Differential impact of obesity on the pathogenesis of RA or preclinical models is contingent on the disease status

ObjectiveStudies were performed to uncover the significance of obesity in rheumatoid arthritis (RA) and preclinical models.MethodsPreclinical arthritis models were used to examine the impact of obesity on disease onset and remission. Conditioned media from RA adipose tissues were used to investigate the mechanism contributing to joint neutrophil influx and M1 macrophage differentiation observed in early and remission phases of arthritis.ResultsWe report that mice fed with high fat diet (HFD) have an earlier onset of collagen-induced arthritis (CIA) compared with mice on regular diet. However, the differences in CIA joint swelling between the two diet groups are lost once disease is established. We found that early arthritis triggered by obesity is due to elevated joint MIP2/interleukin-8 levels detected in CIA as well as in the RA and mouse adipose tissues and the effect of this chemokine on neutrophil recruitment. Although active disease progression is similarly affected in both diet groups, arthritis resolution is accelerated in lean mice while joint inflammation is sustained in obese mice. We document that HFD can prolong toll-like receptor (TLR)4-induced arthritis by increasing joint monocyte migration and further remodelling the recruited cells into M1 macrophages. Consistently, we show that adipose condition media can transform RA and wild-type naïve myeloid cells into M1 macrophages; however, this function is impaired by TLR4 blockade or deficiency.ConclusionsWe conclude that despite established disease being unaffected by obesity, the early and the resolution phases of RA are impacted by obesity through different mechanisms.

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Reprogrammed M1 macrophages with inhibited STAT3, STAT6 and/or SMAD3 extends lifespan of mice with experimental carcinoma

ZHurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia» ◽

10.25557/0031-2991.2017.02.4-9 ◽

2017 ◽

pp. 4-9

Author(s):

С.В. Калиш ◽

С.В. Лямина ◽

А.А. Раецкая ◽

И.Ю. Малышев

Keyword(s):

Tumor Growth ◽

Culture Medium ◽

Ehrlich Carcinoma ◽

Macrophage Phenotype ◽

M1 Macrophages ◽

M1 Macrophage ◽

Ec Cells ◽

Experimental Carcinoma

Цель исследования. Репрограммирование М1 фенотипа макрофагов с ингибированными факторами транскрипции М2 фенотипа STAT3, STAТ6 и SMAD и оценка их влияния на развитие карциномы Эрлиха (КЭ) in vitro и in vivo. Методика. Рост опухоли иницировали in vitro путем добавления клеток КЭ в среду культивирования RPMI-1640 и in vivo путем внутрибрюшинной инъекции клеток КЭ мышам. Результаты. Установлено, что M1макрофаги и in vitro, и in vivo оказывают выраженный противоопухолевый эффект, который превосходит антиопухолевые эффекты М1, M1, M1 макрофагов и цисплатина. Заключение. М1 макрофаги с ингибированными STAT3, STAT6 и/или SMAD3 эффективно ограничивают рост опухоли. Полученные данные обосновывают разработку новой технологии противоопухолевой клеточной терапии. Objective. Reprogramming of M1 macrophage phenotype with inhibited M2 phenotype transcription factors, such as STAT3, STAT6 and SMAD and assess their impact on the development of Ehrlich carcinoma (EC) in vitro and in vivo . Methods. Tumor growth in vitro was initiated by addition of EC cells in RPMI-1640 culture medium and in vivo by intraperitoneal of EC cell injection into mice. Results. It was found that M1 macrophages have a pronounced anti-tumor effect in vitro , and in vivo , which was greater than anti-tumor effects of M1, M1, M1 macrophages and cisplatin. Conclusion. M1 macrophages with inhibited STAT3, STAT6 and/or SMAD3 effectively restrict tumor growth. The findings justify the development of new anti-tumor cell therapy technology.

