Adipositas, Typ-2-Diabetes und das Mikrobiom, unser zweites Genom

 

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Zusammenfassung

Die Darmbakterien wurden lange Zeit als Kommensale oder Nebenschauspieler bei Darmerkrankungen und weiterer Infektionen aufgefasst. Dank moderner Sequenzierungsmethoden ist es in den letzten 10 Jahren gelungen diese auf kompositioneller und funktioneller Ebene zu charakterisieren. Es bestehen vielfältige Hinweise für eine Schlüsselrolle der Darmmikrobiota in der Entstehung von Adipositas und Diabetes mellitus Typ 2, aber auch chronisch entzündlichen Darmerkrankungen, neurologischen und psychiatrischen Erkrankungen sowie bestimmten Krebsarten.

Das Darmmikrobiom ist teilweise vererbbar, jedoch primär durch multiple Umwelteinflüsse modulierbar. Bis zur Ausreifung des Mikrobioms mit dem 3. Lebensjahr können vielfältige Störfaktoren wie Antibiotikaexposition, die Umwelt, aber auch die Ernährung dessen Komposition verändern und dadurch vermutlich lebenslange tiefgreifende Verschiebungen im Stoffwechsel und Phänotyp des Wirts hervorrufen.

Vor allem Studien im Mausmodell zeigen eine überzeugende Kausalität zwischen Veränderungen im Darmmikrobiom und dem Auftreten kardiometabolischer Erkrankungen.

Genaue pathophysiologische Mechanismen, die zur Entwicklung und Progression des metabolischen Syndroms führen, werden in der Wechselwirkung von bakteriellen Produkten mit dem Immunsystem des Wirts vermutet. Diese können beispielsweise Lipopolysacchariden aus der Hülle gramnegativer Bakterien, kurzkettige Fettsäuren aus der Fermentation von unlöslichen Ballaststoffen oder weitere Metabolite sein. Daraus resultieren eine gestörte Darmpermeabilität sowie eine systemische subklinische Inflammation. Zudem können sie in Glukose- und Fettstoffwechselkaskaden eingreifen und Veränderungen in der Funktion des Fettgewebes hervorrufen.

Die Darmbakterien fungieren somit als Bindeglied zwischen äusserer und innerer Umwelt. Besonders attraktiv erscheint deshalb die Möglichkeit die bakterielle Dysfunktion gezielt mittels Modulierung der Darmmikrobiota zu behandeln. Dies kann über entsprechende Umwelteinflüsse, Ernährung, Medikamente oder individuelle Bakteriotherapien wie Präbiotika-, Probiotika-, Antibiotika- oder Synbiotikaeinsatz erfolgen.

Ziel dieses Artikels ist es, die aktuelle Datenlage zur Rolle des Darmmikrobioms in der Pathophysiologie von Adipositas und Diabetes mellitus Typ 2 darzustellen und auf offene Fragestellungen einzugehen.

Abstract

For a long time overlooked as a mere bystander, a commensal organism or partially a nuisance, the gut microbiota has emerged as a key player in the modulation of the immune system and metabolism. Changes in the composition or function of the microbiota have been reported to be associated with metabolic diseases such as obesity, type 2 diabetes and insulin resistance but also with the development and progression of cardiovascular disease, inflammatory bowel disease, certain types of cancer and psychiatric diseases.

Partially heritable, the gut microbiome is already fully developed within the first 3 years of life of the human host. During this critical phase, the child but also his or her microbiome is susceptible to perturbations via changes in environment, antibiotic exposure and diet leading to possible lifelong impact on the metabolism and the phenotype. Studies in mice have supported a strong causality between shifts in the microbiome and development of the metabolic syndrome.

Mechanisms linking alterations in the microbiome with subsequent diseases include signaling through lipopolysaccharides from gram negative bacteria walls and interactions with the host immune system, fermentation of indigestible fibres to short chain fatty acids, modulation of bile acids and bile acid signaling. Interactions between the microbiome, its products and the immune system may lead to an increased gut permeability resulting in a systemic subclinical inflammation (leaky gut hypothesis), but can also alter signaling pathways influencing glucose and lipid metabolism, fat storage and adipose tissue function. Moreover, host specific factors such as age, diet, antibiotics and environmental exposition, have also been linked to shifts in the microbiota. Based upon available evidence, it can be hypothesized that the microbiota may mediate the influence of environmental and individual factors leading to the development of obesity and type 2 diabetes. Emerging applications such as fecal transplants are showing promising results in the resolution of infectious disease and might pose novel alternatives in the treatment of metabolic diseases, paving the way to an individualized “Bacteriotherapy”.

Thus, the aim of this review is to discuss the potential role of the gut microbiome in the pathophysiology of obesity and type 2 diabetes and shed light on emerging research and clinical applications.

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