Western Diet Promotes Intestinal Colonization by Collagenolytic Microbes and Promotes Tumor Formation After Colorectal Surgery

Abstract

See Covering the Cover synopsis on page 796.BACKGROUND & AIMS: The Western diet, which is high in fat, is a modifiable risk factor for colorectal recurrence after curative resection. We investigated the mechanisms by which the Western diet promotes tumor recurrence, including changes in the microbiome, in mice that underwent colorectal resection. METHODS: BALB/c male mice were fed either standard chow diet or Western-type diet (characterized by high fat, no fiber, and decreased minerals and vitamins) for 4 weeks; some mice were given antibiotics or ABA-PEG20k-Pi20 (Pi-PEG), which inhibits collagenase production by bacteria, but not bacterial growth, in drinking water. Colorectal resections and anastomoses were then performed. The first day after surgery, mice were given enemas containing a collagenolytic rodent-derived strain of Enterococcus faecalis (strain E2), and on the second day they were given mouse colon carcinoma cells (CT26). Twenty-one days later, distal colons were removed, and colon contents (feces, distal colon, and tumor) were collected. Colon tissues were analyzed by histology for the presence of collagenolytic colonies and by 16S ribosomal RNA sequencing, which determined the anatomic distribution of E faecalis at the site of the anastomosis and within tumors using in situ hybridization. Mouse imaging analyses were used to identify metastases. RESULTS: Colorectal tumors were found in 88% of mice fed the Western diet and given antibiotics, surgery, and E faecalis compared with only 30% of mice fed the standard diet followed by the same procedures. Colon tumor formation correlated with the presence of collagenolytic E faecalis and Proteus mirabilis. Antibiotics eliminated collagenolytic E faecalis and P mirabilis but did not reduce tumor formation. However, antibiotics promoted emergence of Candida parapsilosis, a collagenaseproducing microorganism. Administration of a Pi-PEG reduced tumor formation and maintained diversity of the colon microbiome. CONCLUSIONS: We identified a mechanisms by which diet and antibiotic use can promote tumorigenesis by colon cancer cells at the anastomosis after colorectal surgery. Strategies to prevent emergence of these microbe communities or their enzymatic activities might be used to reduce the risk of tumor recurrence in patients undergoing colorectal cancer surgery.

Inulin Fermentable Fiber Ameliorates Type I Diabetes via IL22 and Short-Chain Fatty Acids in Experimental Models

“… 15 Accordingly, many studies use GBC to serve as a high-fiber diet and compare it with a compositionally defined diet (CDD) designed to lack fiber. 16 , 17 By comparison, a widely used “open-source” CDD mimics the overall fat, protein, and carbohydrate levels of GBC, thus justifying its use as a control diet in many studies. However, this commonly used CDD has a total fiber content of only 5%, which is composed entirely of insoluble fiber, cellulose, thus supporting its use as a low-fiber diet.…”

High fat diet, gut microbiome and gastrointestinal cancer

“…The colonization of these bacteria at the anastomosis destroys the healing intestine, resulting in increased permeability and transmigration of cancer cells, which promotes the recurrence of CRC. HFD increased collagenase-producing microbes 194 , accelerating this effect. MCP-1 is a cell factor that acts through its receptor CCR2 to recruit the circulating leukocytes to the site of inflammation 195 .…”

Oral neomycin and bacitracin are effective in preventing surgical site infections in elective colorectal surgery: a multicentre, randomized, parallel, single-blinded trial (COLORAL-1)

“…This need was only partially met with recent studies proposed by Espin et al [ 17 ]. Finally, more than running the risk of generating antibiotic resistance, it is well known the impact that antibiotics have on the gut microbiome that lasts well beyond the surgical intervention [ 18 , 19 ].…”