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Iron Released after Cryo-Thermal Therapy Induced M1 Macrophage Polarization, Promoting the Differentiation of CD4+ T Cells into CTLs

International Journal of Molecular Sciences ◽

10.3390/ijms22137010 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7010

Author(s):

Shicheng Wang ◽

Man Cheng ◽

Peng Peng ◽

Yue Lou ◽

Aili Zhang ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Antitumor Immunity ◽

Macrophage Polarization ◽

Thermal Therapy ◽

High Plasticity ◽

Antitumor Effects ◽

M1 Macrophages ◽

Splenic Macrophages ◽

M1 Macrophage

Macrophages play critical roles in both innate and adaptive immunity and are known for their high plasticity in response to various external signals. Macrophages are involved in regulating systematic iron homeostasis and they sequester iron by phagocytotic activity, which triggers M1 macrophage polarization and typically exerts antitumor effects. We previously developed a novel cryo-thermal therapy that can induce the mass release of tumor antigens and damage-associated molecular patterns (DAMPs), promoting M1 macrophage polarization. However, that study did not examine whether iron released after cryo-thermal therapy induced M1 macrophage polarization; this question still needed to be addressed. We hypothesized that cryo-thermal therapy would cause the release of a large quantity of iron to augment M1 macrophage polarization due to the disruption of tumor cells and blood vessels, which would further enhance antitumor immunity. In this study, we investigated iron released in primary tumors, the level of iron in splenic macrophages after cryo-thermal therapy and the effect of iron on macrophage polarization and CD4+ T cell differentiation in metastatic 4T1 murine mammary carcinoma. We found that a large amount of iron was released after cryo-thermal therapy and could be taken up by splenic macrophages, which further promoted M1 macrophage polarization by inhibiting ERK phosphorylation. Moreover, iron promoted DC maturation, which was possibly mediated by iron-induced M1 macrophages. In addition, iron-induced M1 macrophages and mature DCs promoted the differentiation of CD4+ T cells into the CD4 cytolytic T lymphocytes (CTL) subset and inhibited differentiation into Th2 and Th17 cells. This study explains the role of iron in cryo-thermal therapy-induced antitumor immunity from a new perspective.

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Cervus nippon var. mantchuricus water extract treated with digestive enzymes (CE) modulates M1 macrophage polarization through TLR4/MAPK/NF-κB signaling pathways on murine macrophages

European Journal of Inflammation ◽

10.1177/20587392211000898 ◽

2021 ◽

Vol 19 ◽

pp. 205873922110008

Author(s):

Se Hyang Hong ◽

Jin Mo Ku ◽

Ye Seul Lim ◽

Hyo In Kim ◽

Yong Cheol Shin ◽

...

Keyword(s):

Digestive Enzymes ◽

Macrophage Polarization ◽

Water Extract ◽

Cervus Nippon ◽

No Production ◽

M1 Macrophages ◽

Murine Macrophages ◽

M1 Macrophage ◽

Tnf Α ◽

Cytokine Levels

The objective of this study was to investigate the effects of Cervus nippon var. mantchuricus water extract treated with digestive enzymes (CE) on the promotion of M1 macrophage polarization in murine macrophages. Macrophages polarize either to one phenotype after stimulation with LPS or IFN-γ or to an alternatively activated phenotype that is induced by IL-4 or IL-13. Cell viability of RAW264.7 cells was determined by WST-1 assay. NO production was measured by Griess assay. IL-6, IL-12, TNF-α, and iNOS mRNA levels were measured by RT-PCR. IL-6, IL-12, and IL-10 cytokine levels were determined by ELISA. TLR4/MAPK/NF-κB signaling in RAW264.7 cells was evaluated by western blotting. The level of NF-κB was determined by immunoblotting. CE induced the differentiation of M1 macrophages. CE promoted M1 macrophages to elevate NO production and cytokine levels. CE-stimulated M1 macrophages had enhanced IL-6, IL-12, and TNF-α. CE promoted M1 macrophages to activate TLR4/MAPK/NF-κB phosphorylation. M2 markers were downregulated, while M1 markers were upregulated in murine macrophages by CE. Consequently, CE has immunomodulatory activity and can be used to promote M1 macrophage polarization through the TLR4/MAPK/NF-κB signaling pathways.

