Extracranial Vascular Anomalies Driven by RAS/MAPK Variants: Spectrum and Genotype-Phenotype Correlations.

BACKGROUND: We aimed to correlate alterations in the rat sarcoma virus (RAS)/mitogen-activated protein kinase pathway in vascular anomalies to the clinical phenotype for improved patient and treatment stratification. METHODS AND RESULTS: This retrospective multicenter cohort study included 29 patients with extracranial vascular anomalies containing mosaic pathogenic variants (PVs) in genes of the RAS/mitogen-activated protein kinase pathway. Tissue samples were collected during invasive treatment or clinically indicated biopsies. PVs were detected by the targeted sequencing of panels of genes known to be associated with vascular anomalies, performed using DNA from affected tissue. Subgroup analyses were performed according to the affected genes with regard to phenotypic characteristics in a descriptive manner. Twenty-five vascular malformations, 3 vascular tumors, and 1 patient with both a vascular malformation and vascular tumor presented the following distribution of PVs in genes: Kirsten rat sarcoma viral oncogene (n=10), neuroblastoma ras viral oncogene homolog (n=1), Harvey rat sarcoma viral oncogene homolog (n=5), V-Raf murine sarcoma viral oncogene homolog B (n=8), and mitogen-activated protein kinase kinase 1 (n=5). Patients with RAS PVs had advanced disease stages according to the Schobinger classification (stage 3-4: RAS, 9/13 versus non-RAS, 3/11) and more frequent progression after treatment (RAS, 10/13 versus non-RAS, 2/11). Lesions with Kirsten rat sarcoma viral oncogene PVs infiltrated more tissue layers compared with the other PVs including other RAS PVs (multiple tissue layers: Kirsten rat sarcoma viral oncogene, 8/10 versus other PVs, 6/19). CONCLUSIONS: This comparison of patients with various PVs in genes of the RAS/MAPK pathway provides potential associations with certain morphological and clinical phenotypes. RAS variants were associated with more aggressive phenotypes, generating preliminary data and hypothesis for future larger studies.

Targeting the microenvironment in the treatment of arteriovenous malformations.

Extracranial arteriovenous malformations (AVMs) are regarded as rare diseases and are prone to complications such as pain, bleeding, relentless growth, and high volume of shunted blood. Due to the high vascular pressure endothelial cells of AVMs are exposed to mechanical stress. To control symptoms and lesion growth pharmacological treatment strategies are urgently needed in addition to surgery and interventional radiology. AVM cells were isolated from three patients and exposed to cyclic mechanical stretching for 24 h. Thalidomide and bevacizumab, both VEGF inhibitors, were tested for their ability to prevent the formation of circular networks and proliferation of CD31+ endothelial AVM cells. Furthermore, the effect of thalidomide and bevacizumab on stretched endothelial AVM cells was evaluated. In response to mechanical stress, VEGF gene and protein expression increased in patient AVM endothelial cells. Thalidomide and bevacizumab reduced endothelial AVM cell proliferation. Bevacizumab inhibited circular network formation of endothelial AVM cells and lowered VEGF gene and protein expression, even though the cells were exposed to mechanical stress. With promising in vitro results, bevacizumab was used to treat three patients with unresectable AVMs or to prevent regrowth after incomplete resection. Bevacizumab controlled bleeding, pulsation, and pain over the follow up of eight months with no patient-reported side effects. Overall, mechanical stress increases VEGF expression in the microenvironment of AVM cells. The monoclonal VEGF antibody bevacizumab alleviates this effect, prevents circular network formation and proliferation of AVM endothelial cells in vitro. The clinical application of bevacizumab in AVM treatment demonstrates effective symptom control with no side effects.

Tracheoesophageal Fistula Closure in a Pediatric Patient Using a Supraclavicular Artery Island Flap.

Acquired tracheoesophageal fistulas can lead to large defects with fatal complications. Surgical management is challenging but necessary to prevent respiratory infections and poor weight gain. Therefore, a reliable and pliable flap like the pedicled supraclavicular artery island flap with its wide arc of rotation and robust vascularization is needed for reconstruction. We highlight the surgical technique and postoperative measures in managing a tracheoesophageal fistula due to button battery ingestion in a 9-month-old boy with the supraclavicular artery island flap. In summary, the supraclavicular artery island flap is a safe and successful tool for closure of large acquired tracheoesophageal fistulas in pediatric patients.

