Florentin Constancias

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Constancias

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Florentin

ORCID

0000-0002-8612-384X

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Publications 1 - 10 of 14

Impact of manipulation of glycerol/diol dehydratase activity on intestinal microbiota ecology and metabolism
Ramirez Garcia, Alejandro; Zhang, Jianbo; Greppi, Anna; et al. (2021)
Environmental Microbiology
Glycerol/diol dehydratases (GDH) are enzymes that catalyse the production of propionate from 1,2‐propanediol, and acrolein from glycerol. Acrolein reacts with dietary carcinogenic heterocyclic amines (HCA), reducing HCA mutagenicity, but is itself also an antimicrobial agent and toxicant. Gut microbial GDH activity has been suggested as an endogenous acrolein source; however, there is limited information on the potential of the intestinal microbiota to have GDH activity, and what impact it can have on the intestinal ecosystem and host health. We hypothesized that GDH activity of gut microbiota is determined by the abundance and distribution of GDH‐active taxa and can be enhanced by supplementation of the GDH active Anaerobutyricum hallii, and tested this hypothesis combining quantitative profiling of gdh, model batch fermentations, microbiota manipulation, and kinetic modelling of acrolein formation. Our results suggest that GDH activity is a common trait of intestinal microbiota shared by a few taxa, which was dependent on overall gdh abundance. Anaerobutyricum hallii was identified as a key taxon in GDH metabolism, and its supplementation increased the rate of GDH activity and acrolein release, which enhanced the transformation of HCA and reduced fermentation activity. The findings of this first systematic study on acrolein release by intestinal microbiota indicate that dietary and microbial modulation might impact GDH activity, which may influence host health. © 2021 Society for Applied Microbiology and John Wiley & Sons Ltd.
GABA Production by Human Intestinal Bacteroides spp.: Prevalence, Regulation, and Role in Acid Stress Tolerance
Otaru, Nize; Ye, Kun; Mujezinovic, Denisa; et al. (2021)
Frontiers in Microbiology
The high neuroactive potential of metabolites produced by gut microbes has gained traction over the last few years, with metagenomic-based studies suggesting an important role of microbiota-derived γ-aminobutyric acid (GABA) in modulating mental health. Emerging evidence has revealed the presence of the glutamate decarboxylase (GAD)-encoding gene, a key enzyme to produce GABA, in the prominent human intestinal genus Bacteroides. Here, we investigated GABA production by Bacteroides in culture and metabolic assays combined with comparative genomics and phylogenetics. A total of 961 Bacteroides genomes were analyzed in silico and 17 metabolically and genetically diverse human intestinal isolates representing 11 species were screened in vitro. Using the model organism Bacteroides thetaiotaomicron DSM 2079, we determined GABA production kinetics, its impact on milieu pH, and we assessed its role in mitigating acid-induced cellular damage. We showed that the GAD-system consists of at least four highly conserved genes encoding a GAD, a glutaminase, a glutamate/GABA antiporter, and a potassium channel. We demonstrated a high prevalence of the GAD-system among Bacteroides with 90% of all Bacteroides genomes (96% in human gut isolates only) harboring all genes of the GAD-system and 16 intestinal Bacteroides strains producing GABA in vitro (ranging from 0.09 to 60.84 mM). We identified glutamate and glutamine as precursors of GABA production, showed that the production is regulated by pH, and that the GAD-system acts as a protective mechanism against acid stress in Bacteroides, mitigating cell death and preserving metabolic activity. Our data also indicate that the GAD-system might represent the only amino acid-dependent acid tolerance system in Bacteroides. Altogether, our results suggest an important contribution of Bacteroides in the regulation of the GABAergic system in the human gut.
Periodontitis associates with species-specific gene expression of the oral microbiota
Belstrøm, Daniel; Constancias, Florentin; Drautz-Moses, Daniela I.; et al. (2021)
npj Biofilms and Microbiomes
