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Florence Thirion,1,* Susie Guilly,1,* Sébastien Fromentin,1 Florian Plaza Oñate,1 Anne-Sophie Alvarez,1 Emmanuelle Le Chatelier,1 Nicolas Pons,1 Florence Levenez,1 Benoît Quinquis,1 Stanislav Ehrlich,1 Joel Doré,1,2 Richard Martin,3 Sophie Seité4 1University Paris-Saclay, INRAE, MGP, Jouy-en-Josas, 78350, France; 2University Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France; 3Mercurialis Biotech, Rochecorbon, France; 4La Roche-Posay Dermatological Laboratories, Levallois-Perret, France*These authors contributed equally to this workCorrespondence: Sophie Seit&#x00E9La Roche-Posay Dermatological Laboratories, 62 quai Charles Pasqua, Levallois-Perret, 92300, France, Tel +33 1 49 64 33 40, Email sophie.seite@loreal.comIntroduction: Balneotherapy (BT) is the treatment of disease through the use of thermal spring water (TSW). It has been used for centuries and remains a popular form of treatment for dermatologic diseases such as atopic dermatitis (AD). Recent findings highlighted the role of the gut microbiota in AD and the possible crosstalk between gut and skin microbiomes in this pathology. Nevertheless, changes in the composition of the gut microbiota after balneotherapy remain to be elucidated.Methods: A total of 96 patients, with moderate to severe AD according to the SCORAD, were enrolled. Stool samples were collected prior and post a 3-week balneotherapy at the thermal care center of La Roche-Posay (France). Composition of the gut microbiota was assessed by shotgun metagenomic sequencing.Results: Species associated with high gut microbiota richness tended to correlate negatively with disease severity (SCORAD) and positively with SCORAD reduction, while species associated with low richness displayed the opposite pattern. Relative abundance of 23 species was significantly altered during BT, these changes being significantly associated with SCORAD reduction during BT, suggesting that gut microbiota composition and AD progression were associated through the treatment. Microbial functions related to gut-brain axis such as GABA and tryptophan metabolism were also altered by the treatment. Long-standing AD patients exhibited a better gut microbial profile than recently diagnosed patients, with higher MSP richness and species associated with SCORAD reduction.Conclusion: In patients with AD, clinical disease parameters such as SCORAD or disease duration are intricately linked to the gut microbiota composition. SCORAD reduction occurring during BT was also associated with gut microbiota. The gut-brain-skin axis via neurotransmitter such as GABA should be further studied in diseases such as AD.Keywords: atopic dermatitis, balneotherapy, gut microbiota, shotgun metagenomics, thermal spring water

Gut microbiota imbalance (dysbiosis) is increasingly associated with pathological conditions, both within and outside the gastrointestinal tract. Intestinal Paneth cells are considered to be guardians of the gut microbiota, but the events linking Paneth cell dysfunction with dysbiosis remain unclear. We report a three-step mechanism for dysbiosis initiation. Initial alterations in Paneth cells, as frequently observed in obese and inflammatorybowel diseases patients, cause a mild remodeling of microbiota, with amplification of succinate-producing species. SucnR1-dependent activation of epithelial tuft cells triggers a type 2 immune response that, in turn, aggravates the Paneth cell defaults, promoting dysbiosis and chronic inflammation. We thus reveal a function of tuft cells in promoting dysbiosis following Paneth cell deficiency and an unappreciated essential role of Paneth cells in maintaining a balanced microbiota to prevent inappropriate activation of tuft cells and deleterious dysbiosis. This succinate-tuft cell inflammation circuit may also contribute to the chronic dysbiosis observed in patients.

Anorexia nervosa (AN) is an eating disorder with a high mortality. About 95% of cases are women and it has a population prevalence of about 1%, but evidence-based treatment is lacking. The pathogenesis of AN probably involves genetics and various environmental factors, and an altered gut microbiota has been observed in individuals with AN using amplicon sequencing and relatively small cohorts. Here we investigated whether a disrupted gut microbiota contributes to AN pathogenesis. Shotgun metagenomics and metabolomics were performed on faecal and serum samples, respectively, from a cohort of 77 females with AN and 70 healthy females. Multiple bacterial taxa (for example, Clostridium species) were altered in AN and correlated with estimates of eating behaviour and mental health. The gut virome was also altered in AN including a reduction in viral-bacterial interactions. Bacterial functional modules associated with the degradation of neurotransmitters were enriched in AN and various structural variants in bacteria were linked to metabolic features of AN. Serum metabolomics revealed an increase in metabolites associated with reduced food intake (for example, indole-3-propionic acid). Causal inference analyses implied that serum bacterial metabolites are potentially mediating the impact of an altered gut microbiota on AN behaviour. Further, we performed faecal microbiota transplantation from AN cases to germ-free mice under energy-restricted feeding to mirror AN eating behaviour. We found that the reduced weight gain and induced hypothalamic and adipose tissue gene expression were related to aberrant energy metabolism and eating behaviour. Our 'omics' and mechanistic studies imply that a disruptive gut microbiome may contribute to AN pathogenesis., (© 2023. The Author(s).)

