Gastrointestinal toxicity during induction treatment for childhood acute lymphoblastic leukemia: The impact of the gut microbiota

Pietri, Silvia; Ingham, Anna Cäcilia; Frandsen, Thomas Leth; Rathe, Mathias; Krych, Łukasz; Castro‐Mejía, Josué L.; Nielsen, Dennis Sandris; Nersting, Jacob; Wehner, Peder Skov; Schmiegelow, Kjeld; Hasle, Henrik; Pamp, Sünje Johanna; Müller, Klaus

doi:10.1002/ijc.32942

Cited by 38 publications

(53 citation statements)

References 49 publications

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“…We hypothesized that the bacterial alpha diversity at the first sampling time point (preexamination) might already be lower in these patients as compared to age-matched healthy children due to the treatment given prior to the referral to allo-HSCT and enrolment in this study. To assess this, we compared the gut microbiota at preexamination to that of healthy children (median age 6.8 years) [ 19 ]. As expected, the alpha diversity was 2.4-fold lower in the patients at preexamination (median InvSimpson 11.7) as compared with the healthy children (median InvSimpson 28.2) (Supplementary Figure S1A, Additional File 2 ).…”

Section: Resultsmentioning

confidence: 99%

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Microbiota long-term dynamics and prediction of acute graft-versus-host disease in pediatric allogeneic stem cell transplantation

et al. 2021

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Background Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) exhibit changes in their gut microbiota and are experiencing a range of complications, including acute graft-versus-host disease (aGvHD). It is unknown if, when, and under which conditions a re-establishment of microbial and immunological homeostasis occurs. It is also unclear whether microbiota long-term dynamics occur at other body sites than the gut such as the mouth or nose. Moreover, it is not known whether the patients’ microbiota prior to HSCT holds clues to whether the patient would suffer from severe complications subsequent to HSCT. Here, we take a holobiont perspective and performed an integrated host-microbiota analysis of the gut, oral, and nasal microbiota in 29 children undergoing allo-HSCT. Results The bacterial diversity decreased in the gut, nose, and mouth during the first month and reconstituted again 1–3 months after allo-HSCT. The microbial community composition traversed three phases over 1 year. Distinct taxa discriminated the microbiota temporally at all three body sides, including Enterococcus spp., Lactobacillus spp., and Blautia spp. in the gut. Of note, certain microbial taxa appeared already changed in the patients prior to allo-HSCT as compared with healthy children. Acute GvHD occurring after allo-HSCT could be predicted from the microbiota composition at all three body sites prior to HSCT. The reconstitution of CD4+ T cells, TH17, and B cells was associated with distinct taxa of the gut, oral, and nasal microbiota. Conclusions This study reveals for the first time bacteria in the mouth and nose that may predict aGvHD. Monitoring of the microbiota at different body sites in HSCT patients and particularly through involvement of samples prior to transplantation may be of prognostic value and could assist in guiding personalized treatment strategies. The identification of distinct bacteria that have a potential to predict post-transplant aGvHD might provide opportunities for an improved preventive clinical management, including a modulation of microbiomes. The host-microbiota associations shared between several body sites might also support an implementation of more feasible oral and nasal swab sampling-based analyses. Altogether, the findings suggest that the microbiota and host factors together could provide actionable information to guiding precision medicine.

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Section: Resultsmentioning

confidence: 99%

“…To address certain specific questions, we also analyzed the microbiota (from time point 0) of a cohort of 18 healthy children that were part of a previous study [ 19 ]. The median age of these children was 6.8 years (interquartile range 4.6 to 9.6).…”

Section: Methodsmentioning

confidence: 99%

Microbiota long-term dynamics and prediction of acute graft-versus-host disease in pediatric allogeneic stem cell transplantation

et al. 2021

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“…We hypothesized that the bacterial alpha diversity at the first sampling time point (preexamination) might already be lower in these patients as compared to age-matched healthy children due to the treatment given prior to the referral to allo-HSCT and enrolment in this study. To assess this, we compared the gut microbiota at preexamination to that of healthy children (median age 6.8 years) [19]. As expected, the alpha diversity was 2.4-fold lower in the patients at preexamination (median InvSimpson 11.7) as compared to the healthy children (median InvSimpson 28.2) (Supplementary Figure S1A, Additional File 2).…”

Section: Resultsmentioning

confidence: 99%

Microbiota long-term dynamics and prediction of acute graft-versus-host-disease in pediatric allogeneic stem cell transplantation

