Institut für Ernährungsmedizin

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Saccharomyces boulardii CNCM I-745 supernatant improves markers of gut barrier function and inflammatory response in small intestinal organoids
(2025) Filipe Rosa, Louisa; Gonda, Steffen; Roese, Nadine; Bischoff, Stephan C.; Lachowicz-Wiśniewska, Sabina
Objectives: Saccharomyces boulardii CNCM I-745, a probiotic yeast, is effectively used for the treatment of acute diarrhea as well as for the prevention and treatment of traveller‘s diarrhea and diarrhea under tube feeding. The underlying mechanisms are not fully elucidated. Both antitoxic and regulatory effects on the intestinal barrier, mediated either by the yeast or yeast-derived substrates, have been discussed. Methods: To examine the effects of Saccharomyces boulardii released substrates (S.b.S) on gastrointestinal (GI) barrier function, a murine small intestinal organoid cell model under stress was used. Stress was induced by lipopolysaccharide (LPS) exposure or withdrawal of growth factors from cell culture medium (GFRed). Stressed organoids were treated with S.b.S (200 µg/mL), and markers of GI barrier and inflammatory response were assessed. Results: GFRed-induced stress was characterized by disturbances in selected tight junction (TJ) (p < 0.05), adherent junction (AJ) (p < 0.001), and mucin (Muc) formation (p < 0.01), measured by gene expressions, whereby additional S.b.S treatment was found to reverse these effects by increasing Muc2 (from 0.22 to 0.97-fold change, p < 0.05), Occludin (Ocln) (from 0.37 to 3.5-fold change, p < 0.0001), and Claudin (Cldn)7 expression (from 0.13 ± 0.066-fold change, p < 0.05) and by decreasing Muc1, Cldn2, Cldn5, and junctional adhesion molecule A (JAM-A) expression (all p < 0.01). Further, S.b.S normalized expression of nucleotide binding oligomerization domain (Nod)2- (from 44.5 to 0.51, p < 0.0001) and matrix metalloproteinase (Mmp)7-dependent activation (from 28.3 to 0.02875 ± 0.0044 ** p < 0.01) of antimicrobial peptide defense and reduced the expression of several inflammatory markers, such as myeloid differentiation primary response 88 (Myd88) (p < 0.01), tumor necrosis factor α (Tnfα) (p < 0.01), interleukin (IL)-6 (p < 0.01), and IL-1β (p < 0.001). Conclusions: Our data provide new insights into the molecular mechanisms by which Saccharomyces boulardii CNCM I-745-derived secretome attenuates inflammatory responses and restores GI barrier function in small intestinal organoids.
Serotonin reuptake transporter deficiency promotes liver steatosis and impairs intestinal barrier function in obese mice fed a Western‐style diet
(2023) Rosa, Louisa Filipe; Haasis, Eva; Knauss, Annkathrin; Guseva, Daria; Bischoff, Stephan C.
Background: Intestinal barrier dysfunctions have been associated with liver steatosis and metabolic diseases. Besides nutritional factors, like a Western-style diet (WSD), serotonin has been linked with leaky gut. Therefore, we aimed to evaluate the role of serotonin in the pathogenesis of intestinal barrier dysfunctions and liver steatosis in mice fed high-fat and high-sugar diets. Methods: 6–8 weeks old male serotonin reuptake transporter knockout mice (SERT−/−) and wild-type controls (SERT+/+) were fed either a WSD or a control diet (CD) ad libitum with or without fructose 30% (F) added to the drinking water for 12 weeks. Markers of liver steatosis and intestinal barrier function were assessed. Key Results: SERT−/− mice showed increased weight gain compared with SERT+/+ mice when fed a WSD ± F for 12 weeks (p < 0.05), whereby SERT−/− mice exhibited reduced energy (−21%) intake. Furthermore, SERT knockout resulted in a more pronounced liver steatosis (p < 0.05), enhanced levels of endotoxin in portal vein plasma (p < 0.05), and increased liver expression of Tnf and Myd88 (p < 0.05), when mice were fed a WSD ± F. Finally, SERT−/− mice, when compared with SERT+/+ mice, had a decreased mRNA expression of Muc2 (p < 0.01), Ocln (p < 0.05), Cldn5 (p = 0.054) and 7 (p < 0.01), Defa5 (p < 0.05) and other antimicrobial peptides in the ileum. On the protein level, ZO-1 (p < 0.01) and DEFA5 protein (p < 0.0001) were decreased. Conclusion and Inferences: Our data demonstrate that SERT knockout causes weight gain, liver steatosis, and leaky gut, especially in mice fed a WSD. Therefore, SERT induction could be a novel therapeutic approach to improve metabolic diseases associated with intestinal barrier dysfunction.
