GUT MICROBIOTA IN PRIMARY SCLEROSING CHOLANGITIS: FROM PROGNOSTIC ROLE TO THERAPEUTIC IMPLICATIONS.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease of unknown etiology characterized by biliary inflammation and periductal fibrosis. The gut microbiota plays a crucial role in the pathogenesis of PSC by regulating bile acids metabolism, inflammation and immune response. On the other hand, liver disease progression affects the composition of the gut microbiota, fostering these mechanisms in a mutual detrimental way. SUMMARY: Recent evidences described a specific pro-inflammatory microbial signature in PSC patients, with an overall reduced bacterial diversity and the loss of beneficial metabolites such as short-chain fatty acids. As effective therapies for PSC are still lacking, targeting the gut microbiota offers a new perspective in the management of this disease. To date, antibiotics, fecal microbiota transplantation and probiotics are the most studied gut microbiota-targeted intervention in PSC, but new potential strategies such as vaccines and bacteriophages represent possible future therapeutic horizons. KEY MESSAGES: In this review, we focus on the role of the gut microbiota in PSC, considering its pathogenetic and prognostic role, and the therapeutic implications.

Corrigendum: PD-1/PD-L1 immune checkpoint therapy demonstrates favorable safety profile in patients with autoimmune and cholestatic liver disease.

[This corrects the article DOI: 10.3389/fimmu.2023.1326078.].

Functional hypothalamic amenorrhea: gut microbiota composition and the effects of exogenous estrogen administration.

Functional hypothalamic amenorrhea (FHA) is characterized by estrogen deficiency that significantly impacts metabolic, bone, cardiovascular, mental, and reproductive health. Given the importance of environmental factors such as stress and body composition, and particularly considering the importance of estrogens in regulating the gut microbiota, some changes in the intestinal microenvironment are expected when all of these factors occur simultaneously. We aimed to assess whether the gut microbiota composition is altered in FHA and to determine the potential impact of hormonal replacement therapy (HRT) on the gut microbiota. This prospective observational study included 33 patients aged 18-34 yr with FHA and 10 age-matched healthy control women. Clinical, hormonal, and metabolic evaluations were performed at baseline for the FHA group only, whereas gut microbiota profile was assessed by 16S rRNA gene amplicon sequencing for both groups. All measurements were repeated in patients with FHA after receiving HRT for 6 mo. Gut microbiota alpha diversity at baseline was significantly different between patients with FHA and healthy controls (P < 0.01). At the phylum level, the relative abundance of Fusobacteria was higher in patients with FHA after HRT (P < 0.01), as was that of Ruminococcus and Eubacterium at the genus level (P < 0.05), which correlated with a decrease in circulating proinflammatory cytokines. FHA is a multidimensional disorder that is interconnected with dysbiosis through various mechanisms, particularly involving the gut-brain axis. HRT appears to induce a favorable shift in the gut microbiota in patients with FHA, which is also associated with a reduction in the systemic inflammatory status.NEW & NOTEWORTHY Our study marks the first comprehensive analysis of gut microbiota composition in FHA and the impact of HRT on it, along with biochemical, anthropometric, and psychometric aspects. Our results indicate distinct gut microbiota composition in patients with FHA compared with healthy individuals. Importantly, HRT prompts a transition toward a more beneficial gut microbiota profile and reduced inflammation. This study validates the concept of FHA as a multifaceted disorder