Publications by authors named "Philippe Langella"

214 Publications

Deletion of both Dectin-1 and Dectin-2 affects the bacterial but not fungal gut microbiota and susceptibility to colitis in mice.

Microbiome 2022 06 14;10(1):91. Epub 2022 Jun 14.

Universite Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Domaine de Vilvert, 78352, Jouy en Josas, France.

Background: Innate immunity genes have been reported to affect susceptibility to inflammatory bowel diseases (IBDs) and colitis in mice. Dectin-1, a receptor for fungal cell wall β-glucans, has been clearly implicated in gut microbiota modulation and modification of the susceptibility to gut inflammation. Here, we explored the role of Dectin-1 and Dectin-2 (another receptor for fungal cell wall molecules) deficiency in intestinal inflammation.

Design: Susceptibility to dextran sodium sulfate (DSS)-induced colitis was assessed in wild-type, Dectin-1 knockout (KO), Dectin-2KO, and double Dectin-1KO and Dectin-2KO (D-1/2KO) mice. Inflammation severity, as well as bacterial and fungal microbiota compositions, was monitored.

Results: While deletion of Dectin-1 or Dectin-2 did not have a strong effect on DSS-induced colitis, double deletion of Dectin-1 and Dectin-2 significantly protected the mice from colitis. The protection was largely mediated by the gut microbiota, as demonstrated by fecal transfer experiments. Treatment of D-1/2KO mice with opportunistic fungal pathogens or antifungal agents did not affect the protection against gut inflammation, suggesting that the fungal microbiota had no role in the protective phenotype. Amplicon-based microbiota analysis of the fecal bacterial and fungal microbiota of D-1/2KO mice confirmed the absence of changes in the mycobiota but strong modification of the bacterial microbiota. We showed that bacteria from the Lachnospiraceae family were at least partly involved in this protection and that treatment with Blautia hansenii was enough to recapitulate the protection.

Conclusions: Deletion of both the Dectin-1 and Dectin-2 receptors triggered a global shift in the microbial gut environment, affecting, surprisingly, mainly the bacterial population and driving protective effects in colitis. Members of the Lachnospiraceae family seem to play a central role in this protection. These findings provide new insights into the role of the Dectin receptors, which have been described to date as affecting only the fungal population, in intestinal physiopathology and in IBD. Video Abstract.
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http://dx.doi.org/10.1186/s40168-022-01273-4DOI Listing
June 2022

Prebiotics and the Human Gut Microbiota: From Breakdown Mechanisms to the Impact on Metabolic Health.

Nutrients 2022 May 17;14(10). Epub 2022 May 17.

Micalis Institute, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (INRAE), AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France.

The colon harbours a dynamic and complex community of microorganisms, collectively known as the gut microbiota, which constitutes the densest microbial ecosystem in the human body. These commensal gut microbes play a key role in human health and diseases, revealing the strong potential of fine-tuning the gut microbiota to confer health benefits. In this context, dietary strategies targeting gut microbes to modulate the composition and metabolic function of microbial communities are of increasing interest. One such dietary strategy is the use of prebiotics, which are defined as substrates that are selectively utilised by host microorganisms to confer a health benefit. A better understanding of the metabolic pathways involved in the breakdown of prebiotics is essential to improve these nutritional strategies. In this review, we will present the concept of prebiotics, and focus on the main sources and nature of these components, which are mainly non-digestible polysaccharides. We will review the breakdown mechanisms of complex carbohydrates by the intestinal microbiota and present short-chain fatty acids (SCFAs) as key molecules mediating the dialogue between the intestinal microbiota and the host. Finally, we will review human studies exploring the potential of prebiotics in metabolic diseases, revealing the personalised responses to prebiotic ingestion. In conclusion, we hope that this review will be of interest to identify mechanistic factors for the optimization of prebiotic-based strategies.
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http://dx.doi.org/10.3390/nu14102096DOI Listing
May 2022

Human CD4+CD8α+ Tregs induced by Faecalibacterium prausnitzii protect against intestinal inflammation.

JCI Insight 2022 Jun 22;7(12). Epub 2022 Jun 22.

Sorbonne University, INSERM, Saint-Antoine Center of Research, Centre De Recherche scientifique Saint-Antoine, Assistance Publique - Hôpitaux de Paris (AP-HP), Saint Antoine Hospital, Gastroenterology Department, Paris, France.

Abundance of Faecalibacterium prausnitzii, a dominant bacterium of the human microbiota that exhibits antiinflammatory effects, is decreased in patients with inflammatory bowel diseases (IBD). In humans, colonic lamina propria contains IL-10-secreting, Foxp3- Tregs characterized by a double expression of CD4 and CD8α (DP8α) and a specificity for F. prausnitzii. This Treg subset is decreased in IBD. The in vivo effect of DP8α cells has not been evaluated yet to our knowledge. Here, using a humanized model of a NSG immunodeficient mouse strain that expresses the HLA D-related allele HLA-DR*0401 but not murine class II (NSG-Ab° DR4) molecules, we demonstrated a protective effect of a HLA-DR*0401-restricted DP8α Treg clone combined with F. prausnitzii administration in a colitis model. In a cohort of patients with IBD, we showed an independent association between the frequency of circulating DP8α cells and disease activity. Finally, we pointed out a positive correlation between F. prausnitzii-specific DP8α Tregs and the amount of F. prausnitzii in fecal microbiota in healthy individuals and patients with ileal Crohn's disease.
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http://dx.doi.org/10.1172/jci.insight.154722DOI Listing
June 2022

Description of a Newly Isolated Strain and Its Benefit in Mouse Models of Post-Influenza Secondary Enteric and Pulmonary Infections.

