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1.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809421

RESUMO

COVID-19 is a major pandemic facing the world today, which has implications on current microbiome-based treatments such as fecal microbiota transplantation (FMT) used for recurrent Clostridioides difficile infections. The bidirectional relationship between the inhabitants of our gut, the gut microbiota, and COVID-19 pathogenesis, as well as the underlying mechanism involved, must be elucidated in order to increase FMT safety and efficacy. In this perspective, we discuss the crucial cross-talk between the gut microbiota and the lungs, known as the gut-lung axis, during COVID-19 infection, as well as the putative effect of these microorganisms and their functional activity (i.e., short chain fatty acids and bile acids) on FMT treatment. In addition, we highlight the urgent need to investigate the possible impact of COVID-19 on FMT safety and efficacy, as well as instilling stringent screening protocols of donors and recipients during COVID-19 and post-COVID-19 pandemic to produce a cohesive and optimized FMT treatment plan across all centers and in all countries across the globe.


Assuntos
/epidemiologia , Transplante de Microbiota Fecal/métodos , Pandemias , Infecções por Clostridium/terapia , Transplante de Microbiota Fecal/efeitos adversos , Microbioma Gastrointestinal , Humanos , Pulmão/fisiopatologia , Resultado do Tratamento
2.
Rev Med Suisse ; 17(734): 726-731, 2021 Apr 14.
Artigo em Francês | MEDLINE | ID: mdl-33852207

RESUMO

In clinical practice, fecal microbiota transplantation (FMT) has been established as an unparalleled therapy to date for multiple recurrent Clostridioides difficile infections (CDI). The implementation of the FMT in practice requires a significant investment to meet legal, security and financial requirements. Research on the microbiota is booming and multiple investigations on FMT in indications other than CDI are ongoing.


Assuntos
Infecções por Clostridium , Microbiota , Infecções por Clostridium/terapia , Transplante de Microbiota Fecal , Humanos , Recidiva , Resultado do Tratamento
3.
Medicine (Baltimore) ; 100(14): e25390, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33832129

RESUMO

OBJECTIVE: Functional constipation is a prevalent, burdensome gastrointestinal disorder whose treatment remains challenging. Combined therapy uniting multiple treatments may be promising. Fecal microbiota transplantation (FMT) which tends to be an etiological treatment has been increasingly investigated in its management. Meanwhile, laxatives are widely used to relieve constipation temporarily, but their overall efficacy is poor. Therefore, we performed meta-analyses of randomized controlled trials to evaluate the joint efficacy of FMT and laxatives in functional constipation. METHODS: We performed a systematic literature search of 6 electronic databases as of August 11, 2020. Randomized controlled trial of FMT together with laxatives vs laxatives alone in functional constipation in adults were included. Two reviewers independently performed the screening, data extraction, and bias assessment. Dichotomous outcome data were synthesized by risk ratio, and measurement data by weighted mean difference (WMD). RESULTS: A total of 1400 records were identified, of which 5 were eligible (409 patients). Overall, compared to laxatives alone, combined therapy of FMT and laxatives more significantly improved total effective rate (risk ratio: 1.35; 95% confidence interval [CI]: 1.14, 1.60; I2 = 13%), Bristol stool form scale score (WMD: 1.04; 95% CI: 0.57, 1.51; I2 = 76%), reduce Wexner score (WMD: -3.25; 95% CI: -5.58, -0.92; I2 = 92%), Knowles-Eccersley-Scott-Symptom (KESS) score (WMD: -5.65; 95% CI: -7.62, -3.69; I2 = 0%) and patient assessment of constipation quality of life score (WMD: -18.56; 95%; CI: -26.43, -10.68; I2 = 78%). No serious adverse events were reported. The majority of included studies had poor methodological quality. CONCLUSION: Combined therapy of FMT and laxatives may be a reasonably effective and safe treatment for people with functional constipation. However, caution is needed with the interpretation of these data due to the small sample size, high heterogeneity, and low quality of the studies. Besides, we expect that more studies will be performed exploring the efficacy and safety of combined therapy for functional constipation.


