BlautiaAbundance and Mucosal Barrier Injury: A Complex Play of Cause and Effect

To the editor—We read with interest the article by Rashidi et al, who proposed a model in which the commensal microbe Blautia protects against neutropenic fever (NF) by improving intestinal health [1]. They constructed their model based on 2 important findings: the negative association between Blautia and NF in a matched case-control analysis of allogeneic hematopoietic cell transplantation (HCT) recipients, where cases were selected based on the first episode of fever between day −7 and +28 after transplant, and the observation that greater Blautia abundances in stool samples from patients with acute leukemia treated with chemotherapy predicted higher serum levels of next-day citrulline, a biomarker of total enterocyte mass. We thank the authors for referring to our work that demonstrates that the kinetics of citrulline levels is quite predictable, with little interindividual variation, after various conditioning regimens [2, 3]. We recently extended this work with multiple conditioning regimens and intensive cytarabine-based chemotherapy ("3 + 7") [4]. Citrulline concentrations <10 µmol/L are designated as hypocitrullinemia and regarded to reflect severe intestinal damage. Figure 1 depicts the time course of prospectively collected citrulline samples after start of conditioning in 155 autologous or allogeneic HCT recipients [2, 3, 5]. The predicted citrulline concentration was calculated for each day and used to calculate duration of hypocitrullinemia and citrulline nadir. Mean duration of hypocitrullinemia varied between 2.3 (Flu-Cyclo) and 16.6 (Ida-Cyclo-TBI), covering the interval of −7 until +28 of Rashidi et al's report. It is obvious looking at these time courses that making statements based on randomly obtained citrulline samples poses a serious problem because the extent of intestinal injury is not reflected by just one sample. The authors' suggestion that greater abundance of Blautia predicts higher citrulline levels can be easily reversed to instead suggest that the integrity of the intestinal barrier (indicated by low citrulline levels) might dictate lower Blautia abundance. The intensive therapy-induced mucosal barrier injury (MBI) creates a hostile environment for this class of anaerobes that are normally dependent on an intact mucus barrier, and changes in Blautia may reflect preceding changes in epithelial integrity. Complementary to our suggestion that MBI precedes dysbiosis is the work of Shouval et al [6] and Peled et al [7] that shows that during microbial injury, loss of diversity is dependent on the intensity of the conditioning regimens and is independent of empiric antibiotic use. There are very complex interactions between gut MBI, microbiota, antibiotics, and inflammation that cannot be dissected easily, especially in a single sample. Cause and effect are not easily determined. However, changes in microbiota usually occur after the use of (prophylactic) antibiotics and onset of MBI, as does the occurrence of NF [8]. Furthermore, temporal changes in diversity occur strikingly simultaneous to changes in citrulline. So, Blautia may simply be regarded as a "surrogate biomarker" (just like citrulline) of gut MBI severity that itself results in fever ("febrile mucositis"), rather than a protective microorganism per se. We encourage Rashidi and colleagues to consider the complexity of this interaction and welcome longitudinal analyses to dissect the temporal dynamics of MBI and microbial disruption.