RATIONALE: Severe alcohol-associated hepatitis (SAH) is the most critical, acute, inflammatory phenotype within the alcohol-associated liver disease (ALD) spectrum, characterized by high 30- and 90-day mortality. Since several decades, corticosteroids (CS) are the only approved pharmacotherapy offering highly limited survival benefits. Contextually, there is an evident demand for 3PM innovation in the area meeting patients' needs and improving individual outcomes. Fecal microbiota transplantation (FMT) has emerged as one of the new potential therapeutic options. In this study, we aimed to address the crucial 3PM domains in order to assess (i) the impact of FMT on mortality in SAH patients beyond CS, (ii) to identify factors associated with the outcome to be improved (iii) the prediction of futility, (iv) prevention of suboptimal individual outcomes linked to increased mortality, and (v) personalized allocation of therapy. METHODS: We conducted a prospective study (NCT04758806) in adult patients with SAH who were non-responders (NR) to or non-eligible (NE) for CS between January 2018 and August 2022. The intervention consisted of five 100 ml of FMT, prepared from 30 g stool from an unrelated healthy donor and frozen at - 80 °C, administered daily to the upper gastrointestinal (GI) tract. We evaluated the impact of FMT on 30- and 90-day mortality which we compared to the control group selected by the propensity score matching and treated by the standard of care; the control group was derived from the RH7 registry of patients hospitalized at the liver unit (NCT04767945). We have also scrutinized the FMT outcome against established and potential prognostic factors for SAH - such as the model for end-stage liver disease (MELD), Maddrey Discriminant Function (MDF), acute-on-chronic liver failure (ACLF), Liver Frailty Index (LFI), hepatic venous-portal pressure gradient (HVPG) and Alcoholic Hepatitis Histologic Score (AHHS) - to see if the 3PM method assigns them a new dimension in predicting response to therapy, prevention of suboptimal individual outcomes, and personalized patient management. RESULTS: We enrolled 44 patients with SAH (NR or NE) on an intention-to-treat basis; we analyzed 33 patients per protocol for associated factors (after an additional 11 being excluded for receiving less than 5 doses of FMT), and 31 patients by propensity score matching for corresponding individual outcomes, respectively. The mean age was 49.6 years, 11 patients (33.3%) were females. The median MELD score was 29, and ACLF of any degree had 27 patients (81.8%). FMT improved 30-day mortality (p = 0.0204) and non-significantly improved 90-day mortality (p = 0.4386). Univariate analysis identified MELD ≥ 30, MDF ≥ 90, and ACLF grade > 1 as significant predictors of 30-day mortality, (p = 0.031; p = 0.014; p = 0.034). Survival was not associated with baseline LFI, HVPG, or AHHS. CONCLUSIONS AND RECOMMENDATIONS IN THE FRAMEWORK OF 3PM: In the most difficult-to-treat sub-cohort of patients with SAH (i.e., NR/NE), FMT improved 30-day mortality. Factors associated with benefit included MELD ≤ 30, MDF ≤ 90, and ACLF < 2. These results support the potential of gut microbiome as a therapeutic target in the context of 3PM research and vice versa - to use 3PM methodology as the expedient unifying template for microbiome research. The results allow for immediate impact on the innovative concepts of (i) personalized phenotyping and stratification of the disease for the clinical research and practice, (ii) multilevel predictive diagnosis related to personalized/precise treatment allocation including evidence-based (ii) prevention of futile and sub-optimally effective therapy, as well as (iii) targeted prevention of poor individual outcomes in patients with SAH. Moreover, our results add to the existing evidence with the potential to generate new research along the SAH's pathogenetic pathways such as diverse individual susceptibility to alcohol toxicity, host-specific mitochondrial function and systemic inflammation, and the role of gut dysbiosis thereof. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-024-00381-5.

• Klíčová slova
• Alcohol toxicity, Cost-efficacy, Dysbiosis, Fecal microbiota transplantation, Gut microbiota, Health policy, Individualized patient profile, Mitochondrial health, Multi-level diagnostics, Patient stratification, Phenotyping, Predictive preventive personalized medicine (PPPM / 3PM), Severe alcohol-associated hepatitis, Survival, Systemic inflammation, Tailored therapy,
• Publikační typ
• časopisecké články MeSH

The crucial physiological process of heme breakdown yields biliverdin (BV) and bilirubin (BR) as byproducts. BV, BR, and the enzymes involved in their production (the "yellow players-YP") are increasingly documented as endogenous modulators of human health. Mildly elevated serum bilirubin concentration has been correlated with a reduced risk of multiple chronic pro-oxidant and pro-inflammatory diseases, especially in the elderly. BR and BV per se have been demonstrated to protect against neurodegenerative diseases, in which heme oxygenase (HMOX), the main enzyme in the production of pigments, is almost always altered. HMOX upregulation has been interpreted as a tentative defense against the ongoing pathologic mechanisms. With the demonstration that multiple cells possess YP, their propensity to be modulated, and their broad spectrum of activity on multiple signaling pathways, the YP have assumed the role of an adjustable system that can promote health in adults. Based on that, there is an ongoing effort to induce their activity as a therapeutic option, and natural compounds are an attractive alternative to the goal, possibly requiring only minimal changes in the life style. We review the most recent evidence of the potential of natural compounds in targeting the YP in the context of the most common pathologic condition of adult and elderly life.