Assuntos
Terapia Combinada/métodos , Constipação Intestinal/fisiopatologia , Constipação Intestinal/terapia , Transplante de Microbiota Fecal/métodos , Laxantes/uso terapêutico , Adulto , Idoso , Estudos de Casos e Controles , China/epidemiologia , Terapia Combinada/efeitos adversos , Constipação Intestinal/psicologia , Gerenciamento de Dados , Transplante de Microbiota Fecal/efeitos adversos , Feminino , Humanos , Laxantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Segurança , Resultado do Tratamento
4.
J Equine Vet Sci ; 98: 103360, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33663713

RESUMO

Fecal microbiota transplant (FMT), a technique used to restore normal intestinal microbial communities, has been successful in treating humans with Clostridioides difficile colitis. Subsequently, FMT is being used in veterinary patients with suspected intestinal dysbiosis. Unfortunately, little data are available regarding best practices for FMT in horses. The objective of this study was to evaluate the effects of storing manure prepared for equine FMT (MP-FMT) at -20°C for up to 4 weeks and passage through a simulated proximal gastrointestinal (GI) tract on the viability of MP-FMT. The results of this study indicate that storage at -20°C for greater than 1 week and exposure to conditions consistent with the proximal GI tract significantly decreased viability of the microbial population, with gram-negative enteric bacteria most significantly impacted. This preliminary evaluation indicates that further work is necessary to determine best practices to preserve the viability MP-FMT in horses.


Assuntos
Microbioma Gastrointestinal , Doenças dos Cavalos , Microbiota , Animais , Disbiose/veterinária , Transplante de Microbiota Fecal/veterinária , Fezes , Cavalos
6.
Aliment Pharmacol Ther ; 53(9): 999-1009, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33694229

RESUMO

BACKGROUND: A defined bacterial mixture could be a safer alternative to faecal microbiota transplantation (FMT). AIMS: To compare the efficacy of a 12-strain mixture termed rectal bacteriotherapy with either FMT or vancomycin for recurrent Clostridioides difficile infection (CDI) in an open-label 3-arm randomised controlled trial. METHODS: We screened all individuals positive for C difficile from May 2017 to March 2019. Persons with laboratory-confirmed recurrent CDI were included. Before FMT and rectal bacteriotherapy, we pre-treated with vancomycin for 7-14 days. Rectal bacteriotherapy was applied by enema on three consecutive days and FMT by enema once with possible repetition for two to three infusions within 14 days. The vancomycin group was treated for 14 days with additional five weeks of tapering for multiple recurrences. The primary outcome was clinical cure within 90 days. A secondary outcome was 180-day all-cause mortality. RESULTS: Participants in the FMT group (n = 34) were cured more often than participants receiving vancomycin (n = 31), 76% vs 45% (OR 3.9 (1.4-11.4), P < 0.01) or rectal bacteriotherapy (n = 31), 76% vs 52% (OR 3.0 (1.1-8.8), P = 0.04). Rectal bacteriotherapy and vancomycin performed similarly (P = 0.61). The mortality rate was 6% in the FMT group, 13% in the bacteriotherapy group and 23% in the vancomycin group. FMT tended to reduce mortality compared with vancomycin, OR 0.2 (0.04-1.12), P = 0.07. CONCLUSIONS: Rectal bacteriotherapy appears as effective as vancomycin but less effective than 1-3 FMTs. FMT by enema with 1-3 infusions is superior to vancomycin for treating recurrent C difficile infections and might reduce mortality.