Clinical Outcome and Quality of Life of Multimodal Treatment of Extracranial Arteriovenous Malformations: The APOLLON Study Protocol.

PURPOSE: Arteriovenous malformations (AVMs) as rare diseases are diagnostically and therapeutically challenging. Due to the limited evidence regarding treatment outcome, prospective data are needed on how different treatment regimens affect outcome. The aims of this prospective trial are to determine effectiveness, safety, and clinical outcome of multimodal treatment in patients with extracranial AVMs. MATERIALS AND METHODS: After clinical and magnetic resonance imaging (MRI)-based diagnosis and informed consent, 146 patients (> 4 years and < 70 years) undergoing multimodal therapy in tertiary care vascular anomalies centers will be included in this prospective observational trial. Treatment options include conservative management, medical therapy, minimally invasive image-guided procedures (embolization, sclerotherapy) and surgery as well as combinations of the latter. The primary outcome is the patient-reported QoL 6 months after completion of treatment using the short form-36 health survey version 2 (SF-36v2) and the corresponding short form-10 health survey (SF-10) for children. In addition, clinical presentation (physician-reported signs), MRI imaging (radiological assessment of devascularization), recurrence rate, and therapeutic safety will be analyzed. Further follow-up will be performed after 12, 24, and 36 months. Moreover, liquid biopsies are being obtained from peripheral blood at multiple time points to investigate potential biomarkers for therapy response and disease progression. DISCUSSION: The APOLLON trial is a prospective, multicenter, observational open-label trial with unequal study groups to generate prospective evidence for multimodal treatment of AVMs. A multicenter design with the potential to assess larger populations will provide an increased understanding of multimodal therapy outcome in this orphan disease. TRIAL REGISTRATION: German Clinical Trials Register (identification number: DRKS00021019) https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00021019 .

TIMolol Nasal Spray as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia (TIM-HHT)-A Prospective, Randomized, Double-Blind, Controlled, Cross-Over Trial.

To date, there is no approved local therapeutic agent for the treatment of epistaxis due to hereditary hemorrhagic telangiectasia (HHT). Several case reports suggest the topical use of timolol. This monocentric, prospective, randomized, placebo-controlled, double-blinded, cross-over study investigated whether the effectiveness of the standard treatment with a pulsed diode laser can be increased by also using timolol nasal spray. The primary outcome was severity of epistaxis after three months, while the main secondary outcome was severity of epistaxis and subjective satisfaction after one month. Twenty patients were allocated and treated, of which 18 patients completed both 3-month treatment sequences. Timolol was well tolerated by all patients. Epistaxis Severity Score after three months, the primary outcome measure, showed a beneficial, but statistically nonsignificant (p = 0.084), effect of additional timolol application. Epistaxis Severity Score (p = 0.010) and patients' satisfaction with their nosebleeds after one month (p = 0.050) showed statistically significant benefits. This placebo-controlled, randomized trial provides some evidence that timolol nasal spray positively impacts epistaxis severity and subjective satisfaction in HHT patients when additively applied to standard laser therapy after one month. However, the effect of timolol was observed to diminish over time. Trials with larger sample sizes are warranted to confirm these findings.

HHT-Related Epistaxis and Pregnancy-A Retrospective Survey and Recommendations for Management from an Otorhinolaryngology Perspective.

Appropriate management of hereditary hemorrhagic telangiectasia (HHT) is of particular importance in females, as HHT-mediated modifications of the vascular bed and circulation are known to increase the risk of complications during pregnancy and delivery. This study was undertaken to evaluate female HHT patients' awareness of and experience with HHT during pregnancy and delivery, with a focus on epistaxis. In this retrospective study, 46 females (median age: 60 years) with confirmed HHT completed a 17-item questionnaire assessing knowledge of HHT and its pregnancy-associated complications, the severity of epistaxis during past pregnancies and deliveries, and the desire for better education and counselling regarding HHT and pregnancy. Results revealed that 85% of participants were unaware of their disease status prior to the completion of all pregnancies. Further, 91% reported no knowledge of increased pregnancy-related risk due to HHT. In regard to epistaxis, 61% of respondents reported experiencing nosebleeds during pregnancy. Finally, approximately a third of respondents suggested that receiving counseling on the risks of HHT in pregnancy could have been helpful. Findings suggest that awareness of HHT and its potential for increasing pregnancy-related risk is poor. Best practices in HHT management should be followed to minimize negative effects of the disorder.

