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Inclusion criteria were an acute diarrhoea episode defined as at least three watery stools per day over a period of 48 hours or less, and patients with usually normal bowel movements, that is, at least three normal stools per week and three or less normal stools per day.
Droylefaix MT, Drouet Y, Schatz B. Sodium glycodeoxycholate and spinability of gastrointestinal mucus-protective effect of smectite. Gastroenterology. 1985;88:1369. Newly diagnosed ambulatory patients suffering from acute diarrhoea presumed to be of infectious origin were randomized to receive diosmectite or placebo. During their participation, patients recorded in diaries their stool frequency, presence of blood in stools, and abdominal pain/cramps. An acute diarrhoea episode was regarded to have resolved after the patient had one formed stool followed by a nonwatery stool. P-value correspond to Mann–Whitney test for quantitative variables (age, Bristol scale, MGS richness), and for Chi-squared test for categorical variables (sex, country expressed as Great Britain percentage). Quantitative values are displayed as mean±standard deviation We validated this method and confirmed that MGS were not impacted by diosmectite treatment using another approach (non-parametric tests for longitudinal data, see Supplementary Fig.3, Additional File 1, Supplementary Table 1 in Additional File 2).
A fluorescence focus assay in the MA104 cell monolayers was used to determine the viral titre, expressed as focus-forming units per millilitre of virus (FFU/ml). Briefly, MA104 cells were grown in 8-chamber slides (Lab-Tek chamber Slide, Nunc Inc, USA) and then infected with supernatants from the Caco-2 infection experiments. After viral absorption, the cells were fixed in methanol and probed with fluorescein isothiocyanate (FITC) conjugated anti-RV antibody (Abcam, ab31435). Fluorescence foci were counted individually on a Nikon Eclipse 80i epifluorescence microscope (FITC filter). The viral titre was calculated from the average number of foci per well adjusted for well volume and expressed as FFU/ml. As a negative control, a mixture of titanium dioxide, maltodextrin and glucose monohydrate was used (TMG). Virus strain and Caco-2 cell infection protocol We further looked for diosmectite impact at the species level. Considering the 450 MGS that were present in more than 10% of samples, the AUC analysis showed that 18 MGS had a different evolution before and after treatment ( p≤0.05, Wilcoxon signed-rank test). Among them, only 4 and 5 MGS had a significantly different abundance in at least one of the three time points before treatment or during treatment, respectively (p≤0.05, Friedman test). The five MGS whose abundance changed during the treatment had low prevalence at D-1 (32%±0.1, see Additional file 1, Supplementary Fig.2) and accounted for only 0.3%±0.5 of the total microbiota. Moreover, we found the same number of MGS ( n=35) whose abundance changed significantly before the treatment (at D-30, D-14 or D-1, Friedman test, p≤0.05), or during the treatment (at D-1, D8, D35, Friedman test, p≤0.05), suggesting even more random variations instead of an effect of the treatment. Additionally, after correction for multiple testing only one MGS was significantly altered before the treatment, and none during the treatment. Diosmectite is proposed as an active treatment for acute gastroenteritis (AGE). The key treatment of AGE in children is the administration of oral rehydration solution (ORS) [ 9], but this neither shortens the duration of diarrhoea nor reduces the frequency of stool output. Therefore, active therapies are now recommended as an adjunct to ORS. The updated ESPGHAN/ESPID guidelines for managing children with gastroenteritis suggests the use of DS to reduce stool output [ 9] based on the results of randomized controlled clinical trials [ 10]. The latter have shown that DS reduces the stool volume in children with gastroenteritis, including those infected with RV [ 3, 11]. Yao-Zong Y, Shi-Rong L, Delvaux M. Comparative efficacy of dioctahedral smectite (Smecta) and a probiotic preparation in chronic functional diarrhoea. Dig liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver. 2004;36:824–8 Netherlands.
Watery diarrhoea results from increased chloride secretion mainly induced by the viral enterotoxin NSP4 [ 18], which stimulates cAMP-dependent Cl − secretion by increasing the intracellular Ca 2+ concentration [ 18] and inhibiting Na + absorption [ 13], ultimately causing the activation of the TMEM16A transporter protein [ 19]. However, the chloride conductance of CFTR is unaffected by NSP4 [ 19]. Individuals were segregated based on k-means method, a classification method used to create groups of individuals without prior knowledge of number of classes. Individuals are aggregated around K mean “centers” so the groups are composed of the most similar individuals. Here, several K were tested and K = 3 (stratification into three groups) was selected according to the relevance of the groups obtained, confirmed by statistical analysis. The input given to the K-means algorithm were the delta values of the Bristol stool scores at D8, D35 and D125, using D-1 as the reference. Area Under Curve
Diosmectite
Williams LB, Haydel SE. Evaluation of the medicinal use of clay minerals as antibacterial agents. Int Geol Rev. 2010;52:745–70. Dupont C, Foo JLK, Garnier P, Moore N, Mathiex-Fortunet H, Salazar-Lindo E. Oral diosmectite reduces stool output and diarrhea duration in children with acute watery diarrhea. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2009;7:456–62 United States. Mahraoui L, Heyman M, Plique O, Droy-Lefaix MT, Desjeux JF. Apical effect of diosmectite on damage to the intestinal barrier induced by basal tumour necrosis factor-alpha. Gut. 1997;40:339–43.
