Impact and consequences of intensive chemotherapy on intestinal barrier and microbiota in acute myeloid leukemia: the role of mucosal strengthening

Abstract

Induction chemotherapy (7 + 3 regimen) remains the gold standard for patients with acute myeloid leukemia (AML) but is responsible for gut damage leading to several complications such as bloodstream infection (BSI). We aimed to investigate the impact of induction chemotherapy on the intestinal barrier of patients with AML and in wild-type mice. Next, we assessed the potential benefit of strengthening the mucosal barrier in transgenic mice releasing a recombinant protein able to reinforce the mucus layer (Tg222). In patients, we observed a decrease of plasma citrulline, which is a marker of the functional enterocyte mass, of short-chain fatty acids and of fecal bacterial load, except for Escherichia coli and Enterococcus spp., which became dominant. Both the α and βdiversities of fecal microbiota decreased. In wild-type mice, citrulline levels decreased under chemotherapy along with an increase of E. coli and Enterococcus spp load associated with concomitant histologic impairment. By comparison with wild-type mice, Tg222 mice, 3 days after completing chemotherapy, had higher citrulline levels, a faster healing epithelium, and preserved α-diversity of their intestinal microbiota. This was associated with reduced bacterial translocations. Our results highlight the intestinal damage and the dysbiosis induced by the 7 + 3 regimen. As a proof of concept, our transgenic model suggests that strengthening the intestinal barrier is a promising approach to limit BSI and improve AML patients' outcome.

Antibiotic-induced disruption of the microbiome exacerbates chemotherapy-induced diarrhoea and can be mitigated with autologous faecal microbiota transplantation

“…Disruption of the host microbiota is now considered a critical event in the initiation of various treatment complications, many of which are catalysed by breakdown of the mucosal barrier [3,4]. Although mucosal barrier injury (MBI) is initiated by acute cytotoxic injury to the intestinal stem cell niche, it is perpetuated by innate immune responses that are thought to be dictated by hostmicrobe interactions at the mucosal interface [5].…”

Fatal infection with enterocolitis from methicillin-resistant Staphylococcus aureus and the continued value of culture in the era of molecular diagnostics

“…In this case, Crohn's disease may have played a role in the development of MRSA enterocolitis [17] . This, coupled with chemotherapy, neutropenia, and antibiotic exposure may have predisposed to mucosal damage and dysbiosis allowing for MRSA overgrowth and enterotoxin susceptibility [ 4 , 18 , 19 ]. Although MRSA enterocolitis can present similarly to CDI, it more frequently affects the small bowel, is associated with fever and vomiting, results in more profuse diarrhea, and mucosal invasion is often observed on histopathology [ 4 , 20 ].…”

Citrulline, Biomarker of Enterocyte Functional Mass and Dietary Supplement. Metabolism, Transport, and Current Evidence for Clinical Use

“…Citrulline changes are associated with microbial changes in the gut, for example, after chemotherapy [ 127 ]. Gut bacteria are known to use AAs, including arginine, for both protein synthesis and the production of arginine-derived metabolites such as polyamines or nitric oxide, as reviewed by Baier et al [ 128 ].…”