A third hand to the surgeon: the use of an endoscope holding arm in endonasal sinus surgery and well beyond.

BACKGROUND: Extended endoscopic endonasal operations of the sinuses and the frontal skull base require a bimanual action of the surgeon in many cases. Thus, typically an assistant guides the endoscope and centers the field of view. In this study, we investigate in which cases an endoscope holding arm can be used alternatively. MATERIALS AND METHODS: The electromagnetic system ENDOFIXexo was used in different surgical interventions of the paranasal sinuses and beyond questioning ergonomics and geometrical limitations. The realized degrees of freedom were documented, and a topography of possible applications compiled. RESULTS: The presented system is limited by the anatomy of the anterior ethmoid and dynamic working conditions in the sagittal direction. Especially in extended interventions in the posterior ethmoid, in which parts of the nasal septum have been resected and a static position of the endoscope is desired the surgeon can greatly benefit from the robotic arm. Moreover, through the high flexibility of the endoscopic arm surgeries of the pharynx and larynx were performed, questioning the current gold standard of microscope-assisted surgical procedures. CONCLUSION: Under the impression of an urging staff shortage and due to its unlimited patience, the ENDOFIXexo arm seems promising. Taking into account the complex anatomy and the limited access, we especially see a favorable field of application in the surgery of the pituitary gland and skull base tumors.

Management and Mid-Term Outcome After "Real SCIWORA" in Children and Adolescents.

STUDY DESIGN: Retrospective analysis. OBJECTIVE: The SCIWORA Syndrome (Spinal Cord Injury Without Radiographic Abnormalities) is a rare but potentially severe injury with a peak in childhood and adolescence. With a better understanding of injury patterns and advances in MRI, there is ongoing discussion regarding the "Real SCIWORA" syndrome, a clinical picture of neurologic deficits on clinical examination but absence of radiographic pathologies even on MRI. The purpose of this study was to evaluate mid-term clinical outcome and the psychological impact of the "Real SCIWORA." METHODS: In this retrospective analysis, we evaluated 32 patients treated for "Real SCIWORA" between 2007-2019. Inclusion criteria were: neurologic deficit after trauma, no other cerebral or skeletal injury and a lack of pathological findings in spinal MRI. All patients were followed until complete recovery from initial symptoms. 25/32 patients were re-evaluated after 6.9 years (1-14 years) using the Oswestry Disability Index, the Frankel Score, the EQ-5D score, and the Breslau Short Screening Scale for PTSD. RESULTS: Initial neurologic presentation ranged from Frankel Grade A-D. All patients recovered neurologically during 1-13 days to a Frankel Grade E. The analysis of HR-QoL revealed no difference between the cohort of SCIWORA patients and the German population norm, Oswestry Disability Index showed only minimal disabilities. 4/25 patients showed signs of PTSD. CONCLUSIONS: The "Real SCIWORA" syndrome is a diagnosis per exclusionem requiring a full spinal MRI to ensure exclusion of structural and potentially serious reasons of the neurologic impairment. Further clinical re-evaluation, psychological support seems to be essential. LEVEL OF EVIDENCE: IV-retrospective study.

Non-beta blocker enantiomers of propranolol and atenolol inhibit vasculogenesis in infantile hemangioma.

Propranolol and atenolol, current therapies for problematic infantile hemangioma (IH), are composed of R(+) and S(-) enantiomers: the R(+) enantiomer is largely devoid of beta blocker activity. We investigated the effect of R(+) enantiomers of propranolol and atenolol on the formation of IH-like blood vessels from hemangioma stem cells (HemSCs) in a murine xenograft model. Both R(+) enantiomers inhibited HemSC vessel formation in vivo. In vitro, similar to R(+) propranolol, both atenolol and its R(+) enantiomer inhibited HemSC to endothelial cell differentiation. As our previous work implicated the transcription factor sex-determining region Y (SRY) box transcription factor 18 (SOX18) in propranolol-mediated inhibition of HemSC to endothelial differentiation, we tested in parallel a known SOX18 small-molecule inhibitor (Sm4) and show that this compound inhibited HemSC vessel formation in vivo with efficacy similar to that seen with the R(+) enantiomers. We next examined how R(+) propranolol alters SOX18 transcriptional activity. Using a suite of biochemical, biophysical, and quantitative molecular imaging assays, we show that R(+) propranolol directly interfered with SOX18 target gene trans-activation, disrupted SOX18-chromatin binding dynamics, and reduced SOX18 dimer formation. We propose that the R(+) enantiomers of widely used beta blockers could be repurposed to increase the efficiency of current IH treatment and lower adverse associated side effects.