The purpose of the present investigation was to characterize species-specific bacterial activity of the oral microbiota in periodontitis. We tested the hypotheses that chronic inflammation, i.e., periodontitis, associates with bacterial gene expression of the oral microbiota. Oral microbial samples were collected from three oral sites—subgingival plaque, tongue, and saliva from patients with periodontitis and healthy controls. Paired metagenomics and metatranscriptomics were used to perform concomitant characterization of taxonomic composition and to determine species-specific bacterial activity as expressed by the ratio of specific messenger RNA reads to their corresponding genomic DNA reads. Here, we show the association of periodontitis with bacterial gene expression of the oral microbiota. While oral site was the main determinant of taxonomic composition as well as bacterial gene expression, periodontitis was significantly associated with a reduction of carbohydrate metabolism of the oral microbiota at three oral sites (subgingival plaque, tongue, and saliva). Data from the present study revealed the association of periodontitis with bacterial gene expression of the oral microbiota. Conditions of periodontitis was associated with bacterial activity of local subgingival plaque, but also on tongue and the salivary microbiota. Collectively, data suggest that periodontitis associates with impaired carbohydrate metabolism of the oral microbiota. Future longitudinal and interventional studies are warranted to evaluate the potential pathogenic role of impaired bacterial carbohydrate metabolism not only in periodontitis but also in other diseases with low-grade inflammation, such as type 2 diabetes mellitus.
Gait Disorder among Elderly People, Psychomotor Disadaptation Syndrome: Post-Fall Syndrome, Risk Factors and Follow-Up – A Cohort Study of 70 Patients
Meyer, Maxence; Constancias, Florentin; Vogel, Thomas; et al. (2021)
Gerontology
Introduction: Falls among older people are a major health issue and the first cause of accidental death after 75 years of age. Post-fall syndrome (PFS) is commonly known and yet poorly studied. Objective: Identify risk factors for PFS and do a follow-up 1 year later. Methods: We included all patients over 70 years of age hospitalized after suffering a fall in a case-control study, and then followed them in a cohort study. PFS was retained in case of functional mobility decline (transferring, walking) occurring following a fall in the absence of an acute neurological, orthopedic or rheumatic pathology directly responsible for the decline. The data initially collected were: clinical (anamnestic, emergency and departmental/ward evolution, medical history, lifestyle, treatments, clinical examination items); and imaging if the patient had been subjected to brain imaging in the last 3 years prior to inclusion. Regarding the follow-up at 1 year, we collected from the general physician the occurrence and the characteristics of new falls, functional mobility assessment, hospitalization and death. Results: Inclusion took place from March 29, 2016 to June 7, 2016 and follow-up until June 30, 2017. We included 70 patients. A total of 29 patients exhibited a PFS (41.4 %). Risk factors for PFS included age, walking disorder prior to the fall, the use of a walking aid prior to the fall, no unaccompanied outdoor walk in the week before the fall, visual impairment making close reading impossible, stiffness in ankle dorsiflexion, grip strength and the fear of falling. Among patients with PFS, 52.9% could still perform a transfer at 1 year and 64.7% could still walk against 80.7% and 85.2%, respectively, for patients without PFS. Conclusion: The study showed the existence of body functions/structure impairments and activity limitations prior to the fall among patients exhibiting a PFS. This suggests the existence of a pre-fall syndrome, i.e., a psychomotor disadaptation syndrome existing prior to the fall. Among the 8 risk factors, fear of falling, vision impairment and muscle strength could be targeted for improvement. The diagnosis of PFS could be a marker of loss of functional mobility at 1 year. © 2020 S. Karger AG.
Transgenerational effects of early life stress on the fecal microbiota in mice
Otaru, Nize; Kourouma, Lola; Pugin, Benoît; et al. (2024)
Communications Biology
Stress in early life can affect the progeny and increase the risk to develop psychiatric and cardiometabolic diseases across generations. The cross-generational effects of early life stress have been modeled in mice and demonstrated to be associated with epigenetic factors in the germline. While stress is known to affect gut microbial features, whether its effects can persist across life and be passed to the progeny is not well defined. Here we show that early postnatal stress in mice shifts the fecal microbial composition (binary Jaccard index) throughout life, including abundance of eight amplicon sequencing variants (ASVs). Further effects on fecal microbial composition, structure (weighted Jaccard index), and abundance of 16 ASVs are detected in the progeny across two generations. These effects are not accompanied by changes in bacterial metabolites in any generation. These results suggest that changes in the fecal microbial community induced by early life traumatic stress can be perpetuated from exposed parent to the offspring.