After a screening period of up to 6weeks including a baseline assessment, each subject was dosed with diosmectite TID over 5weeks (Day 1 to Day 35). Feces samples were collected at screening phase (D-30, D-14), at baseline visit (D-1), and over the treatment period (D8, D35). Collection was performed using a kit provided by INRAE using a stabilizing solution (RNAlater®; ThermoFisher Scientific, Waltham, US) (SOP05_V2 from the International Human Microbiome Standards, IHMS) [ 31] allowing samples to be preserved within 24h to 7days at room temperature before to be handled by laboratory. The current use of diosmectite being for chronic as well as acute diarrhea, the potential modification of the gut microbiota induced by a long-term administration, clearly warranted the assessment of its impact on the intestinal microbiome. Considering its importance in the microbiota composition, another limit of the study is the absence of data related to diet apart from the exclusion criteria (artificial feeding or subjects eating shellfish more than two times a week, see Methods).Dupont C, Moreno JL, Barau E, Bargaoui K, Thiane E, Plique O. Effect of diosmectite on intestinal permeability changes in acute diarrhea: a double-blind placebo-controlled trial. J Pediatr Gastroenterol Nutr. 1992;14:413–9 United States. Ciarlet M, Crawford SE, Estes MK. Differential infection of polarized epithelial cell lines by sialic acid-dependent and sialic acid-independent rotavirus strains. J Virol. 2001;75:11834–50. At lower taxonomic ranks, three families (Streptococcaceae, Eggerthellaceae, and Bifidobacteriaceae) and four genera ( Bifidocbacterium, Parasutterella, Streptococcus, and Turicibacter) evolved differently before and during treatment ( p ≤ 0.05). Friedman tests revealed that the three families and Bifidobacterium changed before treatment (p ≤ 0.05) whereas none of these taxa presented a significant evolution during treatment ( p ≥ 0.1).
Thirty-five adults subjects were enrolled, 20 males and 15 females, whose country of residence was Netherlands (NLD; n = 12) or Great Britain (GRB; n = 23). The inclusion criteria were: male or female, between 18 and 60 years old, BMI between 19 and 32 kg/m 2, minimum body weight of 50 kg. They had functional chronic diarrhea defined according to the Rome IV criteria with loose or watery stools according to Bristol stool scale (BSS) grade 6 and 7, occurring in at least 75% of stools for the last 3 months (with symptoms onset at least 6 months before diagnosis), with or without pain [ 24]. Subjects with history of suspected organic or drug induced cause to chronic diarrhea were excluded as well as antibiotic, metformin and/or Proton Pump Inhibitor intake within the month prior to baseline visit or during the study. The inclusion took place from 24 August 2016 to 9 May 2017, in the Netherlands (PRA Healthy Sciences, Groningen, 9728NZ), and in the United Kingdom (MAC Clinical Resarch Limited, Manchester, M13 9NQ). Treatment Amedei A, Munari F, Della Bella C, Niccolai E, Benagiano M, Bencini L, et al. Helicobacter pylori secreted peptidyl prolyl cis, trans-isomerase drives Th17 inflammation in gastric adenocarcinoma. Intern Emerg Med. 2014;9:303–9. This is the first randomized, placebo-controlled trial prospectively comparing diosmectite to placebo for the treatment of acute diarrhoea in adults. This study showed that oral diosmectite sachet 6g three times a day significantly shortened time to recovery in the treatment of acute diarrhoea in adults. This was further supported by the results found in the PP population. This study also confirmed the good safety profile of diosmectite, as illustrated by the limited number of AEs, of which only 3 were considered drug related (constipation). Among the 35 participants, five were missing one or several samples (maximum missing samples: 3 at D-14), leading to a total of 170 samples available for the analysis. DNA extraction and sequencing
Song M, Liu Y, Soares JA, Che TM, Osuna O, Maddox CW, et al. Dietary clays alleviate diarrhea of weaned pigs. J Anim Sci. 2012;90:345–60 United States. Ducrotte P, Dapoigny M, Bonaz B, Siproudhis L. Symptomatic efficacy of beidellitic montmorillonite in irritable bowel syndrome: a randomized, controlled trial. Aliment Pharmacol Ther England. 2005;21:435–44. Reactive oxygen species production was measured using DCFH-DA spectrofluorometry. After stimulation, DCFH-DA (20 µM) was added for 30 min at 37 °C in the dark. Intracellular ROS production was measured in a fluorometer (SFM 25; Kontron Instruments, Japan). For DCF fluorescence imaging, Caco-2 cells were grown on the cover glass for 3 days, fixed and permeabilized with paraformaldehyde 4% and Triton 0.2% for 30 min at 4 °C. Cells were then incubated with DCF-HA 20 µM for 30 min at 37 °C in the dark. Fluorescence images from multiple fields were obtained using a Nikon Eclipse e 80i microscopy. The images were analysed using the NiS Elements D imaging software (Nikon Instruments, Inc., NY, USA). Glutathione assay
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