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Sociodemographic determinants of disability in patients with schizophrenia (Bulgaria, 2018-2019)

European Journal of Public Health ◽

10.1093/eurpub/ckaa166.1016 ◽

2020 ◽

Vol 30 (Supplement_5) ◽

Author(s):

I Veleva ◽

S Yankulovska ◽

K Velikova ◽

M Valkova ◽

G Grancharova

Keyword(s):

Social Functioning ◽

Protective Factor ◽

Paranoid Schizophrenia ◽

Disease Onset ◽

Public Health Problem ◽

Sociodemographic Factors ◽

University Hospital ◽

Psychiatric Clinic ◽

Sociodemographic Determinants ◽

The Impact

Abstract Background Schizophrenia is an increasing public health problem. Despite its low prevalence and mortality, it causes significant disability and has enormous health, social, and economic burden for patients, families, society and health systems worldwide. The aim was to assess the impact of some sociodemographic determinants on disability in patients with paranoid schizophrenia (PS). Methods The study includes 108 patients in Psychiatric Clinic at Pleven University Hospital: 66 males and 42 females, mean age 38.9±10.0, duration of disease 12.8±8.2 years; mean onset of disease - 24 years (Me = 25 and Mo = 22). The study was approved by Ethical Committee. The disease burden was assessed by Positive and Negative Syndrome Scale (Ð ANSS), and level of disability - by 36-item WHO Disability Assessment Schedule 2.0. Four variables (gender, age, education, type of employment) were chosen and their impact on disability was assessed by one-way ANOVA (F-test), Tukey's NDS test, two-sided t-test, Pierson r. Data processing was performed by IBM SPSS v.24. Results The most severe deficits were observed in “getting along with people” (61.34±25.77),”life-activities-household” (55.74±23.45), “participation in society” (53.13±19.12), “understanding and communicating” (41.67±17.67). Age at disease onset and its duration showed weak positive correlation. In most domains, males had higher deficits (р=0.0001). Age had an impact only on “getting around” (r = 0.41;p=0.0001) and “self-care” (r = 0.260;p=0.007). Significant differences (F (2,104)=7.565, p < 0.01) were found between groups by education level and occupation (employed/students, unemployed and disabled) - F (3,103)=16.734; p<0.001. Conclusions Sociodemographic factors play a major role for different function domains deficits in PS patients. Most pronounced is the impact of education and occupation. Patients with higher education and those engaged in study or work demonstrate better social functioning than less educated and disabled people. Key messages Education is an important protective factor for disability. Lower educational level decreases competitiveness in workforce market, both in general population and in patients with schizophrenia. Sociodemographic determinants should be considered in planning appropriate preventive and rehabilitation activities to stimulate better social functioning and adaptation of PS patients.

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AB0043 EFFECT OF ANTI-INFLAMMATORY MEDICATION ON INTERACTION OF SYNOVIAL FIBROBLASTS WITH MACROPHAGES IN RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.247 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1054.1-1054

Author(s):

