Pre-transplant and longitudinal changes in faecal microbiome characteristics are associated with subsequent development of chronic graft-versus-host disease

The role of the gastrointestinal microbiome in predisposing to chronic graft-versus-host disease (cGVHD), an immune-mediated haematopoietic cell transplant (HCT) complication, is not well defined. We examined the relationship of the host faecal microbiome with subsequent cGVHD development by analysing baseline stool samples as well as post-HCT changes in microbiome composition and metabolite pathway analyses. We analysed pre-transplant baseline samples from 11 patients who subsequently developed cGVHD compared to 13 controls who did not develop acute GVHD or cGVHD at any time. We found a significant differential abundance of multiple taxa at baseline between cGVHD versus controls, including the Actinobacteria phylum and Clostridium genus. A subgroup analysis of longitudinal samples within each patient revealed a greater loss of alpha diversity from baseline to post-engraftment in patients who subsequently developed cGVHD. Metabolic pathways analysis revealed that two pathways associated with short-chain fatty acid metabolism were enriched in cGVHD patient microbiomes: β-oxidation and acyl-CoA synthesis, and γ-aminobutyrate shunt. In contrast, a tryptophan catabolism pathway was enriched in controls. Our findings show a distinct pattern of baseline microbiome and metabolic capacity that may play a role in modulating alloreactivity in patients developing cGVHD. These findings support the therapeutic potential of microbiome manipulation for cGVHD prevention.     

Pulmonary Nocardia and Aspergillus co-infection in a patient with chronic graft-versus-host disease.

Immunosuppression and chronic graft-versus-host disease (GVHD) are major risk factors for the development of invasive pulmonary aspergillosis in bone marrow transplant patients. Although nocardial infections are well described in hematopoietic stem cell transplantation (HSCT) recipients, little information is available about the incidence of nocardiosis in patients with chronic GVHD after HSCT. Coexistence of invasive pulmonary aspergillosis and nocardiosis following non-myeloablative HSCT has not been reported previously. With the increasing use of pentostatin in the treatment of chronic GVHD in future and other nucleoside analogues as preparative regimens in patients undergoing reduced-intensity conditioning transplantation, the possibility of co-infection with rare organisms should be kept in mind while assessing at-risk patients.     

Systemic absorption of oral vancomycin in a peripheral blood stem cell transplant patient with severe graft-versus-host disease of the gastrointestinal tract

Abstract : Oral vancomycin is often considered the drug of choice for severe Clostridium difficile- associated disease due to both its efficacy and pharmacokinetics. The potential for absorption is not well described in patients with impaired gastrointestinal (GI) mucosa. We describe a case of significant and potentially toxic absorption of oral vancomycin in a peripheral blood stem cell transplant patient with grade IV graft-versus-host disease (GVHD) of the GI tract. In patients with GI GVHD clinicians need to be aware of the potential for oral absorption and, in select cases, monitoring of levels may be appropriate.     

Gut microbiome in allogeneic hematopoietic stem cell transplantation and specific changes associated with acute graft vs host disease

Allogeneic hematopoietic stem cell transplantation (aHSCT) is a standard validated therapy for patients suffering from malignant and nonmalignant hematological diseases. However, aHSCT procedures are limited by potentially life-threatening complications, and one of the most serious complications is acute graft-versus-host disease (GVHD). During the last decades, DNA sequencing technologies were used to investigate relationship between composition or function of the gut microbiome and disease states. Even if it remains unclear whether these microbiome alterations are causative or secondary to the presence of the disease, they may be useful for diagnosis, prevention and therapy in aHSCT recipients. Here, we summarized the most recent findings of the association between human gut microbiome changes and acute GVHD in patients receiving aHSCT.     

Antidepressant treatment with fluoxetine during pregnancy and lactation modulates the gut microbiome and metabolome in a rat model relevant to depression

ABSTRACT

Up to 10% of women use selective serotonin reuptake inhibitor (SSRI) antidepressants during pregnancy and postpartum. Recent evidence suggests that SSRIs are capable of altering the gut microbiota. However, the interaction between maternal depression and SSRI use on bacterial community composition and the availability of microbiota-derived metabolites during pregnancy and lactation is not clear.

We studied this using a rat model relevant to depression, where adult females with a genetic vulnerability and stressed as pups show depressive-like behaviors. Throughout pregnancy and lactation, females received the SSRI fluoxetine or vehicle. High-resolution 16S ribosomal RNA marker gene sequencing and targeted metabolomic analysis were used to assess the fecal microbiome and metabolite availability, respectively.