Nutrients 2022 04 1;14(7). Epub 2022 Apr 1.

Micalis Institute, Institut National de Recherche pour L'agriculture, L'alimentation et L'environnement (INRAE), AgroParisTech, Université Paris-Saclay, UMR1319, F-78350 Jouy-en-Josas, France.

The expanding knowledge on the systemic influence of the human microbiome suggests that fecal samples are underexploited sources of new beneficial strains for extra-intestinal health. We have recently shown that acetate, a main circulating microbiota-derived molecule, reduces the deleterious effects of pulmonary and enteric serovar Typhimurium bacterial post-influenza superinfections. Considering the beneficial and broad effects of acetate, we intended to isolate a commensal strain, producing acetate and potentially exploitable in the context of respiratory infections. We designed successive steps to select intestinal commensals that are extremely oxygen-sensitive, cultivable after a freezing process, without a proinflammatory effect on IL-8 induction, and producing acetate. We have identified the DSM33383 strain, which decreased the TNFα-induced production of IL-8 by the intestinal epithelial cell line HT-29. The beneficial effect of this bacterial strain was further studied in two preclinical models of post-influenza () and serovar Typhimurium () superinfection. The intragastrical administration of DSM33383 led to protection in influenza-infected mice suffering from an . and, to a lesser extent, from an secondary infection. Altogether, this study showed that DSM33383 could be a promising candidate for preventive management of respiratory infectious diseases.
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http://dx.doi.org/10.3390/nu14071478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9003314PMC
April 2022

Genome Sequence and Assessment of Safety and Potential Probiotic Traits of CNCM I-4884.

Microorganisms 2022 Jan 25;10(2). Epub 2022 Jan 25.

INRAE, AgroParisTech, Micalis Institute, Université Paris-Saclay, 78350 Jouy-en-Josas, France.

The probiotic strain CNCM I-4884 exhibits anti- activity in vitro and in vivo in a murine model of giardiasis. The aim of this study was the identification and characterization of the probiotic potential of CNCM I-4884, as well as its safety assessment. This strain was originally classified as based on 16S gene sequence analysis. Whole genome sequencing led to a reclassification as . A genome-wide search for biosynthetic pathways revealed a high degree of auxotrophy, balanced by large transport and catabolic systems. The strain also exhibits tolerance to low pH and bile salts and shows strong bile salt hydrolase (BSH) activity. Sequencing results revealed the absence of antimicrobial resistance genes and other virulence factors. Phenotypic tests confirm that the strain is susceptible to a panel of 8 antibiotics of both human and animal relevance. Altogether, the in silico and in vitro results confirm that CNCM I-4884 is well adapted to the gastrointestinal environment and could be safely used in probiotic formulations.
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http://dx.doi.org/10.3390/microorganisms10020273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8876136PMC
January 2022

Preterm Delivery: Microbial Dysbiosis, Gut Inflammation and Hyperpermeability.

Front Microbiol 2021 4;12:806338. Epub 2022 Feb 4.

Paris-Saclay University, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France.

Preterm birth is one of the main health problems encountered in the neonatal period, especially because it is also the first cause of death in the critical 1st month of life and the second in children under 5 years of age. Not only preterm birth entails short term health risks due to low weight and underdeveloped organs, but also increases the risk of suffering from non-transmissible diseases in the long term. To date, it is known that medical conditions and lifestyle factors could increase the risk of preterm birth, but the molecular mechanisms that control this process remain unclear. Luteolysis, increased inflammation or oxidative stress have been described as possible triggers for preterm birth and, in some cases, the cause of dysbiosis in preterm neonates. Several murine models have been developed to shed light into the mechanistic of preterm birth but, for the most part, are inflammation-based labor induction models and the offspring health readouts are mainly limited to survival and weight. Using a set of SWISS-CD1 mice born prematurely we analyzed inflammation and gut permeability parameters compared with term pups at weaning age. Overall, preterm mice presented higher systemic inflammation and gastrointestinal tract permeability. In this perspective article, we discuss the recent discoveries on preterm birth and the necessity of non-inflammatory murine models to really understand these phenotypes and be able to design strategies to prevent the sequels of this traumatic event in neonates.
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http://dx.doi.org/10.3389/fmicb.2021.806338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8854986PMC
February 2022

Intraspecific Diversity of Microbial Anti-Inflammatory Molecule (MAM) from .

Int J Mol Sci 2022 Feb 1;23(3). Epub 2022 Feb 1.

Université Paris-Saclay, INRAE, AgroParisTech, Micalis, 78352 Jouy-en-Josas, France.

The commensal bacterium has unique anti-inflammatory properties, at least some of which have been attributed to its production of MAM, the Microbial Anti-inflammatory Molecule. Previous phylogenetic studies of strains have revealed the existence of various phylogroups. In this work, we address the question of whether MAMs from different phylogroups display distinct anti-inflammatory properties. We first performed wide-scale identification, classification, and phylogenetic analysis of MAM-like proteins encoded in different genomes of . When combined with a gene context analysis, this approach distinguished at least 10 distinct clusters of MAMs, providing evidence for functional diversity within this protein. We then selected 11 MAMs from various clusters and evaluated their anti-inflammatory capacities in vitro. A wide range of anti-inflammatory activity was detected. MAM from the M21/2 strain had the highest inhibitory effect (96% inhibition), while MAM from reference strain A2-165 demonstrated only 56% inhibition, and MAM from strain CNCM4541 was almost inactive. These results were confirmed in vivo in murine models of acute and chronic colitis. This study provides insights into the family of MAM proteins and generates clues regarding the choice of strains as probiotics for use in targeting chronic inflammatory diseases.
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http://dx.doi.org/10.3390/ijms23031705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836110PMC
February 2022

AhR/IL-22 pathway as new target for the treatment of post-infectious irritable bowel syndrome symptoms.