M. Schmeller ◽

M. Diller ◽

R. Hasseli ◽

A. Knothe ◽

S. Rehart ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Mononuclear Cells ◽

Joint Inflammation ◽

Synovial Fibroblasts ◽

Therapeutic Effects ◽

Synergistic Activity ◽

M1 Macrophages ◽

Healthy Donors ◽

Proinflammatory Activity ◽

Anti Inflammatory

Background:One of the key mechanisms in the pathogenesis of rheumatoid arthritis (RA) is the interaction of macrophages and synovial fibroblasts during joint inflammation. Increased synergistic proinflammatory activity of both cell types leads to the release of high levels of proinflammatory cytokines, especially of interleukin-6 (IL-6), and of matrix degrading enzymes. If this mechanism is uncontrolled, progressive destruction of articular cartilage and bone will take place.In active disease, immediate anti-inflammatory treatment with glucocorticoids is usually replaced by disease-modifying anti-rheumatic drugs (DMARDS), especially by methotrexate (MTX) and biologics such as TNF-α- or IL-6-inhibitors. This led to great improvements in prognosis and outcome for RA patients. However, about 40% of patients experience no remission or suffer from side effects of medication. To optimize established substances and to develop new treatment strategies, it is necessary to understand the mechanisms underlying the limited therapeutic effects.Objectives:Evaluation of the effect of prednisolone, MTX, adalimumab, tocilizumab on IL-6 secretion by RA synovial fibroblasts (RASF) and macrophages.Methods:RA synovium was used for RASF isolation. Peripheral blood mononuclear cells (PBMCs) were isolated from blood of healthy donors and RA patients by using Ficoll© medium followed by density gradient centrifugation. Mononuclear cells were seeded on six well plates (6x10^6/well) and incubated for one week. Then they were stimulated with Interferon-у (20 ng/ml) and LPS (50 ng/ml) for 48h to initiate differentiation into proinflammatory M1 macrophages. The M1 macrophages were co-cultured with RASF (100.000/well) and different treatments added (prednisolone: 10, 25, 50, 75, 100 nM, 1 µM; adalimumab: 100, 500 µg/ml; tocilizumab: 1, 5 µg/ml; MTX: 0,5, 1, 5, 10, 100 nM, 1µM). After 24h culture supernatants were collected and IL-6- and TNFα-ELISAs were performed.Results:IL-6 concentrations of untreated controls were comparable, regardless whether M1 macrophages from healthy donors or RA-patients were used for co-culture. Prednisolone reduced co-culture-induced IL-6 up to 56% (p<0.001) in co-culture of RASF and M1 macrophages of healthy donors and up to 60% (p<0.001) in co-culture of RASF and RA M1 macrophages. Adalimumab reduced IL-6 up to 28% (p<0.05) in M1 of healthy donors and up to 45% (p<0.01) in RA M1 macrophage co-cultures. A minor reduction by 10-20% of IL-6 was observed with tocilizumab and no significant effect could be achieved after treatment with MTX.Conclusion:Prednisolone and adalimumab clearly decrease but do not eliminate proinflammatory synergistic activity of RASF and M1 macrophages. These results confirm the clinical observation, that there is a large number of RA-patients that independent of anti-inflammatory treatment still suffer from low-level joint inflammation.The synergistic proinflammatory activity of M1 macrophages and RASF seems to be a complex and multifactorial mechanism that is difficult to eliminate by a single treatment substance. Since it is one of the key mechanisms in RA pathogenesis, there is a critical need to investigate how therapy effects could be optimized. This study confirmed RASFs as one of the leading effector cells of increased synergistic proinflammatory activity, thus underlining their promising role as a treatment target in rheumatoid arthritis.Disclosure of Interests:None declared

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The prognosis of gastric adenocarcinoma depends on the crosstalk between immune profiles and tumor genomic alterations.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4035 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4035-4035

Author(s):

Deqiang Wang ◽

Xiaofeng Chen ◽

Yaping Xu ◽

Yuange He ◽

Lifeng Li ◽

...