Presence of active myocarditis at the 6 month follow-up appointment for a severe form of COVID-19: a case report
Vogel, Thomas; Meyer, Anita; Constancias, Florentin; et al. (2021)
ESC Heart Failure
Here, we present the case of an 81-year-old male patient, who was hospitalized for a severe form of COVID-19. Transthoracic echocardiogram (TTE) performed 1 month after symptom onset was normal. Respiratory evolution was favourable, and the patient was discharged at Day 78. At 6 months, despite a good functional recovery, he presented pulmonary sequelae, and the TTE revealed a clear reduction of left ventricular ejection fraction (LVEF) and mild LV dilatation without cardiac symptoms. The cardiac magnetic resonance (CMR) using Lake Louise Criteria (LLC), T1 and T2 mapping showed focal infero-basal LV wall oedema, elevated T1 and T2 myocardial relaxation times especially in basal inferior and infero-lateral LV walls, and sub-epicardial late gadolinium enhancement in those LV walls. The diagnosis of active myocarditis was raised especially based on TTE abnormalities and CMR LLC, T1 and T2 mapping. Currently, we are not aware of published reports of a 6 month post-COVID-19 active myocarditis.
Association of general health and lifestyle factors with the salivary microbiota – Lessons learned from the ADDITION-PRO cohort
Poulsen, Casper Sahl; Nygaard, Nikoline; Constancias, Florentin; et al. (2022)
Frontiers in Cellular and Infection Microbiology
Introduction: Previous research indicates that the salivary microbiota may be a biomarker of oral as well as systemic disease. However, clarifying the potential bias from general health status and lifestyle-associated factors is a prerequisite of using the salivary microbiota for screening. Materials & Methods: ADDDITION-PRO is a nationwide Danish cohort, nested within the Danish arm of the Anglo-Danish-Dutch Study of Intensive treatment in People with Screen-Detected Diabetes in Primary Care. Saliva samples from n=746 individuals from the ADDITION-PRO cohort were characterized using 16s rRNA sequencing. Alpha- and beta diversity as well as relative abundance of genera was examined in relation to general health and lifestyle-associated variables. Permutational multivariate analysis of variance (PERMANOVA) was performed on individual variables and all variables together. Classification models were created using sparse partial-least squares discriminant analysis (sPLSDA) for variables that showed statistically significant differences based on PERMANOVA analysis (p < 0.05). Results: Glycemic status, hemoglobin-A1c (HbA1c) level, sex, smoking and weekly alcohol intake were found to be significantly associated with salivary microbial composition (individual variables PERMANOVA, p < 0.05). Collectively, these variables were associated with approximately 5.8% of the observed differences in the composition of the salivary microbiota. Smoking status was associated with 3.3% of observed difference, and smoking could be detected with good accuracy based on salivary microbial composition (AUC 0.95, correct classification rate 79.6%). Conclusions: Glycemic status, HbA1c level, sex, smoking and weekly alcohol intake were significantly associated with the composition of the salivary microbiota. Despite smoking only being associated with 3.3% of the difference in overall salivary microbial composition, it was possible to create a model for detection of smoking status with a high correct classification rate. However, the lack of information on the oral health status of participants serves as a limitation in the present study. Further studies in other cohorts are needed to validate the external validity of these findings.
Humoral immune response after COVID-19 infection or BNT162b2 vaccine among older adults: evolution over time and protective thresholds
Meyer, Maxence; Constancias, Florentin; Worth, Claudia; et al. (2022)
GeroScience
