Impact and consequences of intensive chemotherapy on intestinal barrier and microbiota in acute myeloid leukemia: the role of mucosal strengthening.
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ABSTRACT:
SUBMITTER: Hueso T
PROVIDER: S-EPMC7524297 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The purpose of this study was to evaluate mechanisms controlling secretory IgA (SIgA) production, thereby ensuring maintenance of ocular surface health.To determine whether the presence of specific gut commensal species regulates SIgA levels and IgA transcripts in the eye-associated lymphoid tissues (EALT), specific-pathogen-free (SPF) Swiss Webster (SW) mice were treated with antibiotic cocktails, germ-free (GF) SW mice were reconstituted with diverse commensal gut microbiota, or monocolonized with gut-specific commensals. Proteomic profiling and quantitative real-time polymerase chain reaction (qRT-PCR) were used to quantify SIgA and IgA levels. 16S rDNA sequencing was carried out to characterize commensal microbiota.Commensal presence regulated ocular surface SIgA levels and mRNA IgA transcripts in EALT. Oral antibiotic cocktail intake significantly reduced gut commensal presence, while maintaining ocular surface commensal levels reduced SIgA and IgA transcripts in EALT. Analysis of gut microbial communities revealed that SPF SW mice carried abundant Bacteroides organisms when compared to SPF C57BL6/N mice, with B. acidifaciens being the most prominent species in SPF SW mice. Monocolonization of GF SW mice with B. acidifaciens, a strict gut anaerobe, resulted in significant increase of IgA transcripts in the EALT, implying generation of B-cell memory.These data illustrated a "gut-eye" axis of immune regulation. Exposure of the host to gut commensal species may serve as a priming signal to generate B-cell repertoires at sites different from the gut, such as EALT, thereby ensuring broad protection.
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Project description:The intestinal bacterial flora of febrile neutropenic patients has been found to be significantly diverse. However, there are few reports of alterations of in adult acute myeloid leukemia (AML) patients. Stool samples of each treatment-naïve AML patient were collected the day before initiation of induction chemotherapy (pretreatment), on the first date of neutropenic fever and first date of bone marrow recovery. Bacterial DNA was extracted from stool samples and bacterial 16s ribosomal RNA genes were sequenced by next-generation sequencing. Relative abundance, overall richness, Shannon's diversity index and Simpson's diversity index were calculated. No antimicrobial prophylaxis was in placed in all participants. Ten cases of AML patients (4 male and 6 female) were included with a median age of 39 years (range: 19-49) and all of patients developed febrile neutropenia. Firmicutes dominated during the period of neutropenic fever, subsequently declining after bone marrow recovery a pattern in contrast to that shown by Bacteroidetes and Proteobacteria. Enterococcus was more abundant in the febrile neutropenia period compared to pretreatment (mean difference +20.2; p < 0.0001) while Escherichia notably declined during the same period (mean difference -11.2; p = 0.0064). At the operational taxonomic unit (OTU) level, there was a significantly higher level of overall richness in the pretreatment period than in the febrile neutropenic episode (mean OTU of 203.1 vs. 131.7; p = 0.012). Both of the diversity indexes of Shannon and Simpson showed a significant decrease during the febrile neutropenic period. Adult AML patients with a first episode of febrile neutropenia after initial intensive chemotherapy demonstrated a significant decrease in gut microbiota diversity and the level of diversity remained constant despite recovery of bone marrow.