Gut Microbes 2022 Jan-Dec;14(1):2022997

NeuroDol, UMR 1107 INSERM, University of Clermont Auvergne, Clermont-Ferrand 63001, France.

Alterations in brain/gut/microbiota axis are linked to Irritable Bowel Syndrome (IBS) physiopathology. Upon gastrointestinal infection, chronic abdominal pain and anxio-depressive comorbidities may persist despite pathogen clearance leading to Post-Infectious IBS (PI-IBS). This study assesses the influence of tryptophan metabolism, and particularly the microbiota-induced AhR expression, on intestinal homeostasis disturbance following gastroenteritis resolution, and evaluates the efficacy of IL-22 cytokine vectorization on PI-IBS symptoms. The infection model in C57BL6/J mice was used to mimic Enterobacteria gastroenteritis. Intestinal homeostasis was evaluated as low-grade inflammation, permeability, mucosa-associated microbiota composition, and colonic sensitivity. Cognitive performances and emotional state of animals were assessed using several tests. Tryptophan metabolism was analyzed by targeted metabolomics. AhR activity was evaluated using a luciferase reporter assay method. One strain carrying an eukaryotic expression plasmid for murine IL-22 () was used to induce IL-22 production in mouse colonic mucosa. -infected mice exhibited persistent colonic hypersensitivity and cognitive impairments and anxiety-like behaviors after pathogen clearance. These post-infectious disorders were associated with low-grade inflammation, increased intestinal permeability, decrease of abundance associated with the colonic layer, and increase of short-chain fatty acids (SCFAs). During post-infection period, the indole pathway and AhR activity were decreased due to a reduction of tryptophol production. Treatment with restored gut permeability and normalized colonic sensitivity, restored cognitive performances and decreased anxiety-like behaviors. Data from the video-tracking system suggested an upgrade of welfare for mice receiving the strain. Our findings revealed that AhR/IL-22 signaling pathway is altered in a preclinical PI-IBS model. IL-22 delivering alleviate PI-IBS symptoms as colonic hypersensitivity, cognitive impairments, and anxiety-like behaviors by acting on intestinal mucosa integrity. Thus, therapeutic strategies targeting this pathway could be developed to treat IBS patients suffering from chronic abdominal pain and associated well-being disorders.
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http://dx.doi.org/10.1080/19490976.2021.2022997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8803069PMC
February 2022

Possible Benefits of for Obesity-Associated Gut Disorders.

Front Pharmacol 2021 2;12:740636. Epub 2021 Dec 2.

Université Paris Saclay, INRAE, AgroParisTech, Micalis, Jouy-en-Josas, France.

Metabolic disorders are an increasing concern in the industrialized world. Current research has shown a direct link between the composition of the gut microbiota and the pathogenesis of obesity and diabetes. In only a few weeks, an obesity-inducing diet can lead to increased gut permeability and microbial dysbiosis, which contributes to chronic inflammation in the gut and adipose tissues, and to the development of insulin resistance. In this review, we examine the interplay between gut inflammation, insulin resistance, and the gut microbiota, and discuss how some probiotic species can be used to modulate gut homeostasis. We focus primarily on , a highly abundant butyrate-producing bacterium that has been proposed both as a biomarker for the development of different gut pathologies and as a potential treatment due to its production of anti-inflammatory metabolites.
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http://dx.doi.org/10.3389/fphar.2021.740636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677946PMC
December 2021

From Short- to Long-Term Effects of C-Section Delivery on Microbiome Establishment and Host Health.

Microorganisms 2021 Oct 9;9(10). Epub 2021 Oct 9.

Micalis Institute, Paris-Saclay University, INRAE, AgroParisTech, 78350 Jouy-en-Josas, France.

The establishment of gut microbiota has been proven to be impacted by several factors during pregnancy, delivery, and neonate periods. The body of evidence describing C-section delivery (CSD) as one of the most disruptive events during early life has expanded in recent years, concluding that CSD results in a drastic change in microbiota establishment patterns. When comparing the gut microbiota composition of CSD babies with vaginally delivered (VD) babies, the former show a microbiome that closely resembles that found in the environment and the mother's skin, while VD babies show a microbiome more similar to the vaginal microbiome. Although these alterations of normal gut microbiota establishment tend to disappear during the first months of life, they still affect host health in the mid-long term since CSD has been correlated with a higher risk of early life infections and non-transmissible diseases, such as inflammatory diseases, allergies, and metabolic diseases. In recent years, this phenomenon has also been studied in other mammals, shedding light on the mechanisms involved in the effects of a CSD on host health. In addition, strategies to revert the disruptions in gut microbiomes caused by a CSD are currently in the process of development and evaluation. In this review, we discuss the recent advances in CSD research, from the alteration of gut microbiota establishment to the possible effects on host health during early life and development.
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http://dx.doi.org/10.3390/microorganisms9102122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537978PMC
October 2021

Age and Infection Impact Canine Gut Microbiota.

Microorganisms 2021 Sep 2;9(9). Epub 2021 Sep 2.

Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350 Jouy-en-Josas, France.

is a flagellated protozoan responsible for giardiosis (also called giardiasis in humans), the most prevalent and widespread parasitic infection in humans and mammals worldwide. The intestinal microbiota is highly diverse and any alteration in its composition may impact on the health of the host. While studies on the mouse model of giardiosis described the role of the gut microbiota in host susceptibility to infection by the parasite, little is known about the gut microbiota during natural infections in dogs and particularly in puppies. In this study, we monitored naturally -infected puppies for 3 months and quantified cyst excretion every 2 weeks. All puppies remained subclinically infected during the sampling period as confirmed by fecal examination. In parallel, we performed 16S Illumina sequencing of fecal samples from the different time points to assess the impact of infection on gut microbiota development of the puppies, as well as gut health markers of immunity such as fecal IgA and calprotectin. Sequencing results revealed that the canine fecal microbiota of -infected puppies becomes more complex and less diverse with increasing age. In addition, significant differences in the structure of the microbiota were observed between puppies with high and low cyst excretion. Chronic subclinical infection appears to be associated with some detrimental structural changes in the gut microbiota. -associated dysbiosis is characterized by an enrichment of facultative anaerobic, mucus-degrading, pro-inflammatory species and opportunistic pathogens, as well as a reduction of at specific time points. Calprotectin levels increased with age, suggesting the establishment of chronic low-grade inflammation in puppies. Further work is needed to demonstrate whether these alterations in the canine gut microbiota could lead to a dysbiosis-related disease, such as irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD).
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http://dx.doi.org/10.3390/microorganisms9091862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469385PMC
September 2021

A Pulmonary Strain Induces Th17 and RORγt Regulatory T Cells and Reduces Lung Inflammation in Tuberculosis.

J Immunol 2021 10 3;207(7):1857-1870. Epub 2021 Sep 3.

Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France;

The lungs harbor multiple resident microbial communities, otherwise known as the microbiota. There is an emerging interest in deciphering whether the pulmonary microbiota modulate local immunity, and whether this knowledge could shed light on mechanisms operating in the response to respiratory pathogens. In this study, we investigate the capacity of a pulmonary strain to modulate the lung T cell compartment and assess its prophylactic potential upon infection with , the etiological agent of tuberculosis. In naive mice, we report that a () strain (CNCM I-5314) increases the presence of lung Th17 cells and of a regulatory T cell (Treg) subset known as RORγt Tregs. In particular, intranasal but not intragastric administration of CNCM I-5314 increases the expansion of these lung leukocytes, suggesting a local rather than systemic effect. Resident Th17 and RORγt Tregs display an immunosuppressive phenotype that is accentuated by CNCM I-5314. Despite the well-known ability of to modulate lung immunity, the immunomodulatory effect by CNCM I-5314 is dominant, as Th17 and RORγt Tregs are still highly increased in the lung at 42-d postinfection. Importantly, CNCM I-5314 administration in -infected mice results in reduction of pulmonary inflammation, without increasing burden. Collectively, our findings provide evidence for an immunomodulatory capacity of CNCM I-5314 at steady state and in a model of chronic inflammation in which it can display a protective role, suggesting that strains found in the lung may shape local T cells in mice and, perhaps, in humans.
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http://dx.doi.org/10.4049/jimmunol.2001044DOI Listing
October 2021

Bioactive Compounds in Food as a Current Therapeutic Approach to Maintain a Healthy Intestinal Epithelium.

Microorganisms 2021 Jul 30;9(8). Epub 2021 Jul 30.

Université Paris-Saclay, AgroParisTech, Micalis Institute, INRAE, 78350 Jouy-en-Josas, France.

The intestinal epithelium serves as an effective barrier against the external environment, hampering the passage of potentially harmful substances (such as pathogenic microbes) that could trigger an exacerbated host immune response. The integrity of this barrier is thus essential for the maintenance of proper intestinal homeostasis and efficient protective reactions against chemical and microbial challenges. The principal consequence of intestinal barrier defects is an increase in intestinal permeability, which leads to an increased influx of luminal stressors, such as pathogens, toxins, and allergens, which in turn trigger inflammation and immune response. The fine and fragile balance of intestinal homeostasis can be altered by multiple factors that regulate barrier function, many of which are poorly understood. This review will address the role of gut microbiota as well as food supplements (such as probiotics, prebiotics, and synbiotics) in modulating gut health and regulating intestinal barrier function. In particular, we will focus on three human pathologies: inflammatory bowel disease, irritable bowel syndrome, and food allergy.
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http://dx.doi.org/10.3390/microorganisms9081634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401766PMC
July 2021

A Toxic Friend: Genotoxic and Mutagenic Activity of the Probiotic Strain Escherichia coli Nissle 1917.

mSphere 2021 08 11;6(4):e0062421. Epub 2021 Aug 11.

IRSD, INSERM, INRAE, Université de Toulouse, ENVT, Toulouse, France.

The probiotic Escherichia coli strain Nissle 1917 (DSM 6601, Mutaflor), generally considered beneficial and safe, has been used for a century to treat various intestinal diseases. However, Nissle 1917 hosts in its genome the pathogenicity island that codes for the biosynthesis of the genotoxin colibactin. Colibactin is a potent DNA alkylator, suspected to play a role in colorectal cancer development. We show in this study that Nissle 1917 is functionally capable of producing colibactin and inducing interstrand cross-links in the genomic DNA of epithelial cells exposed to the probiotic. This toxicity was even exacerbated with lower doses of the probiotic, when the exposed cells started to divide again but exhibited aberrant anaphases and increased gene mutation frequency. DNA damage was confirmed in mouse models of intestinal colonization, demonstrating that Nissle 1917 produces the genotoxin in the gut lumen. Although it is possible that daily treatment of adult humans with their microbiota does not produce the same effects, administration of Nissle 1917 as a probiotic or as a chassis to deliver therapeutics might exert long-term adverse effects and thus should be considered in a risk-versus-benefit evaluation. Nissle 1917 is sold as a probiotic and considered safe even though it has been known since 2006 that it harbors the genes for colibactin synthesis. Colibactin is a potent genotoxin that is now linked to causative mutations found in human colorectal cancer. Many papers concerning the use of this strain in clinical applications ignore or elude this fact or misleadingly suggest that Nissle 1917 does not induce DNA damage. Here, we demonstrate that Nissle 1917 produces colibactin and and induces mutagenic DNA damage. This is a serious safety concern that must not be ignored in the interests of patients, the general public, health care professionals, and ethical probiotic manufacturers.
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http://dx.doi.org/10.1128/mSphere.00624-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386472PMC
August 2021

The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota.

