The interplay between host genetics and the gut microbiome reveals common and distinct microbiome features for complex human diseases.

BACKGROUND: Interest in the interplay between host genetics and the gut microbiome in complex human diseases is increasing, with prior evidence mainly being derived from animal models. In addition, the shared and distinct microbiome features among complex human diseases remain largely unclear. RESULTS: This analysis was based on a Chinese population with 1475 participants. We estimated the SNP-based heritability, which suggested that Desulfovibrionaceae and Odoribacter had significant heritability estimates (0.456 and 0.476, respectively). We performed a microbiome genome-wide association study to identify host genetic variants associated with the gut microbiome. We then conducted bidirectional Mendelian randomization analyses to examine the potential causal associations between the gut microbiome and complex human diseases. We found that Saccharibacteria could potentially decrease the concentration of serum creatinine and increase the estimated glomerular filtration rate. On the other hand, atrial fibrillation, chronic kidney disease and prostate cancer, as predicted by host genetics, had potential causal effects on the abundance of some specific gut microbiota. For example, atrial fibrillation increased the abundance of Burkholderiales and Alcaligenaceae and decreased the abundance of Lachnobacterium, Bacteroides coprophilus, Barnesiellaceae, an undefined genus in the family Veillonellaceae and Mitsuokella. Further disease-microbiome feature analysis suggested that systemic lupus erythematosus and chronic myeloid leukaemia shared common gut microbiome features. CONCLUSIONS: These results suggest that different complex human diseases share common and distinct gut microbiome features, which may help reshape our understanding of disease aetiology in humans. Video Abstract.

Macrophages protect mycoplasma-infected chronic myeloid leukemia cells from natural killer cell killing.

Macrophages (Mϕ) have been reported to downmodulate the cytotoxicity of natural killer (NK) cell against solid tumor cells. However, the collaborative role between NK cells and Mϕ remains underappreciated, especially in hematological cancers, such as chronic myeloid leukemia (CML). We observed a higher ratio of innate immune cells (Mϕ and NK) to adaptive immune cells (T and B cells) in CML bone marrow aspirates, prompting us to investigate the roles of NK and Mϕ in CML. Using coculture models simulating the tumor inflammatory environment, we observed that Mϕ protects CML from NK attack only when CML was itself mycoplasma-infected and under chronic infection-inflammation condition. We found that the Mϕ-protective effect on CML was associated with the maintenance of CD16 level on the NK cell membrane. Although the NK membrane CD16 (mCD16) was actively shed in Mϕ + NK + CML trioculture, the NK mCD16 level was maintained, and this was independent of the modulation of sheddase by tissue inhibitor of metalloproteinase 1 or inhibitory cytokine transforming growth factor beta. Instead, we found that this process of NK mCD16 maintenance was conferred by Mϕ in a contact-dependent manner. We propose a new perspective on anti-CML strategy through abrogating Mϕ-mediated retention of NK surface CD16.

Cytomegalovirus sinusitis in a child with chronic myelogenous leukemia following bone marrow transplantation.

Cytomegalovirus (CMV) is a common opportunistic pathogen. CMV sinusitis has been described in acquired immunodeficiency syndrome (AIDS) patients, but not in other immune compromising conditions. In this report, we describe CMV sinusitis in a child with chronic myelogenous leukemia (CML) following bone marrow transplantation.

Isolation of Salmonella enterica serotype Worthington from a splenic abscess in a patient with chronic myeloid leukemia.

Splenic abscesses are caused by Staphylococcus aureus, Streptococcus and bacteria belonging to the family Enterobacteriaceae. We report a case of splenic abscess caused by an unusual serotype of Salmonella. A 55 year old man was admitted with complaints of fever and abdominal pain. On the basis of clinical findings and laboratory reports, a diagnosis of chronic myeloid leukemia was made. Ultrasonography of the abdomen revealed a single large cystic lesion in the spleen. Percutaneous drainage of the abscess was carried out. Salmonella enterica serotype Worthington was isolated from a pus sample taken from the abscess. The isolate was resistant to ampicillin, gentamicin, cefotaxime, chloramphenicol and tetracycline, and sensitive to amikacin and norfloxacin. Serotype Worthington is an emerging pathogen. This is the first report of isolation of this serotype from a splenic abscess. In seriously ill patients, such infections should be treated with a combination of antibiotics to circumvent problems with multidrug resistance.

