Dysbiosis and Altered Metabolites

When the Colon’s Microbial Ecosystem Loses Functional Balance

The colon contains a complex microbial ecosystem whose members compete, cooperate, and transform dietary material into biologically active compounds. In a stable ecosystem, these microbial activities help support colonocyte metabolism, barrier function, and immune regulation.

Dysbiosis describes a disruption in this ecological balance. It does not refer to one universally unhealthy microbiome or the presence of a single harmful organism. Different individuals may show different microbial patterns. What matters biologically is not only which organisms are present, but also what the microbial community is doing.

A disrupted community may produce a different mixture of metabolites, including:

• Reduced or altered production of short-chain fatty acids
• Changes in bile-acid metabolism
• Increased production of inflammatory or genotoxic compounds
• Changes in the availability of nutriets and respiratory substrates
• Signals that affect the intestinal barrier and immune system

A Potentially Self-Reinforcing Disturbance

Loss of butyrate-producing microbes—or reduced availability of the dietary substrates they ferment—may weaken the cooperative cycle described on the previous page.

Less microbial butyrate may reduce oxidative metabolism in mature colonocytes. Lower oxygen consumption can allow more oxygen to reach the intestinal lumen, creating conditions that favor facultative anaerobic organisms. Some of these organisms can use oxygen or nitrate to expand, potentially pushing the ecosystem further away from its anaerobic state.

Inflammation and impaired barrier function may reinforce this disturbance by changing the nutrients and electron acceptors available to microbes.

What Human Studies Show

Researchers have identified differences in microbial communities and metabolites among people without colorectal lesions, people with adenomas, and people with colorectal cancer. Some studies have detected signs of microbial disruption during the adenoma stage, suggesting that dysbiosis is not limited to established cancer.

However, these studies do not prove that dysbiosis begins the disease process. A developing lesion may also alter its surrounding environment and reshape the microbiome. Cause and effect may operate in both directions.

The EpiNutrition Hypothesis

The hypothesis explored here proposes that dysbiosis may sometimes occur before visible polyp formation and weaken the normal butyrate–colonocyte relationship.

This altered metabolic environment may contribute to a shift away from mitochondrial oxidation and toward greater reliance on glycolytic metabolism. Whether this sequence occurs in humans before adenoma formation—and whether restoring microbial function can reverse it—remains to be established.

Dysbiosis should therefore be understood as a potential biological contributor and research target, not as a clinically validated diagnosis of colorectal cancer risk.

References

1. Nakatsu G, Li X, Zhou H, Sheng J, Wong SH, Wu WKK, et al. Gut mucosal microbiome across stages of colorectal carcinogenesis. Nature Communications. 2015;6:8727. doi: 10.1038/ncomms9727. PMID: 26515465; PMCID: PMC4640069.
2. Yachida S, Mizutani S, Shiroma H, Shiba S, Nakajima T, Sakamoto T, et al. Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer. Nature Medicine. 2019;25(6):968–976. doi: 10.1038/s41591-019-0458-7. PMID: 31171880.
3. Byndloss MX, Olsan EE, Rivera-Chávez F, Tiffany CR, Cevallos SA, Lokken KL, et al. Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion. Science. 2017;357(6351):570–575. doi: 10.1126/science.aam9949. PMID: 28798125; PMCID: PMC5642957.