Was der (Viszeral-)Chirurg als neue Erkenntnisse über die Gallensäuren und deren Zusammenspiel mit dem Darmmikrobiom wissen sollte

Zusammenfassung

Der (Viszeral-)Chirurg lernt auch durch Anlehnung an zahlreiche medizinische Nachbarfächer die (patho)biochemischen und (patho)physiologischen Konsequenzen seines erkrankungsrelevanten operativen Wirkens (Veränderung der Anatomie des GI-Trakts und seiner Anhangsorgane, Medikation etc.) kennen und verstehen.

Ziel & Methode Mit kompakter narrativer Kurzübersicht soll die Verflechtung von Gallensäuren (GS) im Stoffwechsel, insbesondere im Zusammenhang mit geplantem oder ausgeführtem (viszeral)chirurgischen Vorgehen illustriert werden. Dazu wurden i) einschlägige Referenzen der medizinisch-wissenschaftlichen Literatur und ii) eigene fachspezifisch gewonnene Erkenntnisse herangezogen.

Ergebnisse (Eckpunkte) 1. Chirurgie und Biochemie weisen schon früh in der Geschichte einen gemeinsamen Betrachtungsgegenstand auf, u. a. Lebererkrankungen wie z. B. hinsichtlich der Konsequenzen eines gestörten Pfortaderkreislaufs und der Leberzirrhose. 2. GS sind (i) natürliche Detergenzien, (ii) Bestandteile der Cholesterin-Gallensteine und (iii) essenzielle Signalmoleküle der Darm-Leber-Stoffwechselinteraktion. Cholsäure [CA] und Chenodesoxycholsäure [CDCA] dominieren mit je ~35 % den Gallensäure-Pool. Durch Konjugation der GS mit Taurin und Glycin wird ihre Löslichkeit erhöht. Der enterohepatische Kreislauf minimiert die Ausscheidung der GS. 3. Die Bildung der GS in der Leber aus Cholesterin (Umsatz/pro Tag: 0,2–0,6 g Cholesterol) kontrolliert die Cholesterin-7α-Hydroxylase (CYP7A1). Eine toxische GS-Akkumulation wird durch GS-induzierte Repression der CYP7A1-Expression und Sulfatierung der GS (Erhöhung der Harngängigkeit) verhindert. 4. GS haben regulatorische Aktivitäten im Energie-, Glukose-, Lipid- und Lipoproteinstoffwechsel und innerhalb des angeborenen Immunsystems. Durch die Bindung der GS an den Farnesoid-X-Kernrezeptor [FXR] und den membranalen G-Protein-gekoppelten Gallensäurerezeptor-1 [GPBAR1, TGR5] werden vielfältige Wirkungen im Fett- und Kohlenhydratstoffwechsel ausgelöst. 5. GS triggern im braunen Fettgewebe und im Skelettmuskel durch Aktivierung des GPBAR1-MAPK-Signalwegs die Expression der Iodothyronin-Dejodinase (DIO2). Dadurch wird vermehrt Thyroxin (T₄) in Trijodthyronin (T₃) umgewandelt und in der Folge werden die Fettverbrennung und die Thermogenese gesteigert. 6. GS verändern das intestinale Mikrobiom durch bakteriolytische Aktivitäten und andererseits wird das GS-Profil vom Mikrobiom moduliert. Typische mikrobielle Wirkungen auf den GS-Pool sind die (i) Abspaltung der Glycin- und Taurinreste von den konjugierten GS durch „bile salt hydrolases“ und (ii) die chemische Modifizierung freier, primärer GS durch Re-Amidierung, Oxydation-Reduktion, Veresterung und Desulfatierung. 7. GS hemmen das durch Lipopolysaccharide (Membranbestandteil gramnegativer Bakterien) induzierte endotoxine Entzündungsgeschehen. Über die Bindung der GS an Makrophagenrezeptoren (GPBAR1 und FXR) wird (i) die LPS-induzierte proinflammatorische Zytokinbildung vermindert und die Expression des antiinflammatorischen IL-10 befördert. Außerdem werden (ii) das Leukozyten-„Trafficking“ reguliert und (iii) das Inflammasom von Makrophagen und neutrophilen Granulozyten aktiviert. 8. Die mit der Adipositaschirurgie (z. B. beim „Roux-en-Y gastric bypass“ [RYGB]) erzielten gewichtsunabhängigen Veränderungen korrelieren mit einem erhöhten GS-Serumspiegel und einem veränderten intestinalen GS-Profil. Letzteres führt sekundär zum „Umbau“ des Mikrobioms. RYGB hat u. a. positive Wirkungen auf den Stoffwechsel der Kohlenhydrate. So wird die Insulinsensitivität der Leber verbessert und die Sekretion des Glucagon-like peptide 1 gesteigert.

