Colorectal cancer remains a major health burden in Iowa and across the United States. It is among the most common cancers in the state and a leading cause of cancer-related death. Although overall colorectal cancer rates have declined, cases in adults younger than 50 continue to rise, underscoring the need to better understand what drives different forms of the disease.

A new study from Ashutosh Mangalam, PhD’s research laboratory, “The distinct roles of Negativicoccus and Fusobacterium in proximal- and late-onset colorectal cancer,” provides evidence that the gut microbiome, the community of bacteria living in the digestive tract, may contribute to distinct colorectal cancer subtypes. Published in Gut Microbes, the study identifies bacterial signatures associated with tumor location and age at diagnosis and shows that specific bacteria can activate cancer-related pathways in laboratory models. 

The study was led by Soham Ali, MD, who drove the overall project and microbiome analysis. Pashtoon Kasi, MD, MS provided key clinical expertise and helped guide the patient-focused aspects of the work, while Apurva Patel, PhD led the mechanistic laboratory studies examining how specific bacteria influence cancer-related pathways. The broader team, including Peter Lehman, MS; Rachel Fitzjerrells, PhD; and Dr. Ashutosh Mangalam, brought together expertise in oncology, pathology, microbiome science, and computational analysis.

One major barrier in gut microbiome research is sample collection. Stool samples are commonly used but can be inconvenient for patients, and many are never returned. To address this challenge, the team tested whether a simple anal swab collected during a clinic visit could serve as a practical alternative. Among 80 colorectal cancer patients enrolled through the Holden Comprehensive Cancer Center, 95% provided an anal swab, compared with only 41% who provided a stool sample. The bacterial profiles from anal swabs showed strong overlap with stool samples for several major gut bacterial groups, supporting anal swabs as a feasible, patient-friendly approach for microbiome research. 

Using this approach, the researchers identified bacteria associated with different colorectal cancer subtypes. A little-studied bacterial genus called Negativicoccus was enriched in proximal, or right-sided, colon cancers. This is notable because right-sided and left-sided colorectal cancers often differ in their biology, molecular features, and clinical behavior. The study represents the first identification of Negativicoccus enrichment in colorectal cancer subgroups, highlighting its potential as a new microbial marker of proximal tumors. 

The team also found that Fusobacteriota, a bacterial group that includes Fusobacterium, was more strongly associated with late-onset colorectal cancer, defined as cancer diagnosed at age 50 or older. Fusobacterium has previously been linked to colorectal cancer, but these findings suggest that its role may vary by disease subtype and age at diagnosis. 

To understand how these bacteria may influence cancer biology, the investigators performed mechanistic experiments using colon cancer cells. Negativicoccus activated genes in the RAS/MAPK pathway, including c-MYC, KRAS, MAPK1, and Cyclin D1, and increased inflammatory signaling associated with tumor cell growth. In contrast, Fusobacterium affected the WNT/β-catenin pathway and promoted cellular behaviors linked to migration and invasion. Together, the results suggest that different microbes may contribute to colorectal cancer through distinct biological mechanisms. 

The study also highlights the importance of Iowa-specific microbiome research. The gut microbiome is shaped by diet, environment, geography, medication use, and other regional factors, meaning findings from other populations may not fully reflect the microbial landscape of Iowa patients. By focusing on patients treated at the University of Iowa, this work provides regionally relevant data for a disease that continues to have a significant impact in the state.

While promising, the researchers emphasize that this work is an early step. Future studies that follow patients over time, include larger and more diverse cohorts, and link microbiome changes to treatment response will be needed to determine whether these bacterial signatures can help predict outcomes or guide personalized therapies.

Collectively, this study establishes anal swabs as a high-compliance tool for colorectal cancer microbiome research and identifies distinct bacterial pathways that may help explain differences among colorectal cancer subtypes. The findings open the door to future microbiome-based strategies for cancer screening, disease monitoring, and therapeutic development.