Assuntos
Infecções por Clostridium , Infecções por Clostridium/terapia , Transplante de Microbiota Fecal , Fezes , Humanos , Recidiva , Resultado do Tratamento , Vancomicina/uso terapêutico
7.
Microbiome ; 9(1): 59, 2021 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-33678185

RESUMO

BACKGROUND: Spinal cord injury (SCI) patients display disruption of gut microbiome, and gut dysbiosis exacerbate neurological impairment in SCI models. Cumulative data support an important role of gut microbiome in SCI. Here, we investigated the hypothesis that fecal microbiota transplantation (FMT) from healthy uninjured mice into SCI mice may exert a neuroprotective effect. RESULTS: FMT facilitated functional recovery, promoted neuronal axonal regeneration, improved animal weight gain and metabolic profiling, and enhanced intestinal barrier integrity and GI motility in SCI mice. High-throughput sequencing revealed that levels of phylum Firmicutes, family Christensenellaceae, and genus Butyricimonas were reduced in fecal samples of SCI mice, and FMT remarkably reshaped gut microbiome. Also, FMT-treated SCI mice showed increased amount of fecal short-chain fatty acids (SCFAs), which correlated with alteration of intestinal permeability and locomotor recovery. Furthermore, FMT downregulated IL-1ß/NF-κB signaling in spinal cord and NF-κB signaling in gut following SCI. CONCLUSION: Our study demonstrates that reprogramming of gut microbiota by FMT improves locomotor and GI functions in SCI mice, possibly through the anti-inflammatory functions of SCFAs. Video Abstract.


Assuntos
Encéfalo/fisiologia , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/fisiologia , Neuroproteção/fisiologia , Traumatismos da Medula Espinal/terapia , Animais , Ácidos Graxos Voláteis/metabolismo , Fezes/química , Feminino , Interleucina-1beta/metabolismo , Intestinos/microbiologia , Intestinos/fisiologia , Locomoção , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Transdução de Sinais , Traumatismos da Medula Espinal/patologia
8.
Pharmacol Res ; 167: 105548, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33722710

RESUMO

Acute Respiratory Distress Syndrome (ARDS) is triggered by a variety of agents, including Staphylococcal Enterotoxin B (SEB). Interestingly, a significant proportion of patients with COVID-19, also develop ARDS. In the absence of effective treatments, ARDS results in almost 40% mortality. Previous studies from our laboratory demonstrated that resveratrol (RES), a stilbenoid, with potent anti-inflammatory properties can attenuate SEB-induced ARDS. In the current study, we investigated the role of RES-induced alterations in the gut and lung microbiota in the regulation of ARDS. Our studies revealed that SEB administration induced inflammatory cytokines, ARDS, and 100% mortality in C3H/HeJ mice. Additionally, SEB caused a significant increase in pathogenic Proteobacteria phylum and Propionibacterium acnes species in the lungs. In contrast, RES treatment attenuated SEB-mediated ARDS and mortality in mice, and significantly increased probiotic Actinobacteria phylum, Tenericutes phylum, and Lactobacillus reuteri species in both the colon and lungs. Colonic Microbiota Transplantation (CMT) from SEB-injected mice that were treated with RES as well as the transfer of L. reuteri into recipient mice inhibited the production of SEB-mediated induction of pro-inflammatory cytokines such as IFN-γ and IL-17 but increased that of anti-inflammatory IL-10. Additionally, such CMT and L. reuteri recipient mice exposed to SEB, showed a decrease in lung-infiltrating mononuclear cells, cytotoxic CD8+ T cells, NKT cells, Th1 cells, and Th17 cells, but an increase in the population of regulatory T cells (Tregs) and Th3 cells, and increase in the survival of mice from SEB-mediated ARDS. Together, the current study demonstrates that ARDS induced by SEB triggers dysbiosis in the lungs and gut and that attenuation of ARDS by RES may be mediated, at least in part, by alterations in microbiota in the lungs and the gut, especially through the induction of beneficial bacteria such as L. reuteri.


