients' own intestinal cells differs across the three conditions.

Led by researchers at the MAST Program at Cedars-Sinai, with breath gases measured using proprietary gas chromatography by Gemelli Biotech, the study analyzed small-bowel biopsies from 85 participants undergoing upper gastrointestinal endoscopy, measuring which genes were more or less active in their intestinal cells.

The findings point to three biologically distinct conditions. Among patients who had only one of the three, no differentially expressed gene was shared across all three groups, and pairwise overlap was minimal. ISO, associated with elevated hydrogen sulfide, showed by far the broadest changes, involving genes associated with energy production, oxidative balance, immune signaling, and intestinal fluid regulation and transit, a pattern with potential relevance to mechanisms associated with diarrhea-predominant IBS. IMO and SIBO were associated with substantially fewer gene-expression changes in this group. In animal experiments, rats exposed to some hydrogen-sulfide-producing bacteria showed partially concordant changes, while a non-producing strain did not show the same broad ISO-associated pattern.

Because their symptoms overlap, the three conditions can be hard to tell apart clinically. The study suggests that treating them as biologically interchangeable may overlook meaningful differences. The study's breath measurements were performed using Gemelli Biotech's gas chromatography technology, the same technology that enables its Trio-Smart breath test to detect hydrogen sulfide. For Gemelli, the findings add peer-reviewed support to the scientific rationale for distinguishing these conditions.

The physician-led research team concluded that the study "supports the need for individualized therapeutic strategies for each condition in the future."

Ritesh Agarwal, chief executive officer of Gemelli Biotech, said: "For years, patients with elevated hydrogen sulfide could receive breath-test results that appeared normal or incomplete because conventional tests did not directly measure all three gases. This research reinforces that ISO has a biologically distinct profile. Trio-Smart is currently the only clinical breath test in the U.S. that measures hydrogen, methane, and hydrogen sulfide, giving patients and clinicians a more complete picture of intestinal gas production and the conditions associated with it."

About Gemelli Biotech: Gemelli Biotech develops precision laboratory tests that identify measurable imbalances in key biological markers of gut health, available with the convenience of at-home collection. Its core diagnostics are Trio-Smart®, the only at-home breath test that measures all three fermentation gases associated with microbial overgrowth (hydrogen, methane, and hydrogen sulfide) in a single test, and IBS-Smart®, the only licensed, clinically validated blood test for post-infectious IBS, which measures two validated antibody biomarkers (anti-CdtB and anti-vinculin). Developed in partnership with the Medically Associated Science and Technology (MAST) Program at Cedars-Sinai and grounded in peer-reviewed gastrointestinal research, including work referenced in ACG and AGA clinical guidelines, Gemelli's tests are processed in a centralized CLIA-certified laboratory and are available by physician order and patient-directed access across all 50 U.S. states and territories, with more than 100,000 patients and providers served to date.

For more information, visit triosmartbreath.com

Disclosure: Cedars-Sinai has a licensing agreement with Gemelli Biotech. Study authors Ali Rezaie, MD, Mark Pimentel, MD, and Ruchi Mathur, MD, hold equity in Gemelli Biotech.

Additional author disclosures are available in the published article.

Reference: de Freitas Germano J, Leite G, Villanueva-Millan MJ, et al. Transcriptomics profiles in intestinal sulfide overproduction, small intestinal bacterial overgrowth, and intestinal methanogen overgrowth. mSystems. Published online June 29, 2026. https://journals.asm.org/doi/10.1128/msystems.00458-26

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Similar symptoms.Three different conditions. One can reshape the gut.