Browsing by Subject "Colitis"

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Characterization of dietary and genetic influences on the gastrointestinal microbiota
(2023) Bubeck, Alena Marie; Fricke, Florian W.
Although the gut microbiota is known to contribute fundamentally to human health, e.g. by promoting the maturation of the immune system and intestinal homeostasis, the factors shaping its composition are only poorly understood. Extrinsic and intrinsic influences can disturb the tightly controlled equilibrium between the microbiome and the host and induce dysbiosis, which has been linked to diverse health conditions such as obesity, atherosclerotic cardiovascular disease (ACVD) and inflammatory bowel disease (IBD). Therefore, understanding events leading to microbial perturbations and the prediction of associated health outcomes could aid in the prevention and treatment of these conditions. In this work, the impact of dietary and genetic factors on gastrointestinal microbiota compositions were determined, with the diet serving as an exemplary extrinsic, modifiable microbiota-relevant factor and with a genetic deficiency in a mouse model for intestinal inflammation serving as an exemplary intrinsic, non-modifiable microbiota-relevant factor. In both studies, microbial communities obtained from either a human or a murine cohort, respectively, were taxonomically characterized by 16S rRNA gene amplicon sequencing and analyzed in the context of metabolic and inflammatory implications for the host. In ACVD, the reduction of excess blood cholesterol, which is a main risk factor, is tackled by clinical interventions aiming to reduce cholesterol uptake from exogenous, dietary sources or by inhibiting endogenous cholesterol biosynthesis. Cholesterol-to-coprostanol conversion by the intestinal microbiota has also been suggested to reduce intestinal and serum cholesterol availability, but the dependencies of cholesterol conversion on specific bacterial taxa and dietary habits, as well as its association with serum lipid levels remain largely unknown. To study microbiota contributions to human cholesterol metabolism under varying conditions, fecal microbiota and lipid profiles, as well as serum lipid biomarkers, were determined in two independent human cohorts, including individuals with (CARBFUNC study) and without obesity (KETO study) on very low-carbohydrate high-fat diets (LCHF) for three to six months and six weeks, respectively. Across these two geographically independent studies, conserved distributions of cholesterol high and low-converter types were measured. Also, cholesterol conversion was most dominantly linked to the relative abundance of the cholesterol-converting bacterial species Eubacterium coprostanoligenes, which was further increased in low-converters by LCHF diets, shifting them towards a high-conversion state. Lean cholesterol high-converters, which were characterized by adverse serum lipid profiles even before the LCHF diet, responded to the intervention with increased LDL-C, independently of fat, cholesterol and saturated fatty acid intake. These findings identify the cholesterol high-converter type as a potential predictive biomarker for an increased LDL-C response to LCHF diet in metabolically healthy lean individuals. Although the etiology of IBD has not been fully resolved, an interplay between the intestinal microbiota, environmental factors and an individual’s genetic susceptibility is thought to trigger chronic inflammation by a dysregulation of the immune response in the gut. To identify colitis-associated microbiota alterations throughout the development of spontaneous colitis, mice with a genetic deficiency of the anti-inflammatory cytokine Interleukin-10 (IL-10) from different litters were co-housed with wild-type mice and monitored for 20 weeks. The scoring of mice based on their phenotype and stool consistency mirrored the state of mucosal inflammation as assessed based on histopathological examinations and cytokine expression profiles. Also, the state of colitis was characterized by global microbiota alterations and susceptibility to colitis was dependent on litter-specific microbiome compositions that mice adopted early on in their lives. Colitis development was further associated with the presence of the bacterial genus Akkermansia in mature mice shortly before symptoms manifested. This genus was also a good predictor of colitis-related mice withdrawal, suggesting the potential of Akkermansia to serve as an early onset, subclinical colitis marker. In summary, fecal microbiota characterizations in response to LCHF diets in humans and throughout the development of intestinal inflammation in a colitis mouse model highlight the potential of personalized microbiome-based patient classifications to predict clinical outcomes and improve treatment approaches.
Consumption of yeast-fermented wheat and rye breads increases colitis and mortality in a mouse model of colitis
(2022) Zimmermann, Julia; De Fazio, Luigia; Kaden-Volynets, Valentina; Hitzmann, Bernd; Bischoff, Stephan C.