Assuntos
Anti-Inflamatórios/farmacologia , Colo/efeitos dos fármacos , Enterotoxinas , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Resveratrol/farmacologia , Superantígenos , Animais , Linhagem Celular , Colo/imunologia , Colo/metabolismo , Colo/microbiologia , Citocinas/metabolismo , Modelos Animais de Doenças , Disbiose , Feminino , Mediadores da Inflamação/metabolismo , Lactobacillus reuteri/efeitos dos fármacos , Lactobacillus reuteri/crescimento & desenvolvimento , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/microbiologia , Camundongos Endogâmicos C3H , /metabolismo , /microbiologia
9.
Ann Agric Environ Med ; 28(1): 56-60, 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33775068

RESUMO

INTRODUCTION: Cytomegalovirus (CMV) infection in patients with inflammatory bowel disease (IBD) is reactivated by the use of immunosuppressive drugs. CMV infection may produce IBD flares refractory to standard therapy. OBJECTIVE: The aim of our study was to assess the efficacy and safety of faecal microbiota transplantation (FMT) for the treatment of CMV colitis in patients with ulcerative colitis (UC) flare. MATERIAL AND METHODS: A total of 8 children, with mild to severe UC, positive for CMV PCR in colonic biopsies, received 50-100 ml FMT by nasogastric tube on 5 consecutive days in each of 2 weeks. During the study, the subjects were treated with 5ASA and FMT. Immunosuppressant therapy was withdrawn, when CMV colitis was diagnosed by positive DNA PCR in colonic tissues. The clinical response was defined as a decrease of Paediatric UC Activity Index by ≥20 points. RESULTS: At the 6th week of the study, negative colonic CMV DNA PCR was measured after 10 infusions in 7/8 patients. For one boy, 20 infusions were administered to assess CMV elimination from colonic biopsies. A clinical response was observed in 3/8 patients, with clinical remission in 3/8 patients. Faecal calprotectin decreased significantly in 3 patients. CRP normalized in 2 patients after 6 weeks. No serious adverse effects were observed during and after infusions. CONCLUSIONS: FMT seems to be an effective and safe treatment option for CMV colitis in children with UC. This is the first study to demonstrate the application of FMT as a new therapeutic option for CMV colitis.


Assuntos
Colite Ulcerativa/terapia , Infecções por Citomegalovirus/terapia , Citomegalovirus/fisiologia , Transplante de Microbiota Fecal , Adolescente , Criança , Pré-Escolar , Colite Ulcerativa/microbiologia , Colite Ulcerativa/virologia , Colo/microbiologia , Colo/virologia , Infecções por Citomegalovirus/microbiologia , Infecções por Citomegalovirus/virologia , Feminino , Microbioma Gastrointestinal , Humanos , Masculino , Projetos Piloto , Estudos Prospectivos
11.
Acta Gastroenterol Belg ; 84(1): 87-90, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33639698

RESUMO

Hepatic encephalopathy (HE) is a leading cause of hospitalization and morbimortality in advanced cirrhosis with limited therapeutic options available. Given the paramount role of gut microbiota in HE, and the efficacy of fecal microbiota transplantation (FMT) in other diseases, this review intends to summarize the evidence supporting the safety, efficacy and future perspectives of FMT in HE. Current evidence, despite being scarce, points towards FMT being a safe, effective and tolerable procedure in HE. Some unanswered questions remain about the optimal dose, the administration route, the long term effects and the selection of the optimal donor. Future trials, some of which are already underway, will provide us additional evidence and hopefully the necessary answers.


Assuntos
Microbioma Gastrointestinal , Encefalopatia Hepática , Transplante de Microbiota Fecal , Fezes , Encefalopatia Hepática/terapia , Humanos , Cirrose Hepática
12.
Adv Exp Med Biol ; 1278: 191-203, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33523449

RESUMO

Autoimmune conditions affect 23 million Americans or 7% of the US population. There are more than 100 autoimmune disorders, affecting every major organ system in humans. This chapter aims to further explain Treg dysfunction autoimmune disorders, including monogenic primary immune deficiency such as immune dysregulation polyendocrinopathy, enteropathy, X-linked inheritance (IPEX) syndrome, and polygenic autoimmune diseases with Treg dysfunction such as multiple sclerosis (MS), inflammatory bowel disease (IBD), and food allergy. These conditions are associated with an abnormal small intestinal and colonic microbiome. Some disorders clearly improve with therapies aimed at microbial modification, including probiotics and fecal microbiota transplantation (FMT). Approaches to prevent and treat these disorders will need to focus on the acquisition and maintenance of a healthy colonic microbiota, in addition to more focused approaches at immune suppression during acute disease exacerbations.