Not surprisingly, we found that pregnancy and lactation segregate in terms of fecal microbiome diversity and composition, accompanied by changes in metabolite availability. However, we also showed that fluoxetine treatment altered important features of this transition from pregnancy to lactation most clearly in previously stressed dams, with lower fecal amino acid concentrations. Amino acid concentrations, in turn, correlated negatively with the relative abundance of bacterial taxa such as Prevotella and Bacteroides.

Our study demonstrates an important relationship between antidepressant use during the perinatal period and maternal fecal metabolite availability in a rat model relevant to depression, possibly through parallel changes in the gut microbiome. Since microbial metabolites contribute to homeostasis and development, insults to the maternal microbiome by SSRIs might have health consequences for mother and offspring.     

Mesenchymal stem cells expanded in vitro with human serum for the treatment of acute and chronic graft-versus-host disease: results of a phase I/II clinical trial

This trial evaluated the feasibility and efficacy of the infusion of mesenchymal stem cells expanded using human serum for the treatment of refractory acute or chronic graft-versus-host disease. Twenty-eight expansions were started. In 22, a minimum of more than 1x10⁶ mesenchymal stem cells/kg were obtained after a median of 26 days; this threshold was not obtained in the remaining cases. Ten patients received cells for the treatment of refractory or relapsed acute graft-versus-host disease and 8 for chronic disease. One patient treated for acute graft-versus-host disease obtained a complete response, 6 had a partial response and 3 did not respond. One of the chronic patients achieved complete remision, 3 a partial response, and 4 did not respond. The current study supports the use of this approach in less heavily treated patients for both acute and chronic graft-versus-host disease. The trial has been registered at ClinicalTrials.gov: identifier {"type":"clinical-trial","attrs":{"text":"NCT00447460","term_id":"NCT00447460"}}NCT00447460.     

Infectious complications in chronic graft-versus-host disease: a retrospective study of 145 recipients of allogeneic hematopoietic stem cell transplantation with reduced- and conventional-intensity conditioning regimens

Abstract: To assess infectious complications associated with chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) with reduced- and conventional-intensity conditioning regimens (RIC, n =91; CIC, n =54, respectively), we retrospectively analyzed data from 145 consecutive patients with cGVHD after allogeneic HSCT from a human leukocyte antigen-matched related or unrelated donor. In the present retrospective analysis, 57% (83/145) of patients with cGVHD developed infections, with a mortality rate of 27% (22/83). The incidences of bacteremia ( n =28), central venous catheter-related infections ( n =11), bacterial pneumonia ( n =4), invasive aspergillosis ( n =7), and adenoviral hemorrhagic cystitis ( n =8) were significantly higher in patients with prednisolone dose ≥1 mg/kg at the time of diagnosis of cGVHD. The present results suggest that infections associated with cGVHD, especially after high-dose prednisolone, are predictive of poor outcome regardless of whether the patient received RIC or CIC.     

Exercise training-induced modification of the gut microbiota persists after microbiota colonization and attenuates the response to chemically-induced colitis in gnotobiotic mice

Exercise reduces the risk of inflammatory disease by modulating a variety of tissue and cell types, including those within the gastrointestinal tract. Recent data indicates that exercise can also alter the gut microbiota, but little is known as to whether these changes affect host function. Here, we use a germ-free (GF) animal model to test whether exercise-induced modifications in the gut microbiota can directly affect host responses to microbiota colonization and chemically-induced colitis. Donor mice (n = 19) received access to a running wheel (n = 10) or remained without access (n = 9) for a period of six weeks. After euthanasia, cecal contents were pooled by activity treatment and transplanted into two separate cohorts of GF mice. Two experiments were then conducted. First, mice were euthanized five weeks after the microbiota transplant and tissues were collected for analysis. A second cohort of GF mice were colonized by donor microbiotas for four weeks before dextran-sodium-sulfate was administered to induce acute colitis, after which mice were euthanized for tissue analysis. We observed that microbial transplants from donor (exercised or control) mice led to differences in microbiota β-diversity, metabolite profiles, colon inflammation, and body mass in recipient mice five weeks after colonization. We also demonstrate that colonization of mice with a gut microbiota from exercise-trained mice led to an attenuated response to chemical colitis, evidenced by reduced colon shortening, attenuated mucus depletion and augmented expression of cytokines involved in tissue regeneration. Exercise-induced modifications in the gut microbiota can mediate host-microbial interactions with potentially beneficial outcomes for the host.     