Recent advances in the human microbiome characterization have revealed significant oral microbial detection in stools of dysbiotic patients. However, little is known about the potential interactions of these invasive oral microorganisms with commensal intestinal microbiota and the host. In this proof-of-concept study, we proposed a new model of oral-to-gut invasion by the combined use of an in vitro model simulating both the physicochemical and microbial (lumen- and mucus-associated microbes) parameters of the human colon (M-ARCOL), a salivary enrichment protocol, and whole-metagenome shotgun sequencing. Oral invasion of the intestinal microbiota was simulated by injection of enriched saliva in the in vitro colon model inoculated with a fecal sample from the same healthy adult donor. The mucosal compartment of M-ARCOL was able to retain the highest species richness levels over time, while species richness levels decreased in the luminal compartment. This study also showed that oral microorganisms preferably colonized the mucosal microenvironment, suggesting potential oral-to-intestinal mucosal competitions. This new model of oral-to-gut invasion can provide useful mechanistic insights into the role of oral microbiome in various disease processes. IMPORTANCE Here, we propose a new model of oral-to-gut invasion by the combined use of an in vitro model simulating both the physicochemical and microbial (lumen- and mucus-associated microbes) parameters of the human colon (M-ARCOL), a salivary enrichment protocol, and whole-metagenome shotgun sequencing. Our study revealed the importance of integrating the mucus compartment, which retained higher microbial richness during fermentation, showed the preference of oral microbial invaders for the mucosal resources, and indicated potential oral-to-intestinal mucosal competitions. It also underlined promising opportunities to further understand mechanisms of oral invasion into the human gut microbiome, define microbe-microbe and mucus-microbe interactions in a compartmentalized fashion, and help to better characterize the potential of oral microbial invasion and their persistence in the gut.

Background: Multiple sclerosis is a chronic immune-mediated disease of the brain and spinal cord resulting in physical and cognitive impairment in young adults. It is hypothesized that a disrupted bacterial and viral gut microbiota is a part of the pathogenesis mediating disease impact through an altered gut microbiota-brain axis. The aim of this study is to explore the characteristics of gut microbiota in multiple sclerosis and to associate it with disease variables, as the etiology of the disease remains only partially known., Methods: Here, in a case-control setting involving 148 Danish cases with multiple sclerosis and 148 matched healthy control subjects, we performed shotgun sequencing of fecal microbial DNA and associated bacterial and viral microbiota findings with plasma cytokines, blood cell gene expression profiles, and disease activity., Results: We found 61 bacterial species that were differentially abundant when comparing all multiple sclerosis cases with healthy controls, among which 31 species were enriched in cases. A cluster of inflammation markers composed of blood leukocytes, CRP, and blood cell gene expression of IL17A and IL6 was positively associated with a cluster of multiple sclerosis-related species. Bacterial species that were more abundant in cases with disease-active treatment-naïve multiple sclerosis were positively linked to a group of plasma cytokines including IL-22, IL-17A, IFN-β, IL-33, and TNF-α. The bacterial species richness of treatment-naïve multiple sclerosis cases was associated with number of relapses over a follow-up period of 2 years. However, in non-disease-active cases, we identified two bacterial species, Faecalibacterium prausnitzii and Gordonibacter urolithinfaciens, whose absolute abundance was enriched. These bacteria are known to produce anti-inflammatory metabolites including butyrate and urolithin. In addition, cases with multiple sclerosis had a higher viral species diversity and a higher abundance of Caudovirales bacteriophages., Conclusions: Considerable aberrations are present in the gut microbiota of patients with multiple sclerosis that are directly associated with blood biomarkers of inflammation, and in treatment-naïve cases bacterial richness is positively associated with disease activity. Yet, the finding of two symbiotic bacterial species in non-disease-active cases that produce favorable immune-modulating compounds provides a rationale for testing these bacteria as adjunct therapeutics in future clinical trials., (© 2022. The Author(s).)