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Project description:Hemophagocytic lymphohistiocytosis is a condition of immune dysregulation characterized by severe organ damage induced by a hyperinflammatory response and uncontrolled T-cell and macrophage activation. Secondary hemophagocytic lymphohistiocytosis typically occurs in association with severe infections or malignancies. Patients with acute myeloid leukemia may be prone to develop hemophagocytic lymphohistiocytosis because of an impaired immune response and a high susceptibility to severe infections. In a series of 343 patients treated by intensive chemotherapy over a 5-year period in our center, we identified 32 patients (9.3%) with fever, very high ferritin levels, and marrow hemophagocytosis (i.e. patients with hemophagocytic lymphohistiocytosis). Compared to patients without hemophagocytic lymphohistiocytosis, these 32 patients had hepatomegaly, pulmonary or neurological symptoms, liver abnormalities, lower platelet count and higher levels of C-reactive protein as well as prolonged pancytopenia. A microbial etiology for the hemophagocytosis was documented in 24 patients: 14 bacterial infections, 9 Herpesviridae infections and 11 fungal infections. The treatment of hemophagocytic lymphohistiocytosis consisted of corticosteroids and/or intravenous immunoglobulins along with adapted antimicrobial therapy. Patients with hemophagocytic lymphohistiocytosis had a median overall survival of 14.9 months, which was significantly shorter than that of patients without hemophagocytic lymphohistiocytosis (22.1 months) (P=0.0016). Hemophagocytic lymphohistiocytosis was significantly associated with a higher rate of induction failure, mainly due to deaths in aplasia. Hemophagocytic lymphohistiocytosis can be diagnosed in up to 10% of patients with acute myeloid leukemia undergoing intensive chemotherapy and is associated with early mortality. Fever, very high ferritin levels and marrow hemophagocytosis represent the cornerstone of the diagnosis. Further biological studies are needed to better characterize and recognize this syndrome in patients with acute myeloid leukemia.
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Project description:Background and purposeThe mechanism underlying the pathology of neuromyelitis optica spectrum disorders (NMOSD) remains unclear even though antibodies to the water channel protein aquaporin-4 (AQP4) on astrocytes play important roles. Our previous study showed that dysbiosis occurred in the fecal microbiota of NMOSD patients. In this study, we further investigated whether the intestinal barrier and mucosal flora balance are also interrupted in NMOSD patients.MethodsSigmoid mucosal biopsies were collected by endoscopy from six patients with NMOSD and compared with samples from five healthy control (HC) individuals. These samples were processed for electron microscopy and immunohistochemistry to investigate changes in ultrastructure and in the number and size of intestinal inflammatory cells. Changes in mucosal flora were also analyzed by high-throughput 16S ribosomal RNA gene amplicon sequencing.ResultsThe results from bacterial rRNA gene sequencing showed that bacterial diversity was decreased, but Streptococcus and Granulicatella were abundant in the colonic mucosa specimens of NMOSD patients compared to the HC individuals. The intercellular space between epithelia of the colonic mucosa was wider in NMOSD patients compared to the HC subjects (p < 0.01), and the expression of tight junction proteins [occludin, claudin-1 and zonula occludens-1 (ZO-1)] in NMOSD patients significantly decreased compared to that in the HC subjects. We also found numerous activated macrophages with many inclusions within the cytoplasm, mast cells with many particles in their cytoplasm, and enlarged plasma cells with rich developed rough endoplasmic reticulum in the lamina propria of the mucosa of the patients with NMOSD. Quantitative analysis showed that the percentages of small CD38+ and CD138+ cells (plasma cells) were lower, but the percentage of larger plasma cells was higher in NMOSD patients.ConclusionThe present study demonstrated that the intestinal barrier was disrupted in the patients with NMOSD, accompanied by dysbiosis and inflammatory activation of the gut. The mucosal microbiota imbalance and inflammatory responses might allow pathogens to cross the damaged intestinal barrier and participate in pathological process in NMOSD. However, further study on the pathological mechanism of NMOSD underlying gut dysbiosis is warranted in the future.
| S-EPMC7492665 | biostudies-literature
Project description:To improve patient quality of life and reduce health care costs, many conditions formerly thought to require inpatient care are now treated in the outpatient setting. Outpatient induction chemotherapy for acute myeloid leukemia (AML) may confer similar benefits. This possibility prompted a pilot study to explore the safety and feasibility of intensive outpatient initial or salvage induction chemotherapy administration for adults with AML and high-risk myelodysplastic syndrome (MDS). Patients with no significant organ dysfunction and a treatment-related mortality (TRM) score corresponding to a day 28 mortality rate of <5% to 10% were eligible for study. Patients were treated as outpatients with daily evaluation by providers and only admitted to the hospital if mandated by complications. Twenty patients were consented, and 17 were treated. Eight patients received initial induction chemotherapy and 9 received salvage induction chemotherapy. Fourteen patients completed induction chemotherapy administration in the outpatient setting (82.4%; exact 95% confidence interval [CI], 55.8-95.3). Three patients were admitted during the course of chemotherapy administration, 2 for neutropenic fever and 1 for grade 3 mucositis. No patients died within 14 days of the initiation of induction chemotherapy (exact 95% CI, 0-22.9). Results of this pilot study suggest it is feasible to complete outpatient induction chemotherapy in select patients with AML and high-risk MDS. A team including nurses, social workers, medical providers, and pharmacists was key to the successful implementation of outpatient induction.
