Microbiome highlights from Digestive Disease Week 2025

From 3-6 May 2025, GMFH attended Digestive Disease Week in San Diego, USA. The conference featured a diverse range of talks spanning basic, translational, and clinical science in the microbiome.

The overlooked role of the small intestinal microbiome in IBS and IBD

A cutting-edge session focused on basic and translational sciences on the small intestinal microbiome as a modulator of functional and inflammatory gastrointestinal disease. Kerwyn Casey Huang, PhD, from Stanford University, discussed a novel, low-cost capsule that is easy to administer and allows for capturing spatially distinct and shared taxa between the small intestine and stool. The CapScan capsule can detect the pathobiont Klebsiella in the small intestine, which overgrows after a 14-day treatment with rifaximin that disrupts the healthy bacteria in the small intestine.

While IBS is considered to originate from the colon, Premysl Bercik, MD, PhD, from McMaster University, presented unpublished data on the role of the jejunum in inducing pain signaling in IBS. Lysophosphatidylcholine (LPC) and lysophosphatidic acid (LPA), which are phospholipids produced by the gut microbiome metabolism of dietary phosphatidylcholine, induced neuronal activation and visceral hypersensitivity through TRPC5 and LPAR₁/LPAR₃-dependent mechanisms, contributing to explaining periods of high pain in patients with IBS¹. Fecal levels of LPC and LPA were also higher in patients with IBD. Mice colonized with IBD microbiota displayed a reduced preference for light, increased immobility, and higher visceromotor responses to non-noxious stimuli on colorectal distension, suggesting that LPC and LPA-producing microbiota may negatively affect the gut-brain axis by inducing changes in emotional behavior and triggering visceral hypersensitivity².

The central role of the small intestine in IBS is explained by its higher density of immune cells (mast cells), dietary antigen load, and greater availability of substrates for microbial metabolism. Source: Bercik’s presentation at DDW 2025.

Small Intestinal Bacterial Overgrowth – is it clinically relevant?

While SIBO is a potential cause of IBS, not all cases of IBS are explained by SIBO despite its massive popularity on social media. A controversy debate session delved into for and against viewpoints on SIBO. Madhusudan Grover, MD, from the Mayo Clinic, explored clinical controversies surrounding SIBO in neurogastroenterology, emphasizing the need to better understand small bowel microbial ecology in health and disease through new omics and molecular strategies, before wasting patients’ time and resources on managing the unproven link between SIBO and IBS. The prevalence of SIBO in patients with IBS ranges from 4% to 78%, mainly due to the low sensitivity and specificity of breath tests, which measure oro-cecal transit and colonic fermentation rather than small intestinal overgrowth. It is also worth noting that overprescribing antibiotics to treat SIBO and IMO (intestinal methanogen overgrowth) risks further microbial depletion. According to Grover, while awaiting more robust data, clinicians might shift their approach from eradication to manipulation when addressing small intestine microbial overgrowth³.

Breath tests are more reliable for evaluating oro-cecal transit than for suspected small intestine bacterial overgrowth. Source: Grover’s presentation at DDW 2025.

Mark Pimentel, MD, from Cedars-Sinai Medical Center, stated that nowadays SIBO is more than a malabsorptive entity in patients with intestinal stasis, as classically defined. The modern concept of SIBO involves SIBO (hydrogen), IMO (methane), and ISO (hydrogen sulfide), based on the main gas produced by specific microorganisms that overgrow after an acute gastroenteritis⁴. Pimentel presented data supporting the validity of breath testing against small bowel culture and sequencing: CH₄ and H₂S on breath tests correlate with small bowel methanogens and H₂S-producing bacteria by next-generation sequencing, respectively^5,6. When performing the aspiration and culture of small intestinal contents, considered the ‘gold standard’ test for SIBO, Pimentel acknowledged that both researchers and clinicians should use a double-lumen catheter to prevent contamination and later use MacConkey for culture, which avoids double-counting of Gram-negative organisms⁷. In contrast, the use of a single-lumen catheter will be contaminated in 20% of cases⁸ and explains why, in patients with functional symptoms, the presence or absence of quantitative SIBO by aspirate plus culture of duodenal contents does not discriminate patients with and without dysbiosis, defined by 16S ribosomal RNA (rRNA) sequencing⁹. One potential mechanism by which acute gastroenteritis connects to post-infection IBS and SIBO is the development of antibodies against vinculin protein involved in neuronal cell-driven gut motility. New findings showed that normalization of anti-vinculin antibody levels by antibody-depleting therapies correlated with severity of IBS symptoms, which suggest monitoring anti-vinculin levels might assist in IBS management¹⁰.

Outside SIBO, unpublished findings from Amrit Kamboj, MD, and colleagues at Cedars-Sinai found that patients with gastroesophageal reflux disease have significant changes in the small bowel microbiome, including an increase in hydrogen sulfide-producing organisms.

The three main SIBO microtypes: SIBO (small intestinal bacterial overgrowth), IMO (intestinal methanogen overgrowth), and ISO (intestinal sulfide overproduction).
Source: Pimentel’s presentation at DDW 2025.