Assuntos
Doenças Autoimunes , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Doenças Autoimunes/terapia , Disbiose , Transplante de Microbiota Fecal , Humanos , Linfócitos T Reguladores
13.
Science ; 371(6529): 595-602, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33542131

RESUMO

Anti-programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti-PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti-PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti-PD-1 in patients with PD-1-refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti-PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8-expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti-PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 in a subset of PD-1 advanced melanoma.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Transplante de Microbiota Fecal , Melanoma/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/terapia , Linfócitos T CD8-Positivos/imunologia , Microbioma Gastrointestinal , Humanos , Interleucina-8/imunologia , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Células Mieloides/imunologia , Microambiente Tumoral/imunologia
15.
Microbiome ; 9(1): 45, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33593429

RESUMO

BACKGROUND: Graves' disease (GD) is an autoimmune condition in which autoantibodies to the thyrotropin receptor (TSHR) cause hyperthyroidism. About 50% of GD patients also have Graves' orbitopathy (GO), an intractable disease in which expansion of the orbital contents causes diplopia, proptosis and even blindness. Murine models of GD/GO, developed in different centres, demonstrated significant variation in gut microbiota composition which correlated with TSHR-induced disease heterogeneity. To investigate whether correlation indicates causation, we modified the gut microbiota to determine whether it has a role in thyroid autoimmunity. Female BALB/c mice were treated with either vancomycin, probiotic bacteria, human fecal material transfer (hFMT) from patients with severe GO or ddH2O from birth to immunization with TSHR-A subunit or beta-galactosidase (ßgal; age ~ 6 weeks). Incidence and severity of GD (TSHR autoantibodies, thyroid histology, thyroxine level) and GO (orbital fat and muscle histology), lymphocyte phenotype, cytokine profile and gut microbiota were analysed at sacrifice (~ 22 weeks). RESULTS: In ddH2O-TSHR mice, 84% had pathological autoantibodies, 67% elevated thyroxine, 77% hyperplastic thyroids and 70% orbital pathology. Firmicutes were increased, and Bacteroidetes reduced relative to ddH2O-ßgal; CCL5 was increased. The random forest algorithm at the genus level predicted vancomycin treatment with 100% accuracy but 74% and 70% for hFMT and probiotic, respectively. Vancomycin significantly reduced gut microbiota richness and diversity compared with all other groups; the incidence and severity of both GD and GO also decreased; reduced orbital pathology correlated positively with Akkermansia spp. whilst IL-4 levels increased. Mice receiving hFMT initially inherited their GO donors' microbiota, and the severity of induced GD increased, as did the orbital brown adipose tissue volume in TSHR mice. Furthermore, genus Bacteroides, which is reduced in GD patients, was significantly increased by vancomycin but reduced in hFMT-treated mice. Probiotic treatment significantly increased CD25+ Treg cells in orbital draining lymph nodes but exacerbated induced autoimmune hyperthyroidism and GO. CONCLUSIONS: These results strongly support a role for the gut microbiota in TSHR-induced disease. Whilst changes to the gut microbiota have a profound effect on quantifiable GD endocrine and immune factors, the impact on GO cellular changes is more nuanced. The findings have translational potential for novel, improved treatments. Video abstract.