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Project description:Weaning disturbs the intestinal barrier function and increases the risk of infection in piglets. Probiotics exert beneficial health effects, mainly by reinforcing the intestinal epithelium and modulating the gut microbiota. However, the mechanisms of action, and especially, the specific regulatory effects of modulated microbiota by probiotics on the intestinal epithelium have not yet been elucidated. The present study aimed to decipher the protective effects of the probiotic Lactobacillus plantarum strain ZLP001 on the intestinal epithelium and microbiota as well as the effects of modulated microbiota on epithelial function. Paracellular permeability was measured with fluorescein isothiocyanate-dextran (FD-4). Gene and protein expression levels of tight junction (TJ) proteins, proinflammatory cytokines, and host defense peptides were determined by RT-qPCR, ELISA, and western blot analysis. Short-chain fatty acid (SCFA) concentrations were measured by ion chromatography. Fecal microbiota composition was assessed by high-throughput sequencing. The results showed that pretreatment with 108 colony forming units (CFU) mL-1 of L. plantarum ZLP001 significantly counteracted the increase in gut permeability to FD-4 induced by 106 CFU mL-1 enterotoxigenic Escherichia coli (ETEC). In addition, L. plantarum ZLP001 pretreatment alleviated the reduction in TJ proteins (claudin-1, occludin, and ZO-1) and downregulated proinflammatory cytokines IL-6 and IL-8, and TNFα expression and secretion caused by ETEC. L. plantarum ZLP001 also significantly increased the expression of the host defense peptides pBD2 and PG1-5 and pBD2 secretion relative to the control. Furthermore, L. plantarum ZLP001 treatment affected piglet fecal microbiota. The abundance of butyrate-producing bacteria Anaerotruncus and Faecalibacterium was significantly increased in L. plantarum ZLP001-treated piglets, and showed a positive correlation with fecal butyric and acetic acid concentrations. In addition, the cell density of Clostridium sensu stricto 1, which may cause epithelial inflammation, was decreased after L. plantarum ZLP001 administration, while the beneficial Lactobacillus was significantly increased. Our findings suggest that L. plantarum ZLP001 fortifies the intestinal barrier by strengthening epithelial defense functions and modulating gut microbiota.
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Project description:Obesity may aggravate acute pancreatitis (AP) through damaging the intestinal mucosal barrier (IMB). The underlying mechanism remains unclear. This study was aimed to provide further data to clarify the mechanism. 48 rats were divided into 4 groups: 1) normal control (NC), chow-fed rats with sham operation, 2) no-obese rats with AP (NAP), chow-fed rats with taurocholate infusion, 3) obese control (OC), high-fat diet (HFD)-fed rats with sham operation, and 4) obese rats with AP (OAP), HFD-fed rats with taurocholate infusion. Pancreatic pathologic score (11.39?±?1.76 vs. 14.11?±?1.05, p?=?0.005), intestinal permeability to FD4 (0.91?±?0.25??g/ml vs. 7.06?±?3.67??g/ml, p?<?0.001), serum leptin (10.25?±?5.59?ng/ml vs. 79.73?±?38.44?ng/ml, p?<?0.001) and ileal apoptosis (2.05?±?0.73% vs. 4.53?±?2.28%, p?=?0.006) were significantly higher in OAP than in NAP group. The intestinal bacterial richness (Chao 1 and OTUs) was significantly lower in OAP than in NAP rats. The higher abundance of Proteobacteria and reduced proportions of intestinal Actinobacteria, Allobaculum and Barnesiella were detected in OAP group. Obesity may result in decreased intestinal leptin/ObR-b binding, distinct phylogenetic clusters of ileal bacterial communities, increased intestinal inflammatory injury and the insufficient intestinal epithelial cells proliferation during AP attack. Pancreatic injury was aggravated due to obesity associated dysfunction of IMB.