Keyword(s):

Gastric Adenocarcinoma ◽

Transcriptome Sequencing ◽

Clonal Expansion ◽

Genomic Alterations ◽

M1 Macrophages ◽

Mutual Correlation ◽

Cell Counts ◽

M1 Macrophage ◽

Whole Transcriptome Sequencing ◽

Whole Transcriptome

4035 Background: Gastric adenocarcinoma (GAC) is with a complex microenvironment of tumor cells. A better understanding of the immune landscape of GACs may lead to the improved treatment strategies with ICIs. Methods: To determine whether the molecular characteristics can serve in prognostic stratification of GACs, tumor tissue and blood samples were collected from 231 GAC patients. The median follow-up time was 34 months. The TCR profile was determined by TCR-β CDR3 sequencing while mutation and gene expression profiles were determined by whole exon and whole transcriptome sequencing, respectively. Tumour-infiltrating immune cells were characterized using immunofluorescence (IF) staining. Results: The results showed the OS of patients with high levels of TCR clonality (TCR clonal expansion) was significantly improved compared with patients with low levels (HR = 1.80 and 2.22, p = 0.022 and 0.008, respectively) in the whole group and in the subgroup of patients with stages IB to III disease. Furthermore, low local clonality was an independent risk factor for OS (adjusted-HR = 1.68 and 1.95, p = 0.049 and 0.029, respectively). Thus, TCR clonal expansion in tumour tissue had a strong prognostic value for GAC patients, independent of clinicopathological factors. Based on whole exon and whole transcriptome sequencing, RNF43/FBXW7/ARID2 mutations and local TCR clonality jointly impacted prognosis (p < 0.001), and functional changes in corresponding Wnt pathway/Notch pathway/SWI/SNF complex characterized a GAC subset with enhanced tumour immunogenicity and TCR clonal expansion. TCR CDR3 sequence similarity comparisons yielded clusters of TCR clones of likely similar functions. The most expansive TCR clusters negatively correlated with the percentage of subclonal mutations (Pearson r = -0.8183, p < 0.001), indicating that tumors with less genomic heterogeneity might induce a greater immune response. By IF staining and mutual correlation analysis, only M1 macrophages showed a significant positive correlation with local TCR clonality for epithelia, stroma, and total cell counts. Tumors were categorized according to the density of M1 macrophages, M1 macrophage infiltrated subtype was associated with favorable OS (p = 0.040 and 0.043) and its combination with the local TCR clonality improved prognosis stratification (p < 0.001). Finally, the scoring by local TCR clonality, RNF43/FBXW7/ARID2 mutations and M1 infiltration determined the best prognosis (p < 0.001). Conclusions: TCR profiles were associated with genomic alterations and may serve as a prognostic biomarker for GACs. A multi-omic model including TCR profiles might produce an improved stratification for treatments and outcomes.

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NPM1 mutations define a specific subgroup of MDS and MDS/MPN patients with favorable outcomes with intensive chemotherapy

Blood Advances ◽

10.1182/bloodadvances.2018026989 ◽

2019 ◽

Vol 3 (6) ◽

pp. 922-933 ◽

Cited By ~ 17

Author(s):

Guillermo Montalban-Bravo ◽

Rashmi Kanagal-Shamanna ◽

Koji Sasaki ◽

Keyur Patel ◽

Irene Ganan-Gomez ◽

...

Keyword(s):