Pneumocystis carinii pneumonia in patients with malignant haematological diseases: 10 years' experience of infection in GIMEMA centres.

A retrospective survey was conducted over a 10-year period (1990-99) among 52 haematology divisions in order to evaluate the clinical and laboratory characteristics and outcome of patients with proven Pneumocystis carinii pneumonia (PCP) complicating haematological diseases. The study included 55 patients (18 with non-Hodgkin's lymphoma, 10 with acute lymphoblastic leukaemia, eight with acute myeloid leukaemia, five with chronic myeloid leukaemia, four with chronic lymphocytic leukaemia, four with multiple myeloma, three with myelodysplastic syndrome, two with myelofibrosis and one with thalassemia) who developed PCP. Among these, 18 (33%) underwent stem cell transplantation; only two received an oral prophylaxis with trimethroprim/sulphamethoxazole. Twelve patients (22%) developed PCP despite protective isolation in a laminar airflow room. The most frequent symptoms were: fever (86%), dyspnoea (78%), non-productive cough (71%), thoracic pain (14%) and chills (5%); a severe hypoxaemia was present in 39 patients (71%). Chest radiography or computerized tomography showed interstitial infiltrates in 34 patients (62%), alveolar infiltrates in 12 patients (22%), and alveolar-interstitial infiltrates in nine patients (16%). Bronchoalveolar lavage was diagnostic in 47/48 patients, induced sputum in 9/18 patients and lung biopsy in 3/8 patients. The diagnosis was made in two patients at autopsy. All patients except one started a specific treatment (52 patients trimethroprim/sulphamethoxazole, one pentamidine and one dapsone). Sixteen patients (29%) died of PCP within 30 d of diagnosis. Multivariate analysis showed that prolonged steroid treatment (P < 0.006) and a radiological picture of diffuse lung involvement (P < 0.003) were negative diagnostic factors.

Isolation of Salmonella enterica serotype Worthington from a splenic abscess in a patient with chronic myeloid leukemia

Splenic abscesses are caused by Staphylococcus aureus, Streptococcus and bacteria belonging to the family Enterobacteriaceae. We report a case of splenic abscess caused by an unusual serotype of Salmonella. A 55 year old man was admitted with complaints of fever and abdominal pain. On the basis of clinical findings and laboratory reports, a diagnosis of chronic myeloid leukemia was made. Ultrasonography of the abdomen revealed a single large cystic lesion in the spleen. Percutaneous drainage of the abscess was carried out. Salmonella enterica serotype Worthington was isolated from a pus sample taken from the abscess. The isolate was resistant to ampicillin, gentamicin, cefotaxime, chloramphenicol and tetracycline, and sensitive to amikacin and norfloxacin. Serotype Worthington is an emerging pathogen. This is the first report of isolation of this serotype from a splenic abscess. In seriously ill patients, such infections should be treated with a combination of antibiotics to circumvent problems with multidrug resistance.

Specific cutaneous infiltrate caused by Staphylococcus aureus in a patient with chronic myelomonocytic leukemia.

We present a patient with chronic myelomonocytic leukemia who showed disseminated papules and nodules. Arguments in favor of leukemia cutis are the clinical appearance, the cyclic pattern with which the lesions appeared and disappeared, and the histologic features. The lesions reproducibly responded to treatment with antibiotics given for a Staphylococcus aureus infection. We speculate that at least in some patients, leukemic cells are recruited in the skin because of local infection and do not merely reflect autonomous growth but an inflammatory response.

[Atypical mycobacteria. Disseminated infection in patients with hematologic diseases]. / Atypiske mykobakterier. Dissemineret infektion hos hoematologiske patienter.