Next-generation microbiome therapies

Pimentel shared how new data on SIBO are helping guide the future of therapy. Cedars-Sinai investigators showed that low-dose rifaximin was more effective when combined with the antioxidant dietary supplement N-acetylcysteine (NAC) to improve bloating, diarrhea, and pain in patients with diarrhea-predominant IBS. It was suggested that NAC eliminates the mucus barrier, allowing rifaximin to work more effectively in reducing the primary bacterial culprits in SIBO (Escherichia coli, Klebsiella, Desulfovibrio, and Fusobacterium) that typically grow in the small bowel mucus layer and the free fluid layer. The combination therapy also reduced hydrogen sulfide on the breath test. These findings are particularly promising, considering that current antibiotic therapies are effective in only 44% of people with SIBO. New findings in a rat model of constipation showed that a novel microbiome therapy, CS-06 (blocking the enzyme methylenetetrahydromethanopterin dehydrogenase needed for CH₄ production), reduces methane production in stool culture and improves the constipation phenotype¹¹. Data from the TrluMPH phase II study showed EBX-102-02, an oral full spectrum microbiome product, was safe with clinical symptom improvement in 122 adults with IBS-C, with over 70 new species engrafted into the patients’ microbiome after two doses¹².

Basic and translational findings demonstrated the role of genetically-engineered E. coli Nissle in calprotectin-responsive treatment of IBD and in reducing bacterial translocation across the intestinal barrier, as well as the role of inosine produced by Akkermansia muciniphila in relieving diarrhea-predominant IBS via improving intestinal water absorption through aquaporin membrane transport proteins. Engraftment of live biotherapeutics, which is influenced by diet, intestinal inflammation, and the timing of administration, as well as the safety of the product (e.g., the genotoxicity of the E. coli Nissle strain attributed to the synthesis of the genotoxin colibactin), are major challenges when transitioning next-generation probiotics from the bench to the bedside, explained Nicole Siguenza, PhD candidate, from University California San Diego, based on unpublished findings using natural E. coli as the microbial chassis EcAZ-2.

Postbiotics were also featured at DDW 2025, with a systematic review showing their potential benefits in managing IBS symptoms, including symptom severity, pain reduction, and improvement in quality of life, with limited adverse events reported. Additional benefits of postbiotics over probiotics include stability, non-viability (safer profile in individuals with an immunocompromised immune system), and longer shelf life¹³.

A systematic review and meta-analysis of 4 randomized clinical trials showed the potential and safety of postbiotics in alleviating IBS symptoms.
Source: DDW 2025.

Should we be exploring off-label use of live biotherapeutic products?

In a debate around the off-label use of live biotherapeutic products (LBP), Jessica R. Allegretti, MD, from Brigham and Women’s Hospital (Cambridge, Massachusetts), summarized ongoing and published clinical trials of broad consortium of microbes prepared from human stool and narrow consortium composed of live purified Firmicutes spores, with no serious or treatment-related adverse events when used for the FDA indication of recurrent Clostridioides difficile infection in adults following antibiotic treatment. However, Allegretti highlighted that the off-label use of LBPs is not advised, supported by the fact that data from unapproved FMT for IBD and IBS is inconclusive or negative, and the primary source of data on use in IBD and IBS is post hoc analysis from C. difficile trials^14,15. A press release published after the conference announced that an oral, defined bacterial consortium of eight live bacteria for preventing recurrent C. difficile infection did not meet the primary endpoint in ulcerative colitis, which supports that it is too early to recommend the off-label use of LBPs¹⁶. Sahil Khanna, MD, from Mayo Clinic, acknowledged that caution is needed when expecting FMT to work for complex diseases, as it did for CDI. Infections and immune reactions are common safety concerns for FMT, as well as other unexpected outcomes (e.g., obesity) from seemingly safe donors. Ethical issues should also be considered, as administering microbiota products for unapproved conditions may provide false hope and potentially delay patients from receiving established treatments, and a lack of efficacy data makes favorable outcomes uncertain.

Donor, recipient, disease, stool processing, and follow-up considerations for microbial restoration therapies for complex diseases.
Source: Khanna’s presentation at DDW 2025.

Jordan Axelrad, MD, MPH, from NYU Grossman School of Medicine, covered the rationale behind the use of microbiome-targeted treatments in IBS and IBD, such as the role of fructooligosaccharides (FOS) for IBD and IBS, microencapsulated butyrate to boost the growth of bacteria that produce short-chain fatty acids, and traditional probiotics to prevent recurrent pouchitis and alleviate IBS-like symptoms. When it comes to FMT and precision microbiome therapeutics for IBD and IBS, data are mixed¹⁷. Studies of FMT in IBD for non-CDI indications have focused primarily on UC, with a systematic review concluding that FMT is effective for inducing clinical and endoscopic remission of mild-to moderately-active UC without a significantly increased risk of adverse events, while there is a paucity of data for maintenance of remission of UC after FMT¹⁸. A recent systematic review found 64% of FMT participants experienced an improvement in IBS symptoms after 3 months compared to 42% in the placebo, but the overall quality of the evidence was low¹⁹. Given the patient’s interest in microbiome-related treatments and the relatively low incidence of adverse events, and without known drug interactions, Axelrad concluded that it would be worthwhile to try them.