Assuntos
Microbioma Gastrointestinal , Oftalmopatia de Graves/microbiologia , Animais , Modelos Animais de Doenças , Transplante de Microbiota Fecal , Feminino , Oftalmopatia de Graves/imunologia , Oftalmopatia de Graves/metabolismo , Oftalmopatia de Graves/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C
17.
J Med Case Rep ; 15(1): 60, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33557941

RESUMO

BACKGROUND: To investigate the potential beneficial effect of fecal microbiota transplantation (FMT) on gastrointestinal symptoms, gut dysbiosis and immune status in discharged COVID-19 patients. CASE PRESENTATION: A total of 11 COVID-19 patients were recruited in April, 2020, about one month on average after they were discharged from the hospital. All subjects received FMT for 4 consecutive days by oral capsule administrations with 10 capsules for each day. In total, 5 out of 11 patients reported to be suffered from gastrointestinal symptoms, which were improved after FMT. After FMT, alterations of B cells were observed, which was characterized as decreased naive B cell (P = 0.012) and increased memory B cells (P = 0.001) and non-switched B cells (P = 0.012).The microbial community richness indicated by operational taxonomic units number, observed species and Chao1 estimator was marginally increased after FMT. Gut microbiome composition of discharged COVID-19 patients differed from that of the general population at both phylum and genera level, which was characterized with a lower proportion of Firmicutes (41.0%) and Actinobacteria (4.0%), higher proportion of Bacteroidetes (42.9%) and Proteobacteria (9.2%). FMT can partially restore the gut dysbiosis by increasing the relative abundance of Actinobacteria (15.0%) and reducing Proteobacteria (2.8%) at the phylum level. At the genera level, Bifidobacterium and Faecalibacterium had significantly increased after FMT. CONCLUSIONS: After FMT, altered peripheral lymphocyte subset, restored gut microbiota and alleviated gastrointestinal disorders were observe, suggesting that FMT may serve as a potential therapeutic and rehabilitative intervention for the COVID-19.


Assuntos
Subpopulações de Linfócitos B , Disbiose/terapia , Transplante de Microbiota Fecal , Gastroenteropatias/terapia , Microbioma Gastrointestinal , Idoso , Bacteroidetes , Bifidobacterium , Disbiose/microbiologia , Faecalibacterium , Feminino , Gastroenteropatias/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Alta do Paciente , Proteobactérias , Adulto Jovem
18.
Microbiome ; 9(1): 34, 2021 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-33517890

RESUMO

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to identify certain molecule(s) derived from the gut microbiota, which has the potential to manage PD. Osteocalcin (OCN), an osteoblast-secreted protein, has been shown to modulate brain function. Thus, it is of interest to investigate whether OCN could exert protective effect on PD and, if yes, whether the underlying mechanism lies in the subsequent changes in gut microbiota. RESULTS: The intraperitoneal injection of OCN can effectively ameliorate the motor deficits and dopaminergic neuronal loss in a 6-hydroxydopamine-induced PD mouse model. The further antibiotics treatment and fecal microbiota transplantation experiments confirmed that the gut microbiota was required for OCN-induced protection in PD mice. OCN elevated Bacteroidetes and depleted Firmicutes phyla in the gut microbiota of PD mice with elevated potential of microbial propionate production and was confirmed by fecal propionate levels. Two months of orally administered propionate successfully rescued motor deficits and dopaminergic neuronal loss in PD mice. Furthermore, AR420626, the agonist of FFAR3, which is the receptor of propionate, mimicked the neuroprotective effects of propionate and the ablation of enteric neurons blocked the prevention of dopaminergic neuronal loss by propionate in PD mice. CONCLUSIONS: Together, our results demonstrate that OCN ameliorates motor deficits and dopaminergic neuronal loss in PD mice, modulating gut microbiome and increasing propionate level might be an underlying mechanism responsible for the neuroprotective effects of OCN on PD, and the FFAR3, expressed in enteric nervous system, might be the main action site of propionate. Video abstract.