The objectives of this study were to assess the dynamics of the SARS-CoV-2 anti-RBD-IgG response over time among older people after-COVID-19 infection or vaccination and its comparison with indicative levels of protection.Geriatric patients with SARS-CoV-2 serological test results were included and divided into three groups. A vaccine group (n= 34), a group of natural COVID-19 infection (n = 32), and a group who contracted-COVID-19 less than 15 days after the first injection (n = 17). Eighty-three patients were included; the median age with IQR was 87 (81-91) years. In the vaccine group at 1 month since the first vaccination, the median titer of anti-RBD-IgG was 620 (217-1874) BAU/ml with 87% of patients above the theoretical protective threshold of 141 BAU/ml according to Dimeglio et al. (J Infec. 84(2):248-88, [7]). Seven months after the first vaccination, this titer decreased to 30 (19-58) BAU/ml with9.5% of patients > 141 BAU/ml. In the natural COVID-19 infection group, at 1 month since the date of first symptom onset, the median titer was 798 (325-1320) BAU/ml with86.7% of patients > 141 BAU/ml and fell to 88 (37-385) with 42.9% of patients > 141BAU/ml at 2 months. The natural infection group was vaccinated 3 months after the infection.Five months after the vaccination cycle, the median titer was 2048 (471-4386) BAU/ml with83.3% of patients > 141 BAU/ml. This supports the clinical results describing the decrease in vaccine protection over time and suggests that vaccination after infection canmaintain significantly higher antibody titer levels for a prolonged period of time.
Initial butyrate producers during infant gut microbiota development are endospore formers
Appert, Olivia; Garcia, Alejandro R.; Frei, Remo; et al. (2020)
Environmental Microbiology
The acquisition of the infant gut microbiota is key to establishing a host‐microbiota symbiosis. Microbially produced metabolites tightly interact with the immune system, and the fermentation‐derived short‐chain fatty acid butyrate is considered an important mediator linked to chronic diseases later in life. The intestinal butyrate‐forming bacterial population is taxonomically and functionally diverse and includes endospore formers with high transmission potential. Succession, and contribution of butyrate‐producing taxa during infant gut microbiota development have been little investigated. We determined the abundance of major butyrate‐forming groups and fermentation metabolites in faeces, isolated, cultivated and characterized the heat‐resistant cell population, which included endospores, and compared butyrate formation efficiency of representative taxa in batch cultures. The endospore community contributed about 0.001% to total cells, and was mainly composed of the pioneer butyrate‐producing Clostridium sensu stricto. We observed an increase in abundance of Faecalibacterium prausnitzii, butyrate‐producing Lachnospiraceae and faecal butyrate levels with age that is likely explained by higher butyrate production capacity of contributing taxa compared with Clostridium sensu stricto. Our data suggest that a successional arrangement and an overall increase in abundance of butyrate forming populations occur during the first year of life, which is associated with an increase of intestinal butyrate formation capacity.
Elevated c-di-GMP Levels and Expression of the Type III Secretion System Promote Corneal Infection by Pseudomonas aeruginosa
Yam, Joey Kuok Hoong; Aung, Thet Tun; Chua, Song Lin; et al. (2022)
Infection and Immunity
Pseudomonas aeruginosa is generally believed to establish biofilm-associated infections under the regulation of the secondary messenger c-di-GMP. To evaluate P. aeruginosa biofilm physiology during ocular infections, comparative transcriptomic analysis was performed on wild-type P. aeruginosa PAO1, a Delta wspF mutant strain (high c-di-GMP levels), and a p(lac)-yhjH-containing strain (low c-di-GMP levels) from mouse corneal infection, as well as in vitro biofilm and planktonic cultures. The c-di-GMP content in P. aeruginosa during corneal infection was monitored using a fluorescent c-di-GMP reporter strain. Biofilm-related genes were induced in in vivo PAO1 compared to in vitro planktonic bacteria. Several diguanylate cyclases and phosphodiesterases were commonly regulated in in vivo PAO1 and in vitro biofilm compared to in vitro planktonic bacteria. Several exopolysaccharide genes and motility genes were induced and downregulated, respectively, in in vivo PAO1 and the in vivo Delta wspF mutant compared to the in vivo p(lac)-yhjH-containing strain. Elevation of c-di-GMP levels in P. aeruginosa began as early as 2 h postinfection. The Delta wspF mutant was less susceptible to host clearance than the p(lac)-yhjH-containing strain and could suppress host immune responses. The type III secretion system (T3SS) was induced in in vivo PAO1 compared to in vitro biofilm bacteria. Delta wspF mutant with a defective T3SS was more susceptible to host clearance than Delta wspF mutant with a functional T3SS. Our study suggests that elevated intracellular c-di-GMP levels and T3SS activity in P. aeruginosa are necessary for establishment of infection and modulation of host immune responses in mouse cornea.

Publications 1 - 10 of 14

Florentin Constancias

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