Objective: Gut microbiome dysbiosis has previously been reported in spondyloarthritis (SpA) patients and could be critically involved in the pathogenesis of this disorder. The objectives of this study were to further characterize the microbiota structure in SpA patients and to investigate the relationship between dysbiosis and disease activity in light of the putative influence of the genetic background., Methods: Shotgun sequencing was performed on fecal DNA isolated from stool samples from 2 groups of adult volunteers: SpA patients (n = 102) and healthy controls (n = 63). A subset of the healthy controls comprised the age-matched siblings of patients whose HLA-B27 status was known. Changes in gut microbiota composition were assessed based on species diversity, enterotypes, and taxonomic and functional differences., Results: Dysbiosis was confirmed in SpA patients as compared to healthy controls. The restriction of microbiota diversity was detected in patients with the most active disease, and the abundance of several bacterial species was correlated with Bath Ankylosing Spondylitis Disease Activity Index score. Among healthy controls, significant differences in microbiota composition were also detected between the HLA-B27-positive and the HLA-B27-negative siblings of SpA patients. We highlighted a decreased abundance of several species of bacteria in SpA patients, especially those bacteria belonging to the Clostridiales order. Among the few species of bacteria showing increased abundance, Ruminococcus gnavus was one of the top differentiating species., Conclusion: These findings reveal that genetic background and level of disease activity are likely to influence the composition of the gut microbiota of patients with SpA. It may be appropriate for further research on chronic arthritis to focus on these key parameters., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Scope: An imbalance of the gut microbiota ("dysbiosis") is associated with numerous chronic diseases, and its modulation is a promising novel therapeutic approach. Dietary supplementation with soluble fiber is one of several proposed modulation strategies. This study aims at confirming the impact of the resistant dextrin NUTRIOSE (RD), a soluble fiber with demonstrated beneficial health effects, on the gut microbiota of healthy individuals., Methods and Results: Fifty healthy women are enrolled and supplemented daily with either RD (n = 24) or a control product (n = 26) during 6 weeks. Characterization of the fecal metagenome with shotgun sequencing reveals that RD intake dramatically increases the abundance of the commensal bacterium Parabacteroides distasonis. Furthermore, presence in metagenomes of accessory genes from P. distasonis, coding for susCD (a starch-binding membrane protein complex) is associated with a greater increase of the species. This suggests that response to RD might be strain-dependent., Conclusion: Supplementation with RD can be used to specifically increase P. distasonis in gut microbiota of healthy women. The magnitude of the response may be associated with fiber-metabolizing capabilities of strains carried by subjects. Further research will seek to confirm that P. distasonis directly modulates the clinical effects observed in other studies., (© 2022 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH GmbH.)

Background: Diosmectite, a natural colloidal clay, has been used worldwide for a number of approved indications, including the treatment of chronic functional diarrhea. Here, we used high-resolution whole metagenome shotgun sequencing to assess the impact of a 5 weeks administration of diosmectite (3 g/sachet, 3 sachets/day) on the fecal microbiota of 35 adults with functional chronic diarrhea., Results: Gut microbiota was not impacted by diosmectite administration. In particular, richness remained stable and no microbial species displayed a significant evolution. Segregating patients either by diosmectite response (non responder, early responder, late responder) or by nationality (Great-Britain or Netherlands) yielded the same results., Conclusion: We concluded that no microbiota-related physiological alterations are expected upon long-term treatment with diosmectite., Trial Registration: Clinicaltrials.gov NCT03045926., (© 2022. The Author(s).)

Background: Schizophrenia (SCZ) is a heterogeneous neuropsychiatric disorder for which current treatment has insufficient efficacy and severe adverse effects. The modifiable gut microbiome might be a potential target for intervention to improve neurobiological functions through the gut-microbiome-brain axis., Methods: In this case-control study, gut microbiota of 132 patients with SCZ and increased waist circumference were compared with gut microbiota of two age- and sex-matched control groups, composed of 132 healthy individuals and 132 individuals with metabolic syndrome. Shotgun sequencing was used to characterize fecal samples at the taxonomic and functional levels. Cognition of the patients with SCZ was evaluated using the Brief Assessment of Cognition instrument., Results: SCZ gut microbiota differed significantly from those of healthy control subjects and individuals with metabolic syndrome in terms of richness and global composition. SCZ gut microbiota were notably enriched in Flavonifractor plautii , Collinsella aerofaciens , Bilophila wadsworthia , and Sellimonas intestinalis , while depleted in Faecalibacterium prausnitzii , Ruminococcus lactaris , Ruminococcus bicirculans , and Veillonella rogosae . Functional potential of the gut microbiota accounted for 11% of cognition variability. In particular, the bacterial functional module for synthesizing tyrosine, a precursor for dopamine, was in SCZ cases positively associated with cognitive score (ρ = 0.34, q ≤ .1)., Conclusions: Overall, this study shows that the gut microbiome of patients with SCZ differs greatly from that of healthy control subjects or individuals with metabolic syndrome. Cognitive function of patients with SCZ is associated with the potential for gut bacterial biosynthesis of tyrosine, a precursor for dopamine, suggesting that gut microbiota might be an intervention target for alleviation of cognitive dysfunction in SCZ., (© 2022 The Authors.)

