A diet high in foods (such as processed meats) that enrich sulfur-metabolizing bacteria in the gut and thereby increase production of hydrogen sulfide (H2S) is associated with increased risk of early-onset colorectal neoplasia (colorectal adenomas or serrated polyps), researchers report in the November issue of Gastroenterology. These findings might help explain the recent and troubling increase in the incidence of colorectal cancer (CRC) in persons younger than 50 years.
Diet-mediated alterations in specific microbes and their products or metabolites can affect risk for CRC. For example, patterns of food intake associated with enrichment of sulfur-metabolizing microbes can increase production of the carcinogen hydrogen sulfide (H2S). The sulfur microbial diet (a pattern of food intake linked to 43 gut microbes associated with sulfur metabolism) has features linked to CRC risk, such as increased processed meats and decreased vegetables and legumes. Long-term adherence to this pattern was associated with increased risk for CRC in a cohort of older men.
To investigate whether diet-induced alterations of specific gut microbe populations associate with development of early-onset CRC, Long Nguyen et al collected diet and medical data from 30,818 women younger than 50 years in the Nurses Health Study 2.
In this cohort, Nguyen et al documented 2911 cases of early-onset adenoma, diagnosed over 45,843 lower endoscopies, including 1242 conventional adenomas, 1669 serrated lesions, 230 polyps with advanced histology, and 200 polyps that were 1 cm or larger.
After the authors adjusted for established risk factors, higher sulfur microbial diet scores were associated with a 31% increase in risk for early-onset adenomas (a marker of CRC risk), even after they adjusted for other CRC risk factors (multivariable-adjusted ORQ4 vs Q1, 1.31; 95% CI, 1.10–1.56; Ptrend = .02). Sulfur microbial diet scores were not associated with serrated lesions or later-onset adenomas (conventional adenomas in women older than 50 years).
The association with early-onset conventional adenoma was stronger for lesions with advanced histology (and therefore greater malignant potential). A higher sulfur microbial diet score increased risk for adenomas characterized by tubulovillous or villous histology (ORQ4 vs Q1, 1.65; 95% CI, 1.12–2.43; Ptrend = .04) vs tubular adenomas (ORQ4 vs Q1, 1.24; 95% CI, 1.02–1.50, Ptrend = .09). The authors found no clear relationship between the sulfur microbial diet and the size of early-onset conventional adenoma.
The increase in risk for conventional adenomas was greatest for neoplasias of the proximal colon (ORQ4 vs Q1 = 1.58; 95% CI, 1.17–2.14; Ptrend = .01),
When the authors assessed greater adherence to the sulfur microbial diet during adolescence, they found an association with early-onset conventional adenomas. Compared with sulfur microbial diet scores during high school below the median, scores above the median increased the odds for early-onset conventional adenomas by 13%.
Nguyen et al conclude that long-term adherence to a diet that promotes enrichment of sulfur-metabolizing bacteria in the gut was associated with increased risk of early-onset conventional adenomas (with advanced histopathology and arising in the proximal colon). In contrast, no association was found for adenomas diagnosed after age 50.
The authors propose that the increased risk of early-onset adenoma conferred by this diet begins during adolescence, or alternatively, that there is substantial latency between dietary exposure and adenoma occurrence. Diet-induced alterations in gut sulfur could have a stronger effect on the initiation of proximal lesions early in life.
How might H2S produced by gut microbes promote carcinogenesis? Nguyen et al explain that, in the presence of microbially generated H2S, the mucus bilayer in the colon becomes fragmented, which promotes inflammation and carcinogenesis. Furthermore, sulfur-containing amino acids found in meats and preservatives serve as substrates that promote this process. Conversely, plant-based sulfur sources, such as those found in legumes and vegetables, are distinct from animal-based sources, and are composed primarily of glucosinolate compounds that prevent carcinogenesis.
Differences in dietary risk factors could account for the heterogeneity in risk of early-onset adenomas compared with those occurring at or after age 50 years, particularly in younger persons, in whom poor quality diets are widely and increasingly prevalent. Differences in the proportion of diet-attributable risk by intestinal region might be due to differences in microbe populations in these segments.
In an editorial that accompanies the article, Wade Billings and Anna Krigel state that these findings may help to explain, at least in part, the rising rates of early-onset CRC. Other risk factors identified for early-onset adenoma or CRC include obesity, alcohol use, a Western diet, and intake of red and processed meat. The findings of Nguyen et al provide additional evidence for the association between dietary factors and early-onset colorectal neoplasia. Further studies are needed to determine the mechanisms of these interactions and lifestyle modifications that might reduce the risk of CRC in young and older adults.