• Klíčová slova
• Alzheimer’s disease, MAFLD, NRF2, Parkinson’s disease, bilirubin, cancer, heme-oxygenase, herbal medicine, neurodegeneration, nutraceuticals,
• MeSH
• bilirubin MeSH
• biliverdin MeSH
• dospělí MeSH
• hem MeSH
• hemová oxygenasa (decyklizující) MeSH
• játra MeSH
• lidé MeSH
• nemoci mozku * MeSH
• podpora zdraví * MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• bilirubin MeSH
• biliverdin MeSH
• hem MeSH
• hemová oxygenasa (decyklizující) MeSH

Neonatal hyperbilirubinemia or jaundice is associated with kernicterus, resulting in permanent neurological damage or even death. Conventional phototherapy does not prevent hyperbilirubinemia or eliminate the need for exchange transfusion. Here we investigated the potential of therapeutic bile acids ursodeoxycholic acid (UDCA) and obeticholic acid (OCA, 6-α-ethyl-CDCA), a farnesoid-X-receptor (FXR) agonist, as preventive treatment options for neonatal hyperbilirubinemia using the hUGT1*1 humanized mice and Ugt1a-deficient Gunn rats. Treatment of hUGT1*1 mice with UDCA or OCA at postnatal days 10-14 effectively decreased bilirubin in plasma (by 82% and 62%) and brain (by 72% and 69%), respectively. Mechanistically, our findings indicate that these effects are mediated through induction of protein levels of hUGT1A1 in the intestine, but not in liver. We further demonstrate that in Ugt1a-deficient Gunn rats, UDCA but not OCA significantly decreases plasma bilirubin, indicating that at least some of the hypobilirubinemic effects of UDCA are independent of UGT1A1. Finally, using the synthetic, non-bile acid, FXR-agonist GW4064, we show that some of these effects are mediated through direct or indirect activation of FXR. Together, our study shows that therapeutic bile acids UDCA and OCA effectively reduce both plasma and brain bilirubin, highlighting their potential in the treatment of neonatal hyperbilirubinemia.

• MeSH
• bilirubin krev   MeSH
• ileum účinky léků   metabolismus   MeSH
• isoxazoly farmakologie   MeSH
• játra účinky léků   metabolismus   MeSH
• krysa rodu Rattus MeSH
• kyselina chenodeoxycholová analogy a deriváty   terapeutické užití   MeSH
• kyselina ursodeoxycholová terapeutické užití   MeSH
• myši MeSH
• novorozenecká hyperbilirubinemie krev   farmakoterapie   MeSH
• potkani Gunn MeSH
• receptory cytoplazmatické a nukleární agonisté   metabolismus   MeSH
• výsledek terapie MeSH
• žlučové kyseliny a soli terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bilirubin MeSH
• farnesoid X-activated receptor MeSH Prohlížeč
• GW 4064 MeSH Prohlížeč
• isoxazoly MeSH
• kyselina chenodeoxycholová MeSH
• kyselina ursodeoxycholová MeSH
• obeticholic acid MeSH Prohlížeč
• receptory cytoplazmatické a nukleární MeSH
• žlučové kyseliny a soli MeSH

Pigment gallstones, which are much less frequent than cholesterol stones, are classified descriptively as "black" or "brown". They are composed mostly of calcium hydrogen bilirubinate, Ca(HUCB)(2), which is polymerized and oxidized in "black" stones but remains unpolymerized in "brown" stones. Black stones form in sterile gallbladder bile but brown stones form secondary to stasis and anaerobic bacterial infection in any part of the biliary tree, including the gallbladder. Other calcium salts coprecipitate in both stone types; crystalline calcium phosphate and/or carbonate in the case of "black" stones and amorphous calcium salts of long chain saturated fatty acids ("soaps") in the case of "brown" stones. Cholesterol is present in variable proportions in "brown" more than "black" stones and in the latter, the bile sterol may be totally absent. The "scaffolding" of both stone types is a mixed mucin glycoprotein matrix secreted by epithelial cells lining the biliary tree. The critical pathophysiological prerequisite for "black" stone formation is "hyperbilirubinbilia" (biliary hypersecretion of bilirubin conjugates). It is due principally to hemolysis, ineffective erythropoiesis, or pathologic enterohepatic cycling of unconjugated bilirubin. Endogenous biliary β-glucuronidase hydrolysis of bilirubin conjugates in gallbladder bile provides HUCB(-) molecules that precipitate as insoluble salts with ionized Ca. Putatively, reactive oxygen species secreted by an inflamed gallbladder mucosa are responsible for transforming the initial soft yellow precipitates into hard black [Ca(HUCB)(2)](n) polymers. Despite "brown" gallstones being soft and amenable to mechanical removal, chronic anaerobic infection of the biliary tree is often markedly resistant to eradication.

• MeSH
• lidé MeSH
• žlučové kameny etiologie   patofyziologie   MeSH
• žlučové pigmenty MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• žlučové pigmenty MeSH