Microbiome 2021 07 8;9(1):157. Epub 2021 Jul 8.

Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d'Azur, 660 route des Lucioles, 06560, Valbonne, France.

Background: Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice.

Results: Mice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice.

Conclusions: The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD. Video abstract.
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http://dx.doi.org/10.1186/s40168-021-01103-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268286PMC
July 2021

Gut microbiota-derived short-chain fatty acids regulate IL-17 production by mouse and human intestinal γδ T cells.

Cell Rep 2021 07;36(1):109332

Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350 Jouy-en-Josas, France; Paris Center for Microbiome Medicine (PaCeMM) FHU, Paris, France. Electronic address:

Gut interleukin-17A (IL-17)-producing γδ T cells are tissue-resident cells that are involved in both host defense and regulation of intestinal inflammation. However, factors that regulate their functions are poorly understood. In this study, we find that the gut microbiota represses IL-17 production by cecal γδ T cells. Treatment with vancomycin, a Gram-positive bacterium-targeting antibiotic, leads to decreased production of short-chain fatty acids (SCFAs) by the gut microbiota. Our data reveal that these microbiota-derived metabolites, particularly propionate, reduce IL-17 and IL-22 production by intestinal γδ T cells. Propionate acts directly on γδ T cells to inhibit their production of IL-17 in a histone deacetylase-dependent manner. Moreover, the production of IL-17 by human IL-17-producing γδ T cells from patients with inflammatory bowel disease (IBD) is regulated by propionate. These data contribute to a better understanding of the mechanisms regulating gut γδ T cell functions and offer therapeutic perspectives of these cells.
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http://dx.doi.org/10.1016/j.celrep.2021.109332DOI Listing
July 2021

The Keystone commensal bacterium Christensenella minuta DSM 22607 displays anti-inflammatory properties both in vitro and in vivo.

Sci Rep 2021 06 1;11(1):11494. Epub 2021 Jun 1.

Micalis Institute, AgroParisTech, INRAE, Université Paris-Saclay, 78350, Jouy-en-Josas, France.

Christensenellaceae is a family of subdominant commensal bacteria found in humans. It is thought to play an important role in gut health by maintaining microbial symbiosis. Indeed, these bacteria occur at significantly lower levels or are absent in individuals suffering from inflammatory bowel diseases (IBDs). Here, we explored if type species Christensenella minuta (strain: DSM 22607) could have the potential to help treat IBDs. We assessed key properties displayed by the bacterium using a combination of in vitro and in vivo assays. We found that while C. minuta is a strict anaerobe, it is also oxygen tolerant. Additionally, we observed that the species produces high levels of acetate and moderate levels of butyrate. We performed deep phenotyping using Biolog microarrays. Using human intestinal cell lines, we discovered that C. minuta demonstrated strong anti-inflammatory activity, resulting in reduced levels of proinflammatory IL-8 cytokines via the inhibition of the NF-κB signaling pathway. Furthermore, C. minuta protected intestinal epithelial integrity in vitro. Finally, in two distinct animal models of acute colitis, C. minuta prevented intestinal damage, reduced colonic inflammation, and promoted mucosal healing. Together, these results indicate that C. minuta has potent immunomodulatory properties, underscoring its potential use in innovative microbiome-based IBD biotherapies.
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http://dx.doi.org/10.1038/s41598-021-90885-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169850PMC
June 2021

Antioxidant and Anti-Inflammatory Properties of Probiotic Candidate Strains Isolated during Fermentation of Agave ( Haw).

Microorganisms 2021 May 14;9(5). Epub 2021 May 14.

INRAE, AgroParisTech, Micalis Institute, Université Paris-Saclay, 78350 Jouy-en-Josas, France.

Agave species are a source of diverse products for human use, such as food, fiber, and beverages, which include mezcal, a distilled beverage produced by spontaneous fermentation. Agave is an excellent source of high amounts of sugars, minerals, and phenolic compounds, which favor the growth of lactic acid bacteria (LAB) and yeast communities. In this work, 20 promising LAB strains with probiotic characteristics were isolated from the agave fermentation stage in mezcal production. The strains belonged to (15), (2), (2), and (1). These isolates were characterized for their resistance under gastrointestinal conditions, such as lysozyme, acid pH, and bile salts. In addition, the adherence of these LABs to human intestinal epithelial cells (Caco-2 and HT-29 cells) was tested in vitro and their antioxidant and immunomodulatory profile was determined using cellular models. LM07 and LM17 and LM19 strains were selected for their antioxidant properties, and their capacities in an oxidative stress model in intestinal epithelial cells IECs (Caco-2 and HT-29 cells) in the presence of hydrogen peroxide were evaluated. Interestingly, LM07 and LM17 and LM19 strains showed anti-inflammatory properties in TNF-α-stimulated HT-29 cells. Subsequently, bacterial strains exhibiting antioxidant and anti-inflammatory properties were tested in vivo in a mouse model with dinitrobenzene sulfonic acid (DNBS)-induced chronic colitis. Weight loss, intestinal permeability, and cytokine profiles were measured in mice as indicators of inflammation. One of the selected strains, LM17, improved the health of the mice, as observed by reduced weight loss, and significantly decreased intestinal permeability. Altogether, our results demonstrate the potential of LAB (and lactobacilli in particular) isolated from the agave fermentation stage in mezcal production. LM07 and LM17 strains represent potential candidates for developing new probiotic supplements to treat inflammatory bowel disease (IBD).
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http://dx.doi.org/10.3390/microorganisms9051063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156479PMC
May 2021

Aryl hydrocarbon receptor ligand production by the gut microbiota is decreased in celiac disease leading to intestinal inflammation.