Mycobacterium genavense‐induced spindle cell pseudotumor in a pediatric hematopoietic stem cell transplant recipient: Case report and review of the literature

We describe the first reported pediatric patient to our knowledge with a spindle cell pseudotumor caused by Mycobacterium genavense in a hematopoietic stem cell transplant recipient, and review the literature of such an entity in the transplant population.     

Filgrastim treatment of acute myelogenous leukemia (M7) relapse after allogeneic peripheral stem cell transplantation resulting in both graft-versus-leukemia effect with cytogenetic remission and chronic graft-versus-host disease manifesting as polyserositis and subsequent bronchiolitis obliterans with organizing pneumonia

Filgrastim (granulocyte colony-stimulating factor) has recently been reported to successfully treat patients with leukemic relapse after allogeneic peripheral stem cell transplantation (PSCT). However, the majority of the patients who responded also developed graft-versus-host disease (GVHD). Polyserositis as a manifestation of GVHD is a rare phenomenon. We report the first case of polyserositis following the use of filgrastim to treat a patient with acute myelogenous leukemia (M7), who had relapsed after an initially successful allogeneic PSCT. The polyserositis manifested with effusions and was initially controlled with high doses of steroids and pericardial stripping; however, after a quiescent period the patient eventually developed bronchiolitis obliterans with organizing pneumonia that required additional immunosuppressive therapy. We review the literature on GVHD-associated polyserositis and offer potential explanations for its pathogenesis.     

CD34 is a Key Regulator of Hematopoietic Stem Cell Trafficking to Bone Marrow and Mast Cell Progenitor Trafficking in the Periphery

CD34 is a cell‐surface sialomucin widely used for hematopoietic stem cell purification and as a marker of most vascular endothelial cells, including those of capillaries in the majority of tissues. Surprisingly, despite extensive research, the function of this sialomucin has remained elusive, with proposed roles ranging from enhancing proliferation or inhibiting differentiation to acting as a proadhesive L‐selectin ligand. Here, we review our recent studies, which suggest that CD34 does, indeed, play a role in leukocyte and HSC trafficking, but that this is through its action as a regulated blocker of cell adhesion and enhancer of migration.     

Autosomal dominant type 1 von willebrand disease due to G3639T mutation (C1130F) in exon 26 of von Willebrand factor gene: description of five Italian families and evidence for a founder effect

Twenty-four apparently unrelated Italian patients with autosomal dominant type 1 von Willebrand disease (VWD) and a clear autosomal pattern of inheritance of bleeding symptoms were screened for the C1149R and C1130F mutations. None of the patients had the C1149R mutation; three patients and four affected relatives were heterozygous for the C1130F mutation. The mutation appeared to be linked to a single haplotype, defined by five genetic markers [variable number tandem repeat (VNTR) I and II in intron 40, RsaI in exons 13 and 18 and HphI in exon 28], suggesting a founder effect. The patients responded well to desmopressin infusion. The C1130F mutation might have a dominant negative effect on the secretion of the normal protein that desmopressin would appear to overcome.     

Immunopathogenic mechanisms and modulatory approaches to graft-versus-host disease prevention in acute myeloid leukaemia

Allogeneic haematopoietic stem cell transplantation (HSCT) remains the only potential cure for intermediate to high-risk acute myeloid leukaemia (AML). The therapeutic effect of HSCT is largely dependent on the powerful donor-derived immune response against recipient leukaemia cells, known as graft-versus-leukaemia effect (GvL). However, the donor-derived immune system can also cause acute or chronic damage to normal recipient organs and tissues, in a process known as graft-versus-host disease (GvHD). GvHD is a leading cause of non-relapse mortality in HSCT recipients. There are many similarities and cross talk between the immune pathways of GvL and GvHD. Studies have demonstrated that both processes require the presence of mismatched alloantigens between the donor and recipient, and activation of immune responses centered around donor T-cells, which can be further modulated by various recipient or donor factors. Dissecting GvL from GvHD to achieve more effective GvHD prevention and enhanced GvL has been the holy grail of HSCT research. In this review, we focused on the key factors that contribute to the immune responses of GvL and GvHD, the effect on GvL with different GvHD prophylactic strategies, and the potential impact of various AML relapse prevention therapy or treatments on GvHD.