Assuntos
Microbioma Gastrointestinal/fisiologia , Fármacos Neuroprotetores/farmacologia , Osteocalcina/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Propionatos/metabolismo , Animais , Antibacterianos/farmacologia , Modelos Animais de Doenças , Progressão da Doença , Neurônios Dopaminérgicos/efeitos dos fármacos , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/efeitos dos fármacos , Infusões Parenterais , Masculino , Camundongos , Fármacos Neuroprotetores/administração & dosagem , Osteocalcina/administração & dosagem , Oxidopamina , Doença de Parkinson/microbiologia , Doença de Parkinson/fisiopatologia , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/metabolismo
19.
Microbiome ; 9(1): 39, 2021 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-33549144

RESUMO

BACKGROUND: The gut microbiota plays a central role in host physiology and in several pathological mechanisms in humans. Antibiotics compromise the composition and functions of the gut microbiota inducing long-lasting detrimental effects on the host. Recent studies suggest that the efficacy of different clinical therapies depends on the action of the gut microbiota. Here, we investigated how different antibiotic treatments affect the ability of the gut microbiota to control intestinal inflammation upon fecal microbiota transplantation in an experimental colitis model and in ex vivo experiments with human intestinal biopsies. RESULTS: Murine fecal donors were pre-treated with different antibiotics, i.e., vancomycin, streptomycin, and metronidazole before FMT administration to colitic animals. The analysis of the gut microbiome, fecal metabolome, and the immunophenotyping of colonic lamina propria immune cells revealed that antibiotic pre-treatment significantly influences the capability of the microbiota to control intestinal inflammation. Streptomycin and vancomycin-treated microbiota failed to control intestinal inflammation and were characterized by the blooming of pathobionts previously associated with IBD as well as with metabolites related to the presence of oxidative stress and metabolism of simple sugars. On the contrary, the metronidazole-treated microbiota retained its ability to control inflammation co-occurring with the enrichment of Lactobacillus and of innate immune responses involving iNKT cells. Furthermore, ex vivo cultures of human intestinal lamina propria mononuclear cells and iNKT cell clones from IBD patients with vancomycin pre-treated sterile fecal water showed a Th1/Th17 skewing in CD4+ T-cell populations; metronidazole, on the other hand, induced the polarization of iNKT cells toward the production of IL10. CONCLUSIONS: Diverse antibiotic regimens affect the ability of the gut microbiota to control intestinal inflammation in experimental colitis by altering the microbial community structure and microbiota-derived metabolites. Video Abstract.


Assuntos
Antibacterianos/efeitos adversos , Colite/induzido quimicamente , Colite/microbiologia , Modelos Animais de Doenças , Disbiose/microbiologia , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Colite/imunologia , Colite/patologia , Disbiose/induzido quimicamente , Feminino , Microbioma Gastrointestinal/imunologia , Humanos , Masculino , Metronidazol/farmacologia , Camundongos , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/imunologia , Estreptomicina/efeitos adversos , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Vancomicina/efeitos adversos
20.
Nat Commun ; 12(1): 1139, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602945

RESUMO

Changes in the microbiota have been linked to persistent inflammation during treated HIV infection. In this pilot double-blind study, we study 30 HIV-infected subjects on antiretroviral therapy (ART) with a CD4/CD8 ratio < 1 randomized to either weekly fecal microbiota capsules or placebo for 8 weeks. Stool donors were rationally selected based on their microbiota signatures. We report that fecal microbiota transplantation (FMT) is safe, not related to severe adverse events, and attenuates HIV-associated dysbiosis. FMT elicits changes in gut microbiota structure, including significant increases in alpha diversity, and a mild and transient engraftment of donor's microbiota during the treatment period. The greater engraftment seems to be achieved by recent antibiotic use before FMT. The Lachnospiraceae and Ruminococcaceae families, which are typically depleted in people with HIV, are the taxa more robustly engrafted across time-points. In exploratory analyses, we describe a significant amelioration in the FMT group in intestinal fatty acid-binding protein (IFABP), a biomarker of intestinal damage that independently predicts mortality. Gut microbiota manipulation using a non-invasive and safe strategy of FMT delivery is feasible and deserves further investigation. Trial number: NCT03008941.


Assuntos
Transplante de Microbiota Fecal , Infecções por HIV/microbiologia , Infecções por HIV/terapia , Biodiversidade , Biomarcadores/sangue , Análise Discriminante , Microbioma Gastrointestinal , Infecções por HIV/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , Projetos Piloto , Placebos , Doadores de Tecidos
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