Clinical Outcomes ◽

Myeloproliferative Neoplasm ◽

Normal Karyotype ◽

Progression Free Survival ◽

Disease Status ◽

Response To Therapy ◽

Intensive Chemotherapy ◽

Clinicopathologic Characteristics ◽

Mutation Burden ◽

The Impact

Abstract Nucleophosmin (NPM1) mutations are common in acute myeloid leukemia and are associated with high remission rates and prolonged survival with intensive chemotherapy. NPM1 mutations are rare in myelodysplastic syndromes (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and the clinical outcomes of these patients, when treated with intensive chemotherapy, are unknown. We retrospectively evaluated the clinicopathologic characteristics and the impact of therapy in 31 patients with MDS or MDS/MPN and NPM1 mutations. Next-generation sequencing was performed at diagnosis in 22 patients. Median age was 62 years (range, 19-86). Twenty-four patients (77%) had normal karyotype, and all had multilineage dysplasia. Most patients could be classified as MDS with excess blasts (19/31, 61%). NPM1 mutations were detected at a median allele frequency of 0.38 (range, 0.09-0.49). Mutation burden did not correlate with bone marrow blast frequency, and its clearance seemed to be associated with decreased morphologic dysplasia. Ten of the 31 patients (32%) received cytotoxic chemotherapy, 20 (65%) hypomethylating agents, and 1 (4%) lenalidomide. Sequential sequencing was available in 16 (52%) patients, and mutation burden correlated with disease status and response to therapy. Patients treated with chemotherapy had higher complete response rates (90% vs 28%, P = .004), longer median progression-free survival (not reached vs 7.5 months, P = .023), and overall survival (not reached vs 16 months, P = .047). Intensive chemotherapy and allogeneic stem cell transplantation (SCT) may be associated with improved clinical outcomes in patients with NPM1-mutated MDS or MDS/MPN who are candidates for this form of therapy.

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Glucocorticoid maintenance therapy and severe infectious complications in ANCA-associated vasculitis: a retrospective analysis

Rheumatology International ◽

10.1007/s00296-020-04752-9 ◽

2020 ◽

Author(s):

Claudius Speer ◽

Christine Altenmüller-Walther ◽

Jan Splitthoff ◽

Christian Nusshag ◽

Florian Kälble ◽

...

Keyword(s):

Maintenance Therapy ◽

Kidney Function ◽

Patient Survival ◽

Disease Onset ◽

Infectious Complications ◽

Physical Damage ◽

Anca Associated Vasculitis ◽

Time To Relapse ◽

The Impact ◽

Patient Survival Time

AbstractTo study the impact of glucocorticoid maintenance dose and treatment duration on outcomes in patients with AAV (ANCA-associated vasculitis) with emphasis on infectious complications. A total of 130 AAV patients from two German vasculitis centers diagnosed between August 2004 and January 2019 treated with cyclophosphamide and glucocorticoids for induction therapy and glucocorticoids for maintenance therapy were retrospectively enrolled. We investigated the influence of glucocorticoid maintenance therapy on patient survival, time to relapse, kidney function, infectious complications and irreversible physical damage. The patients were divided into the following groups: patients treated according to the predefined reduction scheme (< 7.5 mg) or patients treated with glucocorticoids ≥ 7.5 mg after 6 months. Compared to patients receiving < 7.5 mg glucocorticoids after 6 months, patients receiving $$\ge $$ ≥ 7.5 mg had an increased rate of infectious episodes per patient (1.7 vs. 0.6; p < 0.001), including urinary tract infection (p = 0.007), pneumonia (p = 0.003), opportunistic pneumonia (p = 0.022) and sepsis (p = 0.008). Especially pneumonia during the first 24 months after disease onset [hazard ratio, 3.0 (95% CI 1.5 − 6.1)] led to more deaths from infection (p = 0.034). Glucocorticoid maintenance therapy after 6 months had no impact on relapse rate or patient survival and decline in kidney function was comparable. Glucocorticoid maintenance therapy with $$\ge $$ ≥ 7.5 mg after 6 months is associated with more severe infectious complications leading to an increased frequency of deaths from infection. Glucocorticoid maintenance therapy has no effect on time to relapse or patient survival and should therefore be critically revised throughout the aftercare of AAV patients.

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Dementia risk communication. A user manual for Brain Health Services—part 3 of 6

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00840-5 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Leonie N. C. Visser ◽

Carolina Minguillon ◽

Gonzalo Sánchez-Benavides ◽

Marc Abramowicz ◽

Daniele Altomare ◽

...