Crocodylus moreletii (Morelet's crocodile) and Crocodylus acutus (American crocodile) are generalist, apex predators of subtropical aquatic habitats in Central America. As top predators, crocodiles may be exposed to high levels of micro pollutants, such as trace elements via bioaccumulation that enter the food web as a consequence of human activities. As such, the status of their population can be considered indicative of that of the entire ecosystem - i.e., crocodiles constitute as genuine indicator species. In this study, we report on the concentrations of trace elements found in the caudal scutes of 178 specimens of C. acutus and C. moreletii from Belize. Our objectives were three-fold: (1) to assess variation in trace element concentration between species, sexes, age classes and body index; (2) to identify areas with elevated exposure to trace elements by comparing concentrations in the scutes of crocodiles at various sites in Belize; and (3) to explore links between crocodile trace element load and local land use. All elements tested (Hg, Pb, Cd, As, Cu, Zn, Co) could be detected in at least some scutes. Many of the readings of As and Co were under or close to the detection limit and were not further analyzed. Relatively high Hg concentrations were observed in adults from Chiquibul Forest (median 3.170 µg/g) and Ambergris Caye (0.834 µg/g). Concentrations of Hg and Pb tended to be higher in adult animals than in juveniles, especially in C. acutus. On the other hand, concentrations of Cd, Cu and Zn were higher in juveniles than in subadult adult animals. Concentrations of Cu were higher in C. acutus than in C. moreletii, but otherwise no species-effects were found for the other trace elements. We found a negative correlation between Hg and Zn concentrations; correlations among Cd, Pb, Cu and Zn concentrations tended to be positive. In both juveniles and adults, animals with high concentrations of Zn had lower body-indices (a proxy for physiological condition). None of the other element concentrations correlated with the body-index. Specimens of C. acutus were more often sampled at coastal sites, while C. moreletii sampling points were typically closer to agricultural or forested areas. A canonical correlation analysis revealed a significant association between trace element load and habitat characteristics. Animals sampled inland, near submontane forests, contained higher levels of Hg, while animals sampled near agricultural, urban or lowland habitats tended to have higher concentrations of Cd, Pb, Cu and Zn. This study identifies the most prevalent trace element concentrations impacting Belizean watersheds while highlighting the exposure risk to non-essential trace elements in less-urbanised areas or protected areas., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Some cardiometabolic risk factors such as dyslipidemia and insulin resistance are known to be associated with low gut microbiota richness. A link between gut microbiota richness and the diversity of consumed dietary fibers (DF) has also been reported. We introduced a larger diversity of consumed DF by using a daily consumed bread in subjects at cardiometabolic risk and assessed the impacts on the composition and functions of gut microbiota as well as on cardiometabolic profile. Thirty-nine subjects at cardiometabolic risk were included in a double-blind, randomized, cross-over, twice 8-week study, and consumed daily 150 g of standard bread or enriched with a 7-dietary fiber mixture (5.55 g and 16.05 g of fibers, respectively). Before and after intervention, stool samples were collected for gut microbiota analysis from species determination down to gene-level abundance using shotgun metagenomics, and cardiometabolic profile was assessed. Multi-fiber bread consumption significantly decreased Bacteroides vulgatus , whereas it increased Parabacteroides distasonis, Fusicatenibacter saccharivorans , an unclassified Acutalibacteraceae and an unclassified Eisenbergiella (q < 0.1). The fraction of gut microbiota carrying the gene coding for five families/subfamilies of glycoside hydrolases (CAZymes) were also increased and negatively correlated with peaks and total/incremental area under curve (tAUC/iAUC) of postprandial glycemia and insulinemia. Compared to control bread, multi-fiber bread decreased total cholesterol (-0.42 mM; q < 0.01), LDL cholesterol (-0.36 mM; q < 0.01), insulin (-2.77 mIU/l; q < 0.05), and HOMA (-0.78; q < 0.05). In conclusion, increasing the diversity of DF in a daily consumed product modifies gut microbiota composition and function and could be a relevant nutritional tool to improve cardiometabolic profile.

