Leaky Gut and Chemo

Russo F, Linsalata M, Clemente C, et al. The effects of fluorouracil, epirubicin, and cyclophosphamide (FEC60) on the intestinal barrier function and gut peptides in breast cancer patients: an observational study. BMC Cancer. 2013 Feb 4;13:56.

Prospective observational study of consecutive patients

The study enrolled 60 breast cancer patients who had undergone surgical resection of the tumor and lymph nodes and received adjuvant chemotherapy. Thirty-seven patients completed the study. A questionnaire was used to determine which patients developed diarrhea.

All participants received the same chemotherapy FEC-60 (fluorouracil 600 mg/m2, epirubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days for 6 cycles).

During chemotherapy, intestinal permeability was assessed by lactulose/mannitol (La/Ma) urinary test on days 0 and 14. Levels of several GI peptides, specifically zonulin, glucagon-like peptide-2 (GLP-2), epidermal growth factor (EGF), and ghrelin were measured by ELISA tests at 5 time-points (days 0, 3, 10, 14, and 21).

As the authors explain, zonulin modulates the mucosal barrier by breaking down the tight junctions during inflammation and plays a “role in the pathogenesis of autoimmune diseases such as celiac disease and type-1 diabetes.” The authors note that GLP-2 is an “intestinotrophic growth hormone that promotes many aspects of intestinal function, including rapid enhancements of mucosal growth and the intestinal barrier function.” It is thought that EGF and GLP-2 protect against chemotherapy-induced damage to the intestinal mucosa. Ghrelin, which is produced by GI enteroendocrine cells, is “involved in the control of the mucosal barrier and is considered a potential protective agent against chemotherapy complications. In mice, ghrelin administration has been demonstrated to prevent the doxorubicin-induced GI mucosal damage.”

During chemotherapy, the lactulose-mannitol ratio increased significantly by day 14 from baseline. Zonulin levels were unaffected. GLP-2 and EGF levels decreased significantly. GLP-2 levels on day 14 were significantly lower than on day 0 and day 3, while EGF values were significantly lower on day 10 than at the baseline.

Ghrelin increased significantly at day 3 compared to days 0 and 21. Ten patients (27%) suffered from diarrhea. On day 14 of chemotherapy, a significant increase of the La/Ma ratio occurred in patients with diarrhea compared to patients without it. Patients with diarrhea had significantly lower GLP-2 and higher ghrelin levels.

 

In the patients with diarrhea, an inverse correlation between BLP-2 and the La/Ma ratio was seen at day 14. All patients showed significantly increased intestinal permeability and shifts in GLP-2, ghrelin, and EGF. Those who developed diarrhea during treatment had a different GI peptide profile.¹

These results should not surprise any clinician. Cancer patients undergoing treatment frequently develop diarrhea and it is fair to assume this is linked to increased intestinal permeability. The question is what, if anything, we do about it.

 

This FEC-60 drug cocktail is not alone in causing gut damage. Other cancer treatments are associated with increased gut permeability. For example, bevacizumab, oxaliplatin, 5-fluorouracil, and leucovorin,² abdominal radiation, which causes its own special form of gastritis, is also associated with increased permeability.³

 

What may surprise many people is that this increase in permeability may be a good thing.

 

Several recent papers suggest that with several chemotherapy drugs—the platinum drugs and cyclophosphamide in particular—this increase in permeability and resultant bacterial translocation is important, if not necessary, for the drugs’ anticancer action.

 

In an article published in the November 2013 issue of Science, Viaud et al suggested that certain chemotherapy drugs act only indirectly against cancer; their primary mechanism of action is to trigger intestinal permeability that in turns leads to the translocation of bacteria from the intestine into the body, where their presence triggers an immune response.⁴ In experiments on mice, Viaud et al found that cyclophosphamide wreaked havoc on the gut lining; the villi shrank, and the small intestine’s permeability increased. Several species of bacteria, in particular Gram-positive bacteria, emigrated into the body. Two Lactobacillus species and Enterococcus hirae bacteria found their way into the lymph nodes and spleen. This migration may be key to the drugs’ action. In vitro work suggests these Gram-positive bacteria cause immature T cells to transform first into Th17 cells, and later some of them convert into memory cells allowing a prolonged immune response to the tumor. Mice with cancer who were bred to be germ-free or treated with antibiotics that kill these Gram-positive bacteria did not increase Th17 cells when treated with cyclophosphamide. More importantly, the drug no longer shrank their tumors.

 

In a parallel paper, Iida et al suggest that gut bacteria are necessary for platinum drugs to work.⁵ Pretreatment of mice with antibiotics lessens the drugs’ action against implanted tumors.

 

Oxaliplatin typically works at least in part by increasing reactive oxygen species (ROS) in cancer cells, and this leads to cancer cell apoptosis. In a study of mice implanted with various cancers, Iida’s group treated half with antibiotics before administering oxaliplatin. The mice lacking bacteria did not increase ROS. Within 3 weeks, 80% of the antibiotic-treated mice had died. The mice not given antibiotics still had normal intestinal flora and fared far better; they increased ROS production and 80% were still alive.

 

In mice at least, intestinal bacteria are necessary for certain types of chemotherapy to work. Domino Trincheiri, one of the lead authors, is quoted in Science as saying, “We suspected that platinum therapy may involve some immune pathway on which the gut microbiota could have a modulating effect, but we were surprised by the extent to which inflammatory cell reactive oxygen species production was strictly dependent on the presence of gut microbiota.”⁶

 

This is a new viewpoint. Up until the publication of these studies in Science, we considered bacterial translocation part of the problem. These wandering bacteria are blamed for cancer cachexia and considered a “therapeutic target” and the cause of many adverse reactions.^7,8 Our treatment goal has been to prevent diarrhea and leaky gut.⁹ We have actively employed treatments to prevent or counter intestinal permeability including probiotics, l-glutamine, AND melatonin, thinking we are doing the right thing.^10-13

 

At least with cyclophosphamide and platinum drugs, perhaps we should choose therapies that increase intestinal permeability, such as piperine or fasting, in the hope of gaining more cytotoxic action from chemotherapy.^14,15

 

This is heretical thinking—the opposite of what we have thought or done for years. Of course, these ideas only come from mouse studies; these findings may not be confirmed in people. If they are though, some serious reorganization of our treatment strategies will be in order.