Keyword(s):

Health Services ◽

Risk Communication ◽

Disease Status ◽

Prevention Programs ◽

Brain Health ◽

Individual Level ◽

Risk Profiling ◽

Dementia Risk ◽

Dementia Incidence ◽

The Impact

AbstractGrowing evidence suggests dementia incidence can be reduced through prevention programs targeting risk factors. To accelerate the implementation of such prevention programs, a new generation of brain health services (BHS) is envisioned, involving risk profiling, risk communication, risk reduction, and cognitive enhancement. The purpose of risk communication is to enable individuals at risk to make informed decisions and take action to protect themselves and is thus a crucial step in tailored prevention strategies of the dementia incidence. However, communicating about dementia risk is complex and challenging.In this paper, we provide an overview of (i) perspectives on communicating dementia risk from an ethical, clinical, and societal viewpoint; (ii) insights gained from memory clinical practice; (iii) available evidence on the impact of disclosing APOE and Alzheimer’s disease biomarker test results gathered from clinical trials and observational studies; (iv) the value of established registries in light of BHS; and (v) practical recommendations regarding effective strategies for communicating about dementia risk.In addition, we identify challenges, i.e., the current lack of evidence on what to tell on an individual level—the actual risk—and on how to optimally communicate about dementia risk, especially concerning worried yet cognitively unimpaired individuals. Ideally, dementia risk communication strategies should maximize the desired impact of risk information on individuals’ understanding of their health/disease status and risk perception and minimize potential harms. More research is thus warranted on the impact of dementia risk communication, to (1) evaluate the merits of different approaches to risk communication on outcomes in the cognitive, affective and behavioral domains, (2) develop an evidence-based, harmonized dementia risk communication protocol, and (3) develop e-tools to support and promote adherence to this protocol in BHSs.Based on the research reviewed, we recommend that dementia risk communication should be precise; include the use of absolute risks, visual displays, and time frames; based on a process of shared decision-making; and address the inherent uncertainty that comes with any probability.

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Gut microbiome signatures of risk and prodromal markers of Parkinson’s disease

10.1101/2019.12.11.872481 ◽

2019 ◽

Author(s):

Sebastian Heinzel ◽

Velma T. E. Aho ◽

Ulrike Suenkel ◽

Anna-Katharina von Thaler ◽

Claudia Schulte ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Gut Microbiome ◽

Physical Inactivity ◽

Disease Onset ◽

Rem Sleep Behavior Disorder ◽

Sleep Behavior ◽

Microbiome Composition ◽

Β Diversity ◽

The Impact

AbstractObjectivesAlterations of the gut microbiome in Parkinson’s disease (PD) have been repeatedly demonstrated. However, little is known about whether such alterations precede disease onset and how they may be related to risk and prodromal markers of PD. We investigated associations of these features with gut microbiome composition.MethodsEstablished risk and prodromal markers of PD as well as factors related to diet/lifestyle, bowel function and medication were studied in relation to bacterial α-/β-diversity, enterotypes, and taxonomic composition in stool samples of 666 elderly TREND study participants.ResultsAmong risk and prodromal markers, physical inactivity, constipation and age showed associations with α- and β-diversity, and for both measures subthreshold parkinsonism and physical inactivity showed interaction effects. Moreover, male sex, possible REM-sleep behavior disorder (RBD), smoking as well as body-mass-index, antidiabetic and urate-lowering medication were associated with β-diversity. Physical inactivity and constipation severity were increased in individuals with the Firmicutes-enriched enterotype. Subthreshold parkinsonism was least frequently observed in individuals with the Prevotella-enriched enterotype. Differentially abundant taxa were linked to constipation, physical inactivity, possible RBD, and subthreshold parkinsonism. Substantia nigra hyperechogenicity, olfactory loss, depression, orthostatic hypotension, urinary/erectile dysfunction, PD family history and the overall prodromal PD probability showed no significant microbiome associations.InterpretationSeveral risk and prodromal markers of PD are associated with changes in gut microbiome composition. However, the impact of the gut microbiome on PD risk and potential microbiome-dependent subtypes in the prodrome of PD need further investigation based on prospective clinical and (multi)omics data in incident PD cases.

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