The number of indications for fecal microbiota transplantation is expected to rise, thus increasing the needs for production of readily available frozen or freeze-dried transplants. Using shotgun metagenomics, we investigated the capacity of two novel human fecal microbiota transplants prepared in maltodextrin-trehalose solutions (abbreviated MD and TR for maltodextrin:trehalose, 3:1, w/w, and trehalose:maltodextrin 3:1, w/w, respectively), to colonize a germ-free born mouse model. Gavage with frozen-thawed MD or TR suspensions gave the taxonomic profiles of mouse feces that best resembled those obtained with the fresh inoculum (Spearman correlations based on relative abundances of metagenomic species around 0.80 and 0.75 for MD and TR respectively), while engraftment capacity of defrosted NaCl transplants most diverged (Spearman correlations around 0.63). Engraftment of members of the family Lachnospiraceae and Ruminoccocaceae was the most challenging in all groups of mice, being improved with MD and TR transplants compared to NaCl, but still lower than with the fresh preparation. Improvement of engraftment of this important group in maintaining health represents a challenge that could benefit from further research on fecal microbiota transplant manufacturing.

The development of cardiometabolic (CM) diseases is associated with chronic low-grade inflammation, partly linked to alterations of the gut microbiota (GM) and reduced intestinal integrity. The SINFONI project investigates a multifunctional (MF) nutritional strategy's impact combining different bioactive compounds on inflammation, GM modulation and CM profile. In this randomized crossover-controlled study, 30 subjects at CM-risk consumed MF cereal-products, enriched with polyphenols, fibers, slowly-digestible starch, omega-3 fatty acids or Control cereal-products (without bioactive compounds) for 2 months. Metabolic endotoxemia (lipopolysaccharide (LPS), lipopolysaccharide-binding protein over soluble cluster of differentiation-14 (LBP/sCD14), systemic inflammation and cardiovascular risk markers, intestinal inflammation, CM profile and response to a one-week fructose supplementation, were assessed at fasting and post mixed-meal. GM composition and metabolomic analysis were conducted. Mixed linear models were employed, integrating time (pre/post), treatment (MF/control), and sequence/period. Compared to control, MF intervention reduced intestinal inflammation (fecal calprotectin, p  = 0.007) and endotoxemia (fasting LPS, p  < 0.05), without alteration of systemic inflammation. MF decreased serum branched-chain amino acids compared to control ( p  < 0.05) and increased B.ovatus , B.uniformis , A.butyriciproducens and unclassified Christensenellaceae.CAG-74 ( p  < 0.05). CM markers were unchanged. A 2-month dietary intervention combining multiple bioactive compounds improved intestinal inflammation and induced GM modulation. Such strategy appears as an effective strategy to target low-grade inflammation through multi-target approach.

Objectives: (1) To assess the value of urinary butoxyacetic acid (BAA) measurement for the monitoring of workers exposed to low concentration of 2-butoxyethanol (BE); (2) to evaluate the in vivo effect of low occupational BE exposure on the erythrocyte lineage; and (3) to test the possible influence of genetic polymorphism for cytochrome P450 2E1 (CYP 2E1) on urinary BAA excretion rate., Methods: Thirty-one male workers exposed to BE in a beverage package production plant were examined according to their external (BE) and internal (BAA) solvent exposure. The effect of this exposure on erythrocyte lineage [red blood cell numeration (RBC), hemoglobin (Hb), hematocrit (Htc), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), haptoglobin (Hp), reticulocyte numeration (Ret) and osmotic resistance (OR)], hepatic [aspartate aminotransferase (GOT), alanine aminotransferase (GPT)] and renal [plasmatic creatinine, urinary retinol binding protein (RBP)] parameters was also investigated. DNA purified from whole blood was used for CYP 2E1 genotyping., Results: Average airborne concentration of BE was 2.91 mg/m3 (0.59 ppm) with a standard deviation of 1.30 mg/m3 (0.27 ppm). There was a relatively good correlation between external and internal exposure estimated by measuring BAA in post-shift urine samples (average 10.4 mg/g creatinine; r = 0.55; P = 0.0012). Compared with a matched control group (n = 21) exposed workers had a statistically significant decrease (3.3%; P = 0.03) in Hct while MCHC was increased (2.1%; P = 0.02). No significant difference was observed either in other erythroid parameters or in hepatic and renal biomarkers. One exposed individual exhibited a mutant allele with increased cytochrome P450 oxidative activity which coincided with a very low urinary BAA excretion., Conclusions: Single determination of BAA in post-shift urine samples can be used to assess exposure to low levels of BE. A slight but significant effect on erythroid parameters suggesting membrane damage was observed in exposed workers. The influence of the genetic polymorphism for CYP 2E1 deserves further investigation for the interpretation of urinary BAA measurements.