Hereditary Hemorrhagic Telangiectasia: Success of the Osler Calendar for Documentation of Treatment and Course of Disease.

Hereditary hemorrhagic telangiectasia (HHT; Rendu-Osler-Weber syndrome) affects the capillary and larger vessels, leading to arteriovenous shunts. Epistaxis is the main symptom impairing quality of life. The aim of the Osler Calendar is to offer information about the extent of the systemic disease and the current state of treatment. A care plan with information on the rare disease and self-treatment of epistaxis was created. Organ examinations and ongoing treatments were recorded. A questionnaire documents the treatment success, including patient satisfaction, frequency of hemorrhage and hemoglobin levels. The patients using the Osler Calendar for at least one year (n = 54) were surveyed. Eighty-five percent of patients (n = 46) used the calendar to gain information about HHT. Seventy-two percent (n = 39) used the Osler Calendar for instructions on the self-treatment of nosebleeds. The calendar increased patients' understanding for the need for organ screenings from 48% (n = 26) to 81% (n = 44). Seventy-nine percent (n = 43) of patients confirmed that the Osler Calendar documented their therapeutic process either well or very well. Fifty-two percent (n = 28) saw an improvement in the therapeutic process due to the documentation. The Osler Calendar records the individual intensity of the disease and facilitates the communication between attending physicians. It is a tool for specialists to review treatment strategies. Furthermore, the calendar enhances patients' comprehension of their condition.

Routine restaging after primary non-surgical treatment of laryngeal squamous cell carcinoma-a review.

PURPOSE: Treatment of patients with laryngeal squamous cell carcinoma with radiotherapy or chemoradiation is an established alternative to laryngeal surgery in many cases, but particularly for advanced tumors without cartilage invasion. Imaging modalities face the challenge of distinguishing between posttherapeutic changes and residual disease in the complex anatomic subsite of the larynx. Guidelines concerning restaging of head and neck squamous cell carcinomas (HNSCC) are presented by the National Comprehensive Cancer Network (NCCN) and other national guidelines, but clearly defined recommendations for routine restaging particularly for laryngeal cancer are lacking. METHODS: A systematic search was carried out in PubMed to identify studies evaluating routine restaging methods after primary non-surgical treatment of laryngeal squamous cell carcinoma from 2009 to 2020. RESULTS: Only three studies were deemed eligible, as they included at least ≥50% patients with laryngeal squamous cell carcinoma and evaluated imaging modalities to detect residual cancer. The small number of studies in our review suggest restaging with fluoro-deoxy-glucose positron-emission tomography/computed tomography (FDG PET/CT) 3 months after initial treatment, followed by direct laryngoscopy with biopsy of the lesions identified by FDG PET/CT. CONCLUSION: Studies evaluating restaging methods after organ-preserving non-surgical treatment of laryngeal carcinoma are limited. As radiotherapy (RT), chemoradiotherapy (CRT), systemic therapy followed by RT and radioimmunotherapy are established alternatives to surgical treatment, particularly in advanced laryngeal cancers, further studies are needed to assess and compare different imaging modalities (e.g. PET/CT, MRI, CT, ultrasound) and clinical diagnostic tools (e.g., video laryngoscopy, direct laryngoscopy) to offer patients safe and efficient restaging strategies. PET or PET/CT 3 months after initial treatment followed by direct laryngoscopy with biopsy of the identified lesions has the potential to reduce the number of unnecessary laryngoscopies.

[Diagnostic Criteria and Treatment of Hereditary Hemorrhagic Telangiectasia]. / Diagnostik und Behandlung der hereditären hämorrhagischen Teleangiektasie.

Hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu syndrome; Morbus Osler) represents a syndrome affecting capillary vessels, leading to arteriovenous shunting. With an average worldwide prevalence of 1:5.000-8.000 HHT is considered an orphan disease. Arteriovenous shunts involve predominantly the nasal mucosa, the intestine, lung, liver and central nervous system. Epistaxis is the primary and most bothersome complaint of patients with HHT. A multistage therapeutic concept includes nasal ointment, laser therapy under local anesthesia and surgery under general anesthesia, as well as drug therapies. In addition, screening to determine affection of internal organs is carried out. Lesions that require therapy should be treated in an interdisciplinary setting. Treatment of lesions of the skin, oral and gastrointestinal mucosa and liver is carried out in regard to patients' symptoms, whereas vascular malformations of the lung and brain might need treatment without being symptomatic, due to possible life-threatening complications.

Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice.

Alcoholic liver disease (ALD) is associated with changes in the intestinal microbiota. Functional consequences of alcohol-associated dysbiosis are largely unknown. The aim of this study was to identify a mechanism of how changes in the intestinal microbiota contribute to ALD. Metagenomic sequencing of intestinal contents demonstrated that chronic ethanol feeding in mice is associated with an over-representation of bacterial genomic DNA encoding choloylglycine hydrolase, which deconjugates bile acids in the intestine. Bile acid analysis confirmed an increased amount of unconjugated bile acids in the small intestine after ethanol administration. Mediated by a lower farnesoid X receptor (FXR) activity in enterocytes, lower fibroblast growth factor (FGF)-15 protein secretion was associated with increased hepatic cytochrome P450 enzyme (Cyp)-7a1 protein expression and circulating bile acid levels. Depletion of the commensal microbiota with nonabsorbable antibiotics attenuated hepatic Cyp7a1 expression and reduced ALD in mice, suggesting that increased bile acid synthesis is dependent on gut bacteria. To restore intestinal FXR activity, we used a pharmacological intervention with the intestine-restricted FXR agonist fexaramine, which protected mice from ethanol-induced liver injury. Whereas bile acid metabolism was only minimally altered, fexaramine treatment stabilized the gut barrier and significantly modulated hepatic genes involved in lipid metabolism. To link the beneficial metabolic effect to FGF15, a nontumorigenic FGF19 variant-a human FGF15 ortholog-was overexpressed in mice using adeno-associated viruses. FGF19 treatment showed similarly beneficial metabolic effects and ameliorated alcoholic steatohepatitis. CONCLUSION: Taken together, alcohol-associated metagenomic changes result in alterations of bile acid profiles. Targeted interventions improve bile acid-FXR-FGF15 signaling by modulation of hepatic Cyp7a1 and lipid metabolism, and reduce ethanol-induced liver disease in mice. (Hepatology 2018;67:2150-2166).

IRAK-M Expression in Tumor Cells Supports Colorectal Cancer Progression through Reduction of Antimicrobial Defense and Stabilization of STAT3.

Colorectal cancer (CRC) is associated with loss of epithelial barrier integrity, which facilitates the interaction of the immunological microenvironment with the luminal microbiome, eliciting tumor-supportive inflammation. An important regulator of intestinal inflammatory responses is IRAK-M, a negative regulator of TLR signaling. Here we investigate the compartment-specific impact of IRAK-M on colorectal carcinogenesis using a mouse model. We demonstrate that IRAK-M is expressed in tumor cells due to combined TLR and Wnt activation. Tumor cell-intrinsic IRAK-M is responsible for regulation of microbial colonization of tumors and STAT3 protein stability in tumor cells, leading to tumor cell proliferation. IRAK-M expression in human CRCs is associated with poor prognosis. These results suggest that IRAK-M may be a potential therapeutic target for CRC treatment.

Deficiency of intestinal mucin-2 protects mice from diet-induced fatty liver disease and obesity.