Promote or avoid? The fiber type, gut microbial function, and immune status may determine the effect of fiber in gastrointestinal health

A second debate focused on how dietary fibers impact gastrointestinal diseases and disorders differently. Heather Armstrong, PhD, MSc, from the University of Manitoba (Canada), focused on the downsides of high fiber consumption. While it is true that dietary fiber provides clear health benefits, Armstrong acknowledged that both the type and quantity of dietary factors and the presence of the right gut microbes will lastly affect the fiber’s impact on the host. FOS may fuel inflammation (increased IL-1b secretion) in colonic biopsies from patients with active IBD. Even in adult patients with UC in remission, b-fructans (15 g/d over 6 months) led to symptom relapse (~30% of patients)²⁰. These findings were replicated in animal models in which inulin and FOS (b-fructan fibers) promoted gut damage, progression to colon and liver cancer, and rheumatoid arthritis^21,22,23. Beyond patients with IBD, people with multiple sclerosis also report that fiber has detrimental effects on symptoms²⁴, which a lack of fermentative microbe activities could explain.

The type of fiber and dose also shape the outcomes in the host. Matam Vijay-Kumar, MD, from the University of Toledo College of Medicine, showed that dietary inulin, but not pectin, cellulose, and psyllium, aggravates colitis inflammation in mouse models²⁵. The impact of fibers on host physiology also works in a microbiota-independent manner, involving intestinal barrier function and dampened immune responses^26,27. These findings indicate that purified fibers added to processed foods in the context of an unbalanced diet do not recapitulate the benefits of fibers present in fruits and vegetables.

Microbiome research is helping understanding how dietary fibers impact gastrointestinal conditions.
Source: Armstrong’s presentation at DDW 2025.

Based on available research, B-fructans especially may not be safe for all gastroenterology and hepatology patients, and we need to understand better why, especially in the context of IBD flares and colorectal and liver cancer. Precision nutrition approaches integrating the different host, microbial, and diet features are needed to answer the question of which fiber types should be recommended for GI conditions.

Finally, a central theme addressed in all sessions was that when it comes to translating diet and microbiome-based interventions for gastrointestinal conditions and beyond, challenges include the mechanism of action of the intervention (which is poorly characterized as compared to small molecules and biologics), parameters contributing to the wide heterogeneity in an individual’s microbiome composition, manufacturing and regulatory hurdles, and optimizing robust clinical trial design.

Digestive Disease Week 2026 is scheduled for 2-5 May 2026 in Chicago, USA.

References:

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2. Vicentini FA, Hall Bruce M, Pujo J, et al. Linking microbial phospholipids with visceral hypersensitivity and altered emotional behaviour induced by inflammatory bowel disease (IBD)-associated microbiota. Presentation Number: 759.
3. Kashyap P, Moayyedi P, Quigley EMM, et al. Critical appraisal of the SIBO hypothesis and breath testing: A clinical practice update endorsed by the European society of neurogastroenterology (ESNM) and the American neurogastroenterology and motility society (ANMS). Neurogastroenterol Motil. 2024; 36(6):e14817. doi: 10.1111/nmo.14817.
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6. Villanueva-Millan MJ, et al. Hydrogen sulfide producers in the duodenum by shotgun sequencing correlate with hydrogen sulfide levels on breath testing. Digestive Disease Week 2024. Presentation Number: 705. Available on: https://ddw.digitellinc.com/p/s/hydrogen-sulfide-producers-in-the-duodenum-by-shotgun-sequencing-correlate-with-hydrogen-sulfide-levels-on-breath-testing-7088
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12. Hobson A, et al. A randomized, double-blind, placebo-controlled, phase II trial assessing the safety and efficacy of EBX-102-02, an oral full-spectrum intestinal microbiota product, in patients with irritable bowel syndrome with constipation; the TRluMPH trial. Digestive Disease Week 2025. Abstract number 987b. Available on: https://www.gastrojournal.org/article/S0016-5085(25)05722-1/abstract
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24. Coe S, Tektonidis TG, Coverdale C, et al. A cross sectional assessment of nutrient intake and the association of the inflammatory properties of nutrients and foods with symptom severity in a large cohort from the UK Multiple Sclerosis Registry. Nutr Res. 2021; 85:31-39. doi: 10.1016/j.nutres.2020.11.006.
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26. Yeoh BS, Saha P, Golonka RM, et al. Enterohepatic shunt-driven cholemia predisposes to liver cancer. Gastroenterology. 2022; 163(6):1658-1671.e16.
27. Lancaster SM, Lee-McMullen B, Wilbur Abbott C, et al. Global, distinctive, and personal changes in molecular and microbial profiles by specific fibers in humans. Cell Host Microbe. 2022; 30(6):848-862.e7. doi: 10.1016/j.chom.2022.03.036.