| S-EPMC6329748 | biostudies-literature
Project description:BACKGROUND: Several observations suggest that immunological events early after chemotherapy, possibly during the period of severe treatment-induced cytopenia, are important for antileukemic immune reactivity in acute myeloid leukemia (AML). We therefore investigated the frequencies of various T cell subsets (TC1, TH1, TH17) and CD25+ FoxP3+ TREG cells in AML patients with untreated disease and following intensive chemotherapy. RESULTS: Relative levels of circulating TC1 and TH1 cells were decreased in patients with severe chemotherapy-induced cytopenia, whereas TH17 levels did not differ from healthy controls. Increased levels of regulatory CD25+ FoxP3+ T cells were detected in AML patients with untreated disease, during chemotherapy-induced cytopenia and during regeneration after treatment. TH17 and TH1 levels were significantly higher in healthy males than females, but this gender difference was not detected during chemotherapy-induced cytopenia. Finally, exogenous IL17-A usually had no or only minor effects on proliferation of primary human AML cells. CONCLUSIONS: We conclude that the effect of intensive AML chemotherapy differ between circulating T cell subsets, relative frequencies of TH17 cells are not affected by chemotherapy and this subset may affect AML cells indirectly through their immunoregulatory effects but probably not through direct effects of IL17-A.
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Project description:Bacillus coagulans has a potential role in improving intestinal injury. However, the specific mechanism is still unclear. In this study, the protective effect of B. coagulans MZY531 on intestinal mucosa injury in cyclophosphamide (CYP)-induced immunosuppressed mice were investigated. The results indicated that the immune organ (thymus and spleen) indices of B. coagulans MZY531 treatment groups were significantly increased compared to the CYP group. B. coagulans MZY531 administration promotes the expression of immune proteins (IgA, IgE, IgG, and IgM). B. coagulans MZY531 could upregulate the ileum levels of IFN-γ, IL-2, IL-4, and IL-10 in immunosuppressed mice. Moreover, B. coagulans MZY531 restores the villus height and crypt depth of the jejunum and alleviates injury of intestinal endothelial cells caused by CYP. Furthermore, the western blotting results showed that B. coagulans MZY531 ameliorated CYP-induced intestinal mucosal injury and inflammatory via up-regulates the ZO-1 pathway and down-regulates the expression of the TLR4/MyD88/NF-κB pathway. After treatment with B. coagulans MZY531, the relative abundance of Firmicutes phylum was dramatically increased, as well as the genera of Prevotella and Bifidobacterium, and reducing harmful bacteria. These findings suggested that B. coagulans MZY531 has a potential immunomodulatory activity on chemotherapy-induced immunosuppression.
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Project description:The gastrointestinal (GI) tract has long been hypothesized to play an integral role in the pathophysiology of sepsis, and gut microbiota (GM) dysbiosis may be the key factor. Previous studies have shown that the gut flora was significantly altered in critically ill patients. This study aimed to observe what kind of GM dysbiosis is in the early stage of sepsis and whether the application of fecal microbiota transplantation (FMT) can reconstruct the GM of septic mice and restore its protective function on the intestinal mucosal barrier. The study investigated the effect of FMT on gut microbiota, mucosal barrier function, inflammatory response, and survival in a murine model of sepsis established by cecal ligation and puncture (CLP). It is found that FMT can not only reduce morbidity and mortality and restore the abundance and diversity of the gut flora in septic mice, but can also improve the intestinal barrier function by reducing epithelial cell apoptosis, improving the composition of the mucus layer, upregulating the expression of tight junction proteins, and reducing intestinal permeability and the inflammatory response. After FMT, Lachnospiraceae contributed the most to intestinal protection through enhancement of the L-lysine fermentation pathway. FMT offers a microbe-mediated survival advantage in a murine model of sepsis. Therefore, an improved understanding of the connection between microbiota, and systemic illness may yield new therapeutic strategies for patients with sepsis.
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