Ingham

Kielsen

Mordhorst

et al. 2021

Preprint

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Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) exhibit changes in their gut microbiota and are experiencing a range of complications, including acute graft-versus-host disease (aGvHD). It is unknown if, when, and under which conditions a re-establishment of microbial and immunological homeostasis occurs. It is also unclear whether microbiota long-term dynamics occur at other body sites than the gut such as the mouth or nose. Moreover, it is not known whether the patients microbiota prior to HSCT holds clues to whether the patient would suffer from severe complications subsequent to HSCT. Here, we performed integrated host-microbiota analyses of the gut, oral, and nasal microbiotas in 29 children undergoing allo-HSCT. The bacterial diversity decreased in the gut, nose, and mouth during the first month and reconstituted again 1-3 months after allo-HSCT. The microbial community composition traversed three phases over one year. Distinct taxa discriminated the microbiota temporally at all three body sides, including Enterococcus spp., Lactobacillus spp., and Blautia spp. in the gut. Of note, certain microbial taxa appeared already changed in the patients prior to allo-HSCT as compared to healthy children. Acute GvHD occurring after allo-HSCT could be predicted from the microbiota composition at all three body sites prior to HSCT, in particular from Parabacteroides distasonis, Lachnospiraceae NK4A136 sp. and Lactobacillus sp. abundances in the gut. The reconstitution of CD4+ T cells, TH17 and B cells was associated with distinct taxa of the gut, oral, and nasal microbiota. This study reveals for the first time bacteria in the mouth and nose that may predict aGvHD. Surveillance of the microbiota at different body sites in HSCT may be of prognostic value and could assist in guiding personalized treatment strategies. The identification of distinct bacteria that have a potential to predict post-transplant aGvHD might provide opportunities for an improved preventive clinical management, including a modulation of microbiomes. The host-microbiota associations shared between several body sites might also support an implementation of more feasible oral and nasal swab sampling-based analyses. Altogether, the findings suggest that both, host factors and the microbiota, could provide actionable information to guiding precision medicine.

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“…It is therefore likely that Pglyrp2 plays a secondary role in the development of chemotherapy-induced gastrointestinal mucositis. Chemotherapeutic treatment may cause dysbiosis possibly associated with chemotherapy-induced mucositis, severity of enterocyte loss and systemic inflammation during chemotherapy (42)(43)(44). The effects of PGLYRP2 on the microbiota in the gastrointestinal lumen during chemotherapy remains to be evaluated.…”

Section: Discussionmentioning

confidence: 99%

Peptidoglycan Recognition Peptide 2 Aggravates Weight Loss in a Murine Model of Chemotherapy-Induced Gastrointestinal Toxicity

et al. 2021

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Introduction: Chemotherapy-induced gastrointestinal toxicity (CIGT) is a frequent, severe and dose-limiting side effect. Few treatments have proven effective for CIGT. CIGT is characterized by activation of the nuclear factor kappa B pathway which, leads to upregulation of proinflammatory cytokines. The innate immune protein peptidoglycan recognition peptide 2 (PGLYRP2) binds to and hydrolyzes microbial peptidoglycan. Expression of PGLYRP2 is upregulated in the intestine of chemotherapy-treated piglets. In this experimental study, we investigated the role of Pglyrp2 in the development and severity of murine CIGT.Methods:Pglyrp2 wildtype and Pglyrp2 knockout mice received intraperitoneal injections of chemotherapy (Doxorubicin 20 mg/kg) to induce CIGT. Weight was monitored daily, and animals were euthanized after 2 or 7 days. Expression of proinflammatory cytokines in the jejunum was measured by quantitative real-time polymerase-chain reaction and enzyme-linked immunosorbent assay. Villus height, crypt depth, and histologic inflammation were evaluated on haematoxylin and eosin stained tissue specimens.Results: Chemotherapeutic treatment induced weight loss (p < 0.05), shortening of the small intestine (p < 0.05), elongation of villus height (p < 0.05), increased crypt depth (p < 0.05), and led to elevated mRNA levels of II1β (p < 0.05), II6 (p < 0.05), and Tnf (p < 0.001) at day 2. Protein levels of IL1β, IL6, and TNFα did not change after exposure to chemotherapy. Doxorubicin treated wildtype mice had a more pronounced weight loss compared to knockout mice from day 3 to day 7 (D3-D6: p < 0.05 and D7: p < 0.01). No other phenotypic differences were detected.Conclusion:Pglyrp2 aggravates chemotherapy-induced weight loss but does not induce a specific pattern of inflammation and morphological changes in the small intestine.

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Gastrointestinal toxicity during induction treatment for childhood acute lymphoblastic leukemia: The impact of the gut microbiota

Cited by 38 publications

References 49 publications

Microbiota long-term dynamics and prediction of acute graft-versus-host disease in pediatric allogeneic stem cell transplantation

Microbiota long-term dynamics and prediction of acute graft-versus-host disease in pediatric allogeneic stem cell transplantation

Microbiota long-term dynamics and prediction of acute graft-versus-host-disease in pediatric allogeneic stem cell transplantation

Peptidoglycan Recognition Peptide 2 Aggravates Weight Loss in a Murine Model of Chemotherapy-Induced Gastrointestinal Toxicity

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