Sci Transl Med 2020 10;12(566)

Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Metabolism of tryptophan by the gut microbiota into derivatives that activate the aryl hydrocarbon receptor (AhR) contributes to intestinal homeostasis. Many chronic inflammatory conditions, including celiac disease involving a loss of tolerance to dietary gluten, are influenced by cues from the gut microbiota. We investigated whether AhR ligand production by the gut microbiota could influence gluten immunopathology in nonobese diabetic (NOD) mice expressing DQ8, a celiac disease susceptibility gene. NOD/DQ8 mice, exposed or not exposed to gluten, were subjected to three interventions directed at enhancing AhR pathway activation. These included a high-tryptophan diet, gavage with that produces AhR ligands or treatment with an AhR agonist. We investigated intestinal permeability, gut microbiota composition determined by 16 rRNA gene sequencing, AhR pathway activation in intestinal contents, and small intestinal pathology and inflammatory markers. In NOD/DQ8 mice, a high-tryptophan diet modulated gut microbiota composition and enhanced AhR ligand production. AhR pathway activation by an enriched tryptophan diet, treatment with the AhR ligand producer , or pharmacological stimulation using 6-formylindolo (3,2-b) carbazole (Ficz) decreased immunopathology in NOD/DQ8 mice exposed to gluten. We then determined AhR ligand production by the fecal microbiota and AhR activation in patients with active celiac disease compared to nonceliac control individuals. Patients with active celiac disease demonstrated reduced AhR ligand production and lower intestinal AhR pathway activation. These results highlight gut microbiota-dependent modulation of the AhR pathway in celiac disease and suggest a new therapeutic strategy for treating this disorder.
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http://dx.doi.org/10.1126/scitranslmed.aba0624DOI Listing
October 2020

Butyrate mediates anti-inflammatory effects of in intestinal epithelial cells through .

Gut Microbes 2020 11;12(1):1-16

Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute , Jouy-en-Josas, France.

The commensal bacterium plays a key role in inflammatory bowel disease (IBD) pathogenesis and serves as a general health biomarker in humans. However, the host molecular mechanisms that underlie its anti-inflammatory effects remain unknown. In this study we performed a transcriptomic approach on human intestinal epithelial cells (HT-29) stimulated with TNF-α and exposed to culture supernatant (SN) in order to determine the impact of this commensal bacterium on intestinal epithelial cells. Moreover, modulation of the most upregulated gene after SN contact was validated both and . Our results showed that SN upregulates the expression of , a gene linked to the Wnt/JNK pathway. Interestingly, when we silenced expression, the effect of SN was lost. Butyrate was identified as the effector responsible for modulation. upregulation was also validated in both healthy and inflamed mice treated with either SN or the live bacteria, respectively. Finally, we demonstrated by colon transcriptomics that gut microbiota directly influences expression. This study provides new clues about the host molecular mechanisms involved in the anti-inflammatory effects of the beneficial commensal bacterium .
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http://dx.doi.org/10.1080/19490976.2020.1826748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567499PMC
November 2020

Identification of sulfur components enhancing the anti-Candida effect of Lactobacillus rhamnosus Lcr35.

Sci Rep 2020 10 13;10(1):17074. Epub 2020 Oct 13.

Research and Development Department, BIOSE, 24 avenue Georges Pompidou, 15000, Aurillac, France.

GYNOPHILUS (Lcr REGENERANS) is a live biotherapeutic product (LBP) aimed at restoring the vaginal microbiome and contains the live biotherapeutic microorganism Lactobacillus rhamnosus Lcr35. In this study, the LBP formulation and manufacturing process significantly enhanced the anti-Candida activity of L. rhamnosus Lcr35, with a complete loss of viability of the yeast after 48 h of coincubation. Sodium thiosulfate (STS), one excipient of the product, was used as a potentiator of the anti-Candida spp. activity of Lactobacilli. This contact-independent phenomenon induced fungal cell disturbances, as observed by electron microscopy observations. Nonverbal sensory experiments showed clear odor dissimilarities between cocultures of L. rhamnosus Lcr35 and C. albicans in the presence and absence of STS, suggesting an impact of odor-active metabolites. A volatolomic approach allowed the identification of six odor-active compounds, including one sulfur compound that was identified as S-methyl thioacetate (MTA). MTA was associated with the antifungal effect of Lcr35, and its functional link was established in vitro. We show for the first time that the LBP GYNOPHILUS, which is a highly active product in the reduction of vulvovaginal candidiasis, requires the presence of a sulfur compound to fully achieve its antifungal effect.
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http://dx.doi.org/10.1038/s41598-020-74027-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553951PMC
October 2020

Prophylactic treatment prevents the acute breakdown of colonic epithelial barrier in a preclinical model of pelvic radiation disease.

Gut Microbes 2020 11;12(1):1-15

Department of RAdiobiology and Regenerative MEDicine (SERAMED), Laboratory of MEDical Radiobiology (Lrmed), Institute for Radiological Protection and Nuclear Safety (IRSN ), Fontenay-aux-Roses, France.

