At the 2025 Cholangiocarcinoma Summit, Nadim J. Ajami, PhD, delivered a keynote address on the evolving role of microbiome research in advancing medical therapies. His talk focused on harnessing the microbiome to enhance patient outcomes through precision medicine, innovative therapies, and biomarker discovery, underscoring its transformative potential in oncology.
Dr Ajami began by describing a paradigm shift in microbiome research, from viewing microbes as pathogens to recognizing them as a dynamic, diverse community essential for sustaining health throughout life. He noted that each person’s microbiome is unique, shaped by genetics, diet, environment, and lifestyle, playing a role in diverse functions, such as digestion and immune regulation. Dysbiosis, or microbial imbalance, is associated with cancer, obesity, diabetes, and inflammatory disorders, and microbiome modulation strategies may restore microbial balance and improve outcomes. Unlike the static human genome, the microbiome is adaptable and evolves faster, with microbial communities and their functions changing over time. This flexibility offers significant therapeutic promise, particularly for personalized interventions such as cancer treatment. The microbiome can be utilized to develop biotherapeutics, prebiotics, fecal microbiota transplants, and microbiome-based drugs.
A key part of his discussion drew on insights from the Human Microbiome Project (HMP), a National Institutes of Health–funded initiative that mapped microbial diversity across body sites. The HMP revealed that the human body is covered inside and out with microbes, organized into distinct communities based on anatomical sites such as the oral cavity, skin, urogenital tract, and gastrointestinal tract. He highlighted that stool samples primarily reflect the distal colon and are not representative of the entire gut. The HMP set a new benchmark by taking an integrative approach, sequencing thousands of microbial genomes and isolating bacteria, fungi, viruses, and protists from the same samples to map the full diversity of the human microbiome. Most importantly, although phylogeny varies by site, and individual, core metabolic functions remain conserved, underscoring the principle of “function over phylogeny.” Dr Ajami emphasized that microbiomes are increasingly recognized as actionable hallmarks of cancer, and understanding microbial–host interactions is essential for developing actionable therapeutic strategies. He noted that microbiomes are constantly exchanging genomic elements and influencing each other’s behavior. He introduced MD Anderson Cancer Center’s PRIME-TR platform, which is designed to support comprehensive microbiome research, including observational, mechanistic, and interventional research, and has enabled 12 interventional trials aimed at inducing durable changes in microbiome composition or functionality rather than clinical outcomes.
Dr Ajami then illustrated these concepts with practical applications, including the Patient Mosaic study, which aims to gather microbiome and clinical data from 10,000 patients with cancer. Findings from a cohort of 27 patients with biliary tract cancer (BTC) treated with immune checkpoint inhibitors showed that responders had higher alpha diversity, indicating richer microbial communities, whereas nonresponders exhibited dysbiosis. Specific taxa such as Romboutsia and Ruminococcus were enriched in responders, whereas Streptococcus was enriched in nonresponders, highlighting the potential of microbiome-based biomarkers to inform therapy response and prognosis in BTC.
Dr Ajami also discussed a clinical trial by Seres Therapeutics evaluating SER-401, a spore-based microbiome therapy in patients with melanoma receiving nivolumab, an immunotherapy drug. The trial was randomized with 2 arms, an active arm where patients were pretreated with vancomycin and then treated with SER-401 and nivolumab, and a placebo arm where patients were treated with nivolumab only. The rationale for gut depletion came from prior studies showing that antibiotic pretreatment improved microbial engraftment of similar formulations. Unexpectedly, the placebo arm showed higher response rates (67% vs 25%) than the SER-401 arm, suggesting that vancomycin preconditioning prior to SER-401 administration may have disrupted the gut microbiota, thereby reducing the effectiveness of immunotherapy. This aligns with prior evidence that broad-spectrum antibiotic use before immunotherapy can negatively impact survival outcomes. He stressed the need to optimize antibiotic timing to minimize microbiome disruption during cancer treatment.
In response to a question about whether the microbiome changes throughout the day, Dr Ajami noted that while microbial composition remains stable, functional changes occur as different genes are activated. When asked about challenges with single-species interventions, Dr Ajami advocated for multistrain solutions that reflect the gut’s ecological complexity and are likely to be more stable over time. Responding to a question on classifying immunotherapy responses, Dr Ajami acknowledged variability across studies and emphasized the importance of building robust evidence linking microbiome changes to clinical outcomes.
Overall, Dr Ajami’s keynote highlighted the transformative potential of microbiome research in cancer care, calling for precision-targeted interventions and robust clinical evidence to optimize patient outcomes.
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