During the last decade interest in atypical mycobacteria (AM), especially Mycobacterium avium complex (MAC) has been intense, as a large number of AIDS patients develop disseminated infection with MAC. Disseminated infection has also been reported in other immunocompromised patients, but in much fewer cases. Among haematological diseases hairy cell leukemia (HCL) and chronic myelogenous leukemia (CML) seem to predispose to disseminated AM infection. We review 53 cases of disseminated AM infection in haematological patients reported in the literature, 39 with HCL, ten CML, and four other haematological diseases, and a review of possible treatment is given. The prognosis seems to depend on the course of the underlying haematological disease, and we conclude that early diagnosis and treatment of the infection is of great importance. Blood and bone marrow should therefore be cultivated for mycobacteria in such patients with persistent fever of unknown cause, and in cases with negative cultures and elevated serum values of alkaline phosphatase liver biopsy should be considered.

[Disseminated Mycobacterium avium infection in three patients with hematologic diseases]. / Dissemineret Mycobacterium avium-infektion hos tre haematologiske patienter.

We report three cases of disseminated Mycobacterium avium complex infection in immunocompromised haematological patients. We conclude that in haematological patients with longlasting fever of unknown cause Mycobacterium avium complex infection should be considered and the relevant cultures from blood and bone marrow should be done.

Antifungal prophylaxis during remission induction therapy for acute leukemia fluconazole versus intravenous amphotericin B.

BACKGROUND: Fungal infection is a frequent and often fatal complication in patients undergoing remission induction therapy for acute leukemia. Although candidiasis is the most common infection, mold infections are increasing in frequency. Fluconazole (FLU) is a new antifungal agent that has been used successfully to treat Candida infections and has modest activity against aspergillosis in animal models. Subtherapeutic doses of amphotericin B (AMB) have been considered effective as prophylaxis in these patients. This study was designed to compare the efficacy and toxicity of these agents as antifungal prophylaxis. METHODS: Adults with acute leukemia undergoing remission induction chemotherapy randomly were assigned to receive antifungal prophylaxis with AMB (0.5 mg/kg three times weekly) or FLU (400 mg daily). Trimethoprim-sulfamethoxazole was administered as an antibacterial prophylaxis. Prophylaxis was continued until the patient achieved complete remission or was treated for 8 weeks without antileukemic response. Prophylaxis was discontinued if the patient experienced a possible or proven fungal infection or a serious toxicity. RESULTS: Overall, 58% of the 36 patients assigned to AMB successfully completed prophylaxis compared with 80% of the 41 patients assigned to FLU (< 0.05). Proven, probable, or possible fungal infections occurred in 31% and 17% of the patients, respectively. The risk of discontinuing prophylaxis due to fungal infection or toxicity increased with time in the study and was significantly greater for AMB (P = 0.02). CONCLUSIONS: At the dose used in this study, AMB was no more effective and was more toxic than FLU for prophylaxis of fungal infections in patients undergoing remission induction chemotherapy for acute leukemia.

Therapeutic progress and comparative aspects in chronic myelogenous leukemia (CML): interferon alpha vs. hydroxyurea vs. busulfan and expression of MMTV-related endogenous retroviral sequences in CML. German CML Study Group.

In summary, it can be expected that the availability of unrelated donors will increase the number of CML patients that can be treated curatively with allogeneic BMT. Hydroxyurea has replaced busulfan as first line treatment in CML since it prolongs survival. Ongoing randomized studies comparing IFN-based treatment regimens with standard chemotherapy or IFN-monotherapy probably will answer the question whether IFN can cure a small percentage of CML patients and whether this small percentage can be increased by additional chemotherapy. The present attempts to improve prognostic scores and to apply them to early treatment decisions will allow treatment adaptation more individually. The implications of endogenous retroviral sequences expressed in CML cells are not known now, but may be far reaching.

Expression of HERV-K proviruses in human leukocytes.