Schlussfolgerung GS sind ein Paradebeispiel für metabolische Regulatoren, deren Interaktionen mit vielfältigen (patho)biochemischen und (patho)physiologischen Vorgängen (viszeral)chirurgisch relevante Erkrankungen und (viszeral)chirurgisch-operative Maßnahmen beeinflussen. Ihre biochemisch-physiologischen Aktivitäten und deren Verständnis auf molekularer Ebene sollten zum medizinisch-wissenschaftlichen Rüstzeug des versierten modernen (Viszeral-)Chirurgen gehören.

Abstract

The abdominal surgeon may have the opportunity to steadily learn on the (patho-)biochemical and (-)physiological consequences of his disease-related surgical activity (change of anatomy of the GI tract and its surrounding organs, medication and so on) if he refers closely to several medical disciplines as specifically indicated.

Aim & Method By means of a short compact overview based on (i) topic-related references from the scientific medical literature and (ii) own surgery-specific perceptions, interrelation of cholic acids (CA) with metabolism, in particular, with planned or performed (abdomino-)surgical procedures should be illustrated.

Results (corner points) 1. Surgery and biochemistry have a common and traditionally matured matter of consideration with regard to the consequences of an altered portal vein circulation and liver cirrhosis. 2. CA are (i) natural detergents, (ii) components of cholesterol-associated gall stones and (iii) essential signal molecules of intestine-liver metabolic interaction. CA and chenodesoxycholic acid [CDCA] dominate the CA pool with approximately 35 %. By conjugation of CA with taurine und glycine, its solubility is increased. The enterohepatic circulation minimizes the excretion of CA. 3. The generation of CA out of cholesterol within the liver (turnover/day: 0.2–0.6 g cholesterol) is controlled by cholesterol-7α-hydroxylase (CYP7A1). A toxic CA accumulation is prevented by a CA-induced repression of CYP7A1 expression and sulfation of CA (resulting in an increase of urine solubility). 4. CA show regulatory activities in the energy, glucose, lipid and lipoprotein metabolism and connate immune system. By binding of the CA to the farnesoid X-nuclear receptor [FXR] and the membranous G-protein-coupled CA receptor-1 [GPBAR1, TGR5], mannifold effects within the fat and carbohydrate metabolism are induced. 5. CA trigger the expression of the iodothyronine-dejodinase (DIO2) within the brown fat tissue and skelet muscles by activation of the GPBAR1-MAPK signal pathways. Hence, thyroxine (T₄) is transformed to trijodthyronine (T₃) and, subsequently, fat oxidation and thermogenesis are increased. 6. CA change the intestinal microbioma by bacteriolytic activities and, on the other hand, the CA profile is modulated by the microbioma. Typical microbial effects of the CA pool are (i) separation of glycine and taurine residuals of conjugated CA by “bile salt hydrolases” and (ii) chemical modification of free, primary CA by re-amidation, oxidation-reduction, esterification and desulfation. 7. CA inhibit the endotoxin-based inflammatory response induced by lipopolysaccharides (LPS; membranous component of gram-negative bacteria). Via binding of CA to macrophages-associated receptors (GPBAR1 and FXR), (i) the LPS-induced proinflammatory cytokine generation is reduced and the expression of antiinflammatory IL-10 is promoted. In addition, (ii) white-blood cell “trafficking” is regulated and (iii) inflammasoma is activated by macrophages and neutrophil granulocytes. 8. The body weight-independent changes after bariatric surgery (e. g., in case of “Roux-en-Y gastric bypass” [RYGB]) correlate with an increased CA serum level and an altered intestinal CA profile. The latter leads secundarily to a modification of the microbioma. RYGB has – among others – positive effects onto the carbohydrate metabolism. Thus, insulin sensitivity of the liver is improved and the secretion of the glucagon-like peptide 1 is enhanced.

Conclusion CA are a parade example for metabolic regulators, the interactions of which have an impact onto various (patho-)biochemical and (-)physiological processes, (abdomino-)surgically relevant diseases and (abdomino-)surgical measures. Their biochemical/physiological activities and insight into associated molecular processes should be part of the medical and scientific skills of a modern (abdominal) surgeon with a developed pathophysiological expertise.

Schlüsselwörter

Gallensäuren (GS) - Signalmoleküle - Farnesoid-X-Rezeptor (FXR) - G-Protein-gekoppelter Gallensäurerezeptor-1 (GPBAR1, TGR5) - Lipopolysaccharide (LPS) - Mitogenaktivierte-Proteinkinase(MAPK)-Signalleitung - braunes Fettgewebe - Thermogenese - Mikrobiom - Inflammasom

Key words

cholic acids - signal molecules - farnesoid receptor (FXR) - G-protein bounded cholic acid receptor-1 (GPBAR-1, TGR5) - lipopolysaccharides (LPS) - mitogen-activated protein kinase (MAPK) signalling - brown fat tissue - thermogenesis - microbioma - inflammasoma

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