Every year, millions of people around the world benefit from radiation therapy to treat cancers localized in the pelvic area. Damage to healthy tissue in the radiation field can cause undesirable toxic effects leading to gastrointestinal complications called pelvic radiation disease. A change in the composition and/or function of the microbiota could contribute to radiation-induced gastrointestinal toxicity. In this study, we tested the prophylactic effect of a new generation of probiotic like () on acute radiation-induced colonic lesions. Experiments were carried out in a preclinical model of pelvic radiation disease. Rats were locally irradiated at 29 Gray in the colon resulting in colonic epithelial barrier rupture. Three days before the irradiation and up to 3 d after the irradiation, the A2-165 strain was administered daily (intragastrically) to test its putative protective effects. Results showed that prophylactic treatment limits radiation-induced para-cellular hyperpermeability, as well as the infiltration of neutrophils (MPO+ cells) in the colonic mucosa. Moreover, treatment reduced the severity of the morphological change of crypts, but also preserved the pool of Sox-9+ stem/progenitor cells, the proliferating epithelial PCNA+ crypt cells and the Dclk1+/IL-25+ differentiated epithelial tuft cells. The benefit of was associated with increased production of IL-18 by colonic crypt epithelial cells. Thus, treatment protected the epithelial colonic barrier from colorectal irradiation. New-generation probiotics may be promising prophylactic treatments to reduce acute side effects in patients treated with radiation therapy and may improve their quality of life.
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http://dx.doi.org/10.1080/19490976.2020.1812867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524396PMC
November 2020

Retraction Note to: Lactobacillus casei BL23 regulates T and Th17 T-cell populations and reduces DMH-associated colorectal cancer.

J Gastroenterol 2020 Nov;55(11):1107

INRA, Commensal and Probiotics-Host Interactions Laboratory, UMR 1319 Micalis, 78350, Jouy-en-Josas, France.

This article has been retracted. Please see the retraction notice for more detail: https://doi.org/10.1007/s00535-015-1158-9 .
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http://dx.doi.org/10.1007/s00535-020-01722-7DOI Listing
November 2020

The Infant-Derived Strain CNCM I-4319 Strengthens Gut Functionality.

Microorganisms 2020 Aug 28;8(9). Epub 2020 Aug 28.

Commensal and Probiotics-Host Interactions Laboratory, Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 91190 Jouy-en-Josas, France.

Bifidobacteria are among the first colonisers of the gastrointestinal tract of breast-fed newborns due to, among other things, their ability to metabolise oligosaccharides naturally occurring in human milk. The presence of bifidobacteria in the infant gut has been shown to promote intestinal health and homeostasis as well as to preserve a functional gut barrier, thus positively influencing host health and well-being. Among human-associated gut commensals, has been described as the only species capable of the extracellular degradation of both mucin-type glycans and HMOs, thereby giving this species a special role as a commensal gut forager of both host and diet-derived glycans. In the present study, we assess the possible beneficial properties and probiotic potential of strain CNCM I-4319. In silico genome analysis and growth experiments confirmed the expected ability of this strain to consume HMOs and mucin. By employing various animal models, we were also able to assess the ability of CNCM I-4319 to preserve gut integrity and functionality from stress-induced and inflammatory damage, thereby enforcing its potential as an effective probiotic strain.
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http://dx.doi.org/10.3390/microorganisms8091313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565306PMC
August 2020

The Administration Matrix Modifies the Beneficial Properties of a Probiotic Mix of Bifidobacterium animalis subsp. lactis BB-12 and Lactobacillus acidophilus LA-5.

Probiotics Antimicrob Proteins 2021 04;13(2):484-494

Equipe Interactions des Micro-organismes Commensaux et Probiotiques avec l'Hôte (ProbiHôte), Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France.

Consumption of dairy products is one of the most natural ways to introduce probiotics. However, the beneficial effects of the probiotics might depend on the administration form. The aim of this study was to investigate the beneficial properties of two probiotic strains: Bifidobacterium animalis subsp. lactis (BB-12) and Lactobacillus acidophilus (LA-5) in different administration forms (capsules and yogurt). First, in vitro resistance to gastrointestinal condition, surface properties, and immunomodulation capacities were determined. Then, the anti-inflammatory properties of the probiotic strains administrated on yogurt or capsules were tested in a dinitrobenzene sulfonic acid (DNBS)-induced colitis mouse model. The survival rates of BB-12 and LA-5 strains to gastrointestinal conditions were slightly higher when yogurt was used as carrier. They showed most affinity to hexane (no-polar basic solvent) than ethyl-acetate (polar basic solvent). BB-12 showed the higher binding capacity to HT-29, Caco-2, and mucin. Both probiotic candidates suppress the secretion of IL-8 secretion by HT-29-TNF-α stimulated cells. Finally, administration of BB-12 and LA-5 strains improve colitis in mice. They protect against weight loss, inflammation, and hyperpermeability induced by DNBS. However, these anti-inflammatory effects were limited when mice were treated with the probiotic strain on a yogurt matrix. Overall results indicate that BB-12 and LA-5 positive properties are compromised depending on the matrix. Consequently, the selection of an appropriate matrix is an important criterion to conserve the positive benefits of these probiotic strains.
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http://dx.doi.org/10.1007/s12602-020-09702-2DOI Listing
April 2021

Oral Primo-Colonizing Bacteria Modulate Inflammation and Gene Expression in Bronchial Epithelial Cells.

Microorganisms 2020 Jul 22;8(8). Epub 2020 Jul 22.

Micalis Institute, AgroParisTech, INRAE, Université Paris-Saclay, 78350 Jouy-en-Josas, France.