HERV-K is a 50-copy, human endogenous, class 1 retroviral element that contains some polycistrons with gag, pol, and env open reading frames. Although expression of HERV-K proviruses has been shown in cultured human cell lines, expression of these elements has not been shown in human blood leukocytes. Using both reverse transcriptase-polymerase chain reaction and ribonuclease protection techniques, we show HERV-K pol gene expression in human blood leukocytes. Expression in blood leukocytes from 7 normal individuals was from a variety of different HERV-K proviruses, while restricted expression was observed in blood cells of 5 leukemia patients and 3 polycythemia vera patients. Evidence is presented suggesting that the restricted expression in leukemia blood cells is a result of gene regulation, not gene amplification.

Antiretroviral immune response and plasma interferon in different phases of chronic granulocytic leukemia.

Forty patients with chronic granulocytic leukemia (CGL) were tested for antibodies and lymphocytes reacting with gibbon ape leukemia virus (GaLV) and baboon endogenous virus (BaEV) antigens as well as for plasma interferon levels. Antibodies reacting with envelope antigens of GaLV and BaEV were found frequently and in high titers in patients with the quiescent phase of CGL but rarely and in low titers in the accelerated and blastic phase of the disease. Results of radioimmunoprecipitation studies were in concordance with those obtained in virus neutralization experiments. Cellular and humoral cytotoxic activity of blood plasma and lymphocyte samples against autologous tumor cells showed a similar phase-specific distribution. Most of these activities could be blocked by GaLV and BaEV gp70 antigens. Elevated plasma interferon (IFN)-alpha levels were found in the quiescent and accelerated phase of CGL, whereas no significant differences could be detected between IFN levels of patients with the blastic crisis of CGL and those of the control persons. Follow up studies of four patients confirmed this stage-specific distribution of antiretroviral immune and interferon response.

Expression of human endogenous retrovirus (HERV-K) in chronic myeloid leukemia.

We have previously demonstrated the presence of a reverse transcriptase-like enzyme in retroviral particles from patients with essential thrombocythemia, polycythemia vera, and chronic myelogenous leukemia. It was subsequently shown that the human genome contains 50 copies of HERV-K. HERV-K is a human endogenous class I retroviral element that contains gag, pol, and env open reading frames. Using both reverse transcriptase-polymerase chain reaction and ribonuclease protection assays, it is demonstrated that the HERV-K pol is expressed in human blood leukocytes. The data indicates that this expression is restricted in CML white cells and is the result of gene regulation.

Evaluation of the opportunistic microbial flora and of some antimicrobial factors in the oral cavity of leukaemic patients.

The occurrence of opportunistic pathogens and the concentration of some antimicrobial factors in the oral cavity of both acute and chronic leukaemia patients were studied. Enterobacteria were isolated from both dental plaque and crevicular fluid of all the groups examined, with few differences between healthy volunteers and leukaemic subjects; yeasts were found in both the crevicular fluid and the dental plaque samples of chronic leukaemia patients, but only in the plaque of healthy volunteers. Acute leukaemia patients did not have yeasts, but they were the only group colonized by the pseudomonads. IgA and N-acetyl-D-glucosaminidase (NAGase) significantly increased in chronic leukaemia patients compared with controls, whilst lysozyme seemed to present no marked differences for all groups. A further increase in NAGase concentration and an elevation in lysozyme content of saliva was observed for chronic leukaemia patients with severe periodontal lesions.

Gram-negative enteric bacteria in the oral cavity of leukemia patients.

We examined changes in the bacterial flora in hospitalized patients with leukemia. This study placed special emphasis on enteric microorganisms and their relation to the general status of the patient. One hundred thirty bacterial cultures from 16 leukemia patients and 16 control subjects, were obtained. The organisms were isolated on MacConkey agar and identified by the API-20E system. Enteric microorganisms were isolated from 62.2% of the leukemia patients as compared with 28% from the control group (p < 0.001). The enteric positive cultures were identified as Klebsiella (42.7%), Enterobacter (18.8%), and Pseudomonas (15.6%). In contrast to the negative cultures (1342), enteric microorganisms were cultured from 2948 specimens (p < 0.005).