Nonalcoholic fatty liver disease (NAFLD) and obesity are characterized by altered gut microbiota, inflammation, and gut barrier dysfunction. Here, we investigated the role of mucin-2 (Muc2) as the major component of the intestinal mucus layer in the development of fatty liver disease and obesity. We studied experimental fatty liver disease and obesity induced by feeding wild-type and Muc2-knockout mice a high-fat diet (HFD) for 16 wk. Muc2 deficiency protected mice from HFD-induced fatty liver disease and obesity. Compared with wild-type mice, after a 16-wk HFD, Muc2-knockout mice exhibited better glucose homeostasis, reduced inflammation, and upregulated expression of genes involved in lipolysis and fatty acid ß-oxidation in white adipose tissue. Compared with wild-type mice that were fed the HFD as well, Muc2-knockout mice also displayed higher intestinal and plasma levels of IL-22 and higher intestinal levels of the IL-22 target genes Reg3b and Reg3g. Our findings indicate that absence of the intestinal mucus layer activates the mucosal immune system. Higher IL-22 levels protect mice from diet-induced features of the metabolic syndrome.

Peritoneal carcinomatosis of colorectal cancer is characterized by structural and functional reorganization of the tumor microenvironment inducing senescence and proliferation arrest in cancer cells.

Background : Peritoneal carcinomatosis (PC) is a terminal evolution from primary colorectal cancer (pCRC) associated with poor patient survival. Impact of the immune cell infiltrate on PC pathogenesis is unknown. Therefore, we characterized the immunological tumor microenvironment regarding proliferation, senescence and neovascularization. Methods : Formalin-fixed and paraffin-embedded (FFPE) tissue of PC and pCRC was examined by immunohistochemistry. Cells infiltrating resected tissue were isolated and analyzed by flow cytometry. PCR arrays detected the expression of genes relevant for helper T (TH) cell responses, like TH1, TH2 and TH17 response. Results : PC tumor cells demonstrate significantly lower proliferation rates than pCRC, but show significantly more senescence. PC is surrounded by significantly increased numbers of cytotoxic active Natural Killer (NK) cells, follicular helper T cells (TFH) and B cells, whereas pCRC shows more CD4+ TH cells, CD8+ cytotoxic T (TC) cells, eosinophilic granulocytes, TH17 and regulatory T (Treg) cells. PC is characterized by significantly increased interferon-γ (IFNγ), an upregulation of tumor necrosis factor (TNF) and the NK cell-regulating cytokine interleukin-15 (IL-15). An upregulation of angiogenesis-related genes, like vascular endothelial growth factor-A (VEGF-A), leads to severe neovascularization in PC. Correlations of PC results reveal that elevated numbers of interleukin-17 (IL-17) positive cells are associated with high cancer cell proliferation, whereas high numbers of IFNγ positive cells correlate with more tumor cells in senescence. Conclusion : The cellular immune reaction is modified during metastasis, inducing senescence in PC tumor cells. Immune surveillance in PC is facilitated by NK cells and high levels of IFNγ and TNF. Counteracting this effect, TFH and B cells combined with VEGF-A enhancement promote neovascularization in PC (Illustration 1). During metastasis from primary CRC to PC the immune cell infiltrate changes, accompanied by the induction of senescence in PC cancer cells (marked red): In pCRC, the antitumor immune response is facilitated by CD4+TH cells, CD8+TC cells and PRG2+ eosinophilic granulocytes. The premetastatic niche development is promoted by Treg cells and TH17 cells producing systemic factors like VEGF-A, TGF-ß and TNF. Along with TFH and B cells, as with a pro-tumor immune response, they support metastatic formation and lead to severe neovascularization in PC. This is counterbalanced by the IL-15-induced activation and proliferation of NK cells. The secreted cytokines IFNγ and TNF mediate immunosurveillance.

Alcoholic liver disease: the gut microbiome and liver cross talk.

Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. Alcoholic fatty liver disease can progress to steatohepatitis, alcoholic hepatitis, fibrosis, and cirrhosis. Patients with alcohol abuse show quantitative and qualitative changes in the composition of the intestinal microbiome. Furthermore, patients with ALD have increased intestinal permeability and elevated systemic levels of gut-derived microbial products. Maintaining eubiosis, stabilizing the mucosal gut barrier, or preventing cellular responses to microbial products protect from experimental ALD. Therefore, intestinal dysbiosis and pathological bacterial translocation appear fundamental for the pathogenesis of ALD. This review highlights causes for intestinal dysbiosis and pathological bacterial translocation, their relationship, and consequences for ALD. We also discuss how the liver affects the intestinal microbiota.