Tannic acid and ethacridine lactate attenuate markers of stress-induced intestinal barrier dysfunctions in murine small intestinal organoids
(2025) Filipe Rosa, Louisa; Gonda, Steffen; Roese, Nadine; Bischoff, Stephan C.; Kwok, Hang Fai (Henry); Alaimo, Alessandro
(1) Background: Tannacomp® is a drug consisting of tannin albuminate, a complex of tannic acid (TA) and ethacridine lactate (Eta) used for treating acute and traveler’s diarrhea. TA is thought to modulate gastrointestinal barrier function, but the underlying mechanisms and whether Eta has similar effects remains unclear. (2) Methods: to investigate the effects of TA and Eta on the intestinal barrier, stress responses were induced in murine intestinal organoids by lipopolysaccharide (LPS) exposure or withdrawal of growth factors from cell culture medium (GFRed). Further, organoids were exposed to either TA (0.01 mg/mL) or Eta (0.002 mg/mL) and markers of inflammatory response and gut barrier function were assessed. (3) Results: TA and Eta reduced several inflammatory markers such as interleukin 6, interleukin 1β, tumor necrosis factor α, and myeloid differentiation primary response 88 in stressed organoids. In addition, TA and Eta attenuated LPS- and GFRed-mediated gut barrier dysfunctions, with normalization of tight junction, adherent junction and mucin gene expression and reduction of Nod2- and matrix metalloproteinase 7-dependent activation of antimicrobial peptides. (4) Conclusions: our data show that TA and Eta modulate markers of inflammation and the intestinal barrier and suggest novel mechanisms of action of this drug that could broaden its treatment indications.
Vitamin A- and D-deficient diets disrupt intestinal antimicrobial peptide defense involving Wnt and STAT5 signaling pathways in mice
(2023) Filipe Rosa, Louisa; Petersen, Patricia P.; Görtz, Lisa F.; Stolzer, Iris; Kaden-Volynets, Valentina; Günther, Claudia; Bischoff, Stephan C.
Vitamin A and D deficiencies are associated with immune modulatory effects and intestinal barrier impairment. However, the underlying mechanisms remain unclear. C57BL/6J mice were fed either a diet lacking in vitamin A (VAd), vitamin D (VDd) or a control diet (CD) for 12 weeks. Gut barrier function, antimicrobial peptide (AMP) defense and regulatory pathways were assessed. VAd mice compared to CD mice showed a reduced villus length in the ileum (p < 0.01) and decreased crypt depth in the colon (p < 0.05). In both VAd- and VDd-fed mice, ileal α-defensin 5 (p < 0.05/p < 0.0001 for VAd/VDd) and lysozyme protein levels (p < 0.001/p < 0.0001) were decreased. Moreover, mRNA expression of lysozyme (p < 0.05/p < 0.05) and total cryptdins (p < 0.001/p < 0.01) were reduced compared to controls. Furthermore, matrix metalloproteinase-7 (Mmp7) mRNA (p < 0.0001/p < 0.001) as well as components of the Wnt signaling pathway were decreased. VAd- and VDd-fed mice, compared to control mice, exhibited increased expression of pro-inflammatory markers and β-defensins in the colon. Organoid cell culture confirmed that vitamins A and D regulate AMP expression, likely through the Jak/STAT5 signaling pathway. In conclusion, our data show that vitamin A and D regulate intestinal antimicrobial peptide defense through Wnt and STAT5 signaling pathways.

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