The microbiota of the mouth disperses into the lungs, and both compartments share similar phyla. Considering the importance of the microbiota in the maturation of the immunity and physiology during the first days of life, we hypothesized that primo-colonizing bacteria of the oral cavity may induce immune responses in bronchial epithelial cells. Herein, we have isolated and characterized 57 strains of the buccal cavity of two human newborns. These strains belong to , , , and genera, with being the most represented. The strains were co-incubated with a bronchial epithelial cell line (BEAS-2B), and we established their impact on a panel of cytokines/chemokines and global changes in gene expression. The strains, which appeared soon after birth, induced a high production of IL-8, suggesting they can trigger inflammation, whereas the strains were less associated with inflammation pathways. The genera , and induced differential profiles of cytokine/chemokine/growth factor and set of genes associated with maturation of morphology. Altogether, our results demonstrate that the microorganisms, primo-colonizing the oral cavity, impact immunity and morphology of the lung epithelial cells, with specific effects depending on the phylogeny of the strains.
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http://dx.doi.org/10.3390/microorganisms8081094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464694PMC
July 2020

Evaluation of the Probiotic Properties and the Capacity to Form Biofilms of Various Strains.

Microorganisms 2020 Jul 15;8(7). Epub 2020 Jul 15.

MIcalis Institute, AgroParisTech, INRAE, Université Paris-Saclay, 78350 Jouy-en-Josas, France.

Over the last 20 years, species inhabiting the gastrointestinal tract (GIT) have received much attention, and their health-promoting properties are now well-described. Probiotic effects cannot be generalized, and their uses cover a wide range of applications. It is thus important to proceed to an accurate selection and evaluation of probiotic candidates. We evaluate the probiotic potential of six strains of in different in vitro models representing critical factors of either survival, efficacy, or both. We characterized the strains for their ability to (i) modulate intestinal permeability using transepithelial electrical resistance (TEER), (ii) form biofilms and resist stressful conditions, and (iii) produce beneficial host and/or bacteria metabolites. Our data reveal the specificity of strains to modulate intestinal permeability depending on the cell type. The six isolates were able to form spatially organized biofilms, and we provide evidence that the biofilm form is beneficial in a strongly acidic environment. Finally, we demonstrated the ability of the strains to produce γ-aminobutyric acid (GABA) that is involved in the gut-brain axis and beneficial enzymes that promote the bacterial tolerance to bile salts. Overall, our study highlights the specific properties of strains and their possible applications as biofilms.
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http://dx.doi.org/10.3390/microorganisms8071053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409210PMC
July 2020

Capsular Polysaccharide Cross-Regulation Modulates Bacteroides thetaiotaomicron Biofilm Formation.

mBio 2020 06 23;11(3). Epub 2020 Jun 23.

Institut Pasteur, Genetics of Biofilms Laboratory, Paris, France

is one of the most abundant gut symbiont species, whose contribution to host health through its ability to degrade dietary polysaccharides and mature the immune system is under intense scrutiny. In contrast, adhesion and biofilm formation, which are potentially involved in gut colonization and microbiota structure and stability, have hardly been investigated in this intestinal bacterium. To uncover biofilm-related functions, we performed a transposon mutagenesis in the poorly biofilm-forming reference strain VPI-5482 and showed that capsule 4, one of the eight capsules, hinders biofilm formation. We then showed that the production of capsules 1, 2, 3, 5, and 6 also inhibits biofilm formation and that decreased capsulation of the population correlated with increased biofilm formation, suggesting that capsules could be masking adhesive surface structures. In contrast, we showed that capsule 8 displayed intrinsic adhesive properties. Finally, we demonstrated that , the homolog of the glycosylation locus, competes with capsule production and impacts its adhesion capacity. This study therefore establishes capsule regulation as a major determinant of biofilm formation, providing new insights into how modulation of different surface structures affects biofilm formation. The human gut harbors a complex bacterial community that plays important roles in host health and disease, including nutrient acquisition, maturation of the immune system, and resistance to infections. The capacity to adhere to surfaces and form communities called biofilms is believed to be important for niche colonization and maintenance of gut bacteria. However, little is known about the adhesion capacity of most gut bacteria. In this study, we investigated biofilm formation in , one of the most abundant bacteria of the normal mammalian intestine. We identified that capsules, a group of eight surface-exposed polysaccharidic layers mediating important interactions with the gut environment, are also major determinants of biofilm formation that mask or unmask adhesion factors. Studying how regulates its adhesion properties will allow us to better understand the physiology and specific properties of this important gut symbiont within anaerobic biofilms.
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http://dx.doi.org/10.1128/mBio.00729-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315117PMC
June 2020

Symbioflor2 Genotypes Enhance Ileal and Colonic Gene Expression Associated with Mucosal Defense in Gnotobiotic Mice.

Microorganisms 2020 Apr 3;8(4). Epub 2020 Apr 3.

Micalis Institute, INRAE, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France.

Symbioflor2 is a probiotic product composed of six genotypes, which has a beneficial effect on irritable bowel syndrome. Our objective was to understand the individual impact of each of the six genotypes on the host, together with the combined impact of the six in the compound Symbioflor2. Gnotobiotic mice were mono-associated with one of the six genotypes or associated with the compound product. Ileal and colonic gene expression profiling was carried out, and data were compared between the different groups of gnotobiotic mice, along with that obtained from conventional (CV) mice and mice colonized with the probiotic Nissle 1917. We show that Symbioflor2 genotypes induce intestinal transcriptional responses involved in defense and immune mechanisms. Using mice associated with Symbioflor2, we reveal that the product elicits a balanced response from the host without any predominance of a single genotype. The Nissle strain and the six bacterial genotypes have different effects on the intestinal gene expression, suggesting that the impacts of these probiotics are not redundant. Our data show the effect of the Symbioflor2 genotypes at the molecular level in the digestive tract, which further highlights their beneficial action on several aspects of intestinal physiology.
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http://dx.doi.org/10.3390/microorganisms8040512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232167PMC
April 2020
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