Background: Cereals are known to trigger for wheat allergy, celiac disease and non-celiac wheat sensitivity (NCWS). Inflammatory processes and intestinal barrier impairment are suspected to be involved in NCWS, although the molecular triggers are unclear. Aims: We were interested if different bread types influence inflammatory processes and intestinal barrier function in a mouse model of inflammatory bowel disease. Methods: Epithelial caspase-8 gene knockout (Casp8 ΔIEC ) and control (Casp8 fl ) mice were randomized to eight groups, respectively. The groups received different diets for 28 days (gluten-free diet, gluten-rich diet 5 g%, or different types of bread at 50 g%). Breads varied regarding grain, milling and fermentation. All diets were isocaloric. Results: Regardless of the diet, Casp8 ΔIEC mice showed pronounced inflammation in colon compared to ileum, whereas Casp8 fl mice were hardly inflamed. Casp8 fl mice could tolerate all bread types. Especially yeast fermented rye and wheat bread from superfine flour but not pure gluten challenge increased colitis and mortality in Casp8 ΔIEC mice. Hepatic expression of lipopolysaccharide-binding protein and colonic expression of tumor necrosis factor-α genes were inversely related to survival. The bread diets, but not the gluten-rich diet, also decreased colonic tight junction expression to variable degrees, without clear association to survival and inflammation. Conclusions: Bread components, especially those from yeast-fermented breads from wheat and rye, increase colitis and mortality in Casp8 ΔIEC mice highly susceptible to intestinal inflammation, whereas control mice can tolerate all types of bread without inflammation. Yet unidentified bread components other than gluten seem to play the major role.
The role of the circadian clock, the microbiome and time-restricted feeding on the development and treatment of colitis
(2025) Haasis, Eva Annett Kristin; Lorentz, Axel
Mammals possess an internal circadian clock in almost all tissues that regulates biochemical and physiological processes over the course of 24 hours. In detail, transcription-translation feedback loops regulate the oscillation of genes over 24 hours. Inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD) are chronic immune activations and inflammations in the gastrointestinal tract. The etiology of IBD is not completely understood, but is associated with a disrupted circadian clock, e.g. shift work is an increased risk factor for the development of IBD. The aim of this thesis was to investigate the relationship between circadian clock and IBD. Altered light/dark cycles, consisting of four hours of light and four hours of darkness, were used to disrupt the circadian rhythm in a dextran sulfate sodium (DSS)-induced colitis mouse model and an IL-10 knockout (IL-10-/-) mouse model. Food intake is an important Zeitgeber for the circadian clock. Therefore, the potential of time-restricted feeding (TRF) to restore disturbed circadian rhythms and as a therapy for IBD should be investigated. Since fecal microbiota transplantation (FMT) could also be a possible therapy against colitis by improving the composition of the gut microbiota, the transferability of inflammatory and healthy phenotypes by fecal transplantation should be investigated. As bacterial supplementation, both a bacterium that prevents colitis and a bacterium that potentially promotes colitis were used. DSS treatment over eight days only led to early signs of inflammation and was slightly influenced by external light disruption with alternating 4 hours of light and 4 hours of darkness. The protocol for DSS treatment may not have been well suited. The same light disruption led to different results in IL-10-/- mice in two experiments. While in the first experiment an external light disruption led to an increased incidence of colitis and higher inflammation levels, these results were no longer present in the second experiment. The external light disruption led neither to an increased incidence of colitis nor to increased inflammation values. A further experiment, in which samples were taken every six hours, showed that the external light disruption had an effect in wild type (WT) animals and led to a disruption of circadian gene expression. In IL-10-/- mice, the expression of circadian genes was already disrupted at a normal light/dark rhythm of 12 hours/12 hours and further disruption by external light conditions was not possible, which could be an explanation for the different results regarding the occurrence of colitis in IL-10-/- mice with a disrupted light/dark rhythm. Eight-hour restricted feeding of IL-10-/- mice resulted in reduced incidence of colitis, low levels of inflammation and improved circadian clock expression independent of external circadian clock disruption, suggesting that TRF is an effective and useful therapeutic approach for colitis. This observation should be further tested in human studies. Administration of the fecal microbiota of mice with an inflammatory phenotype only led to increased inflammation levels, while an influence of the litter affiliation of the mice was also found in histologic scores and intestinal clock gene expression. Akkermansia muciniphila (A. muciniphila) was given as a colitis-promoting bacterium and led to increased gene expression of inflammatory markers and tight junction proteins, while Lactobacillus taiwanensis (L. taiwanensis), as a potentially colitis-preventing bacterium, improved the expression of the intestinal circadian clock. Neither FMT nor bacterial supplementation had any influence on the occurrence of colitis. The transfer of different phenotypes by FMT was only possible to a limited extent and does not appear to be an effective treatment option for colitis. A. muciniphila can be regarded as an inflammation-promoting bacterium, while a probiotic effect of L. taiwanensis could not be confirmed. In summary, this thesis has shown that a disrupted circadian clock is associated with intestinal inflammation and that TRF reduces inflammation and delays the onset of colitis, suggesting that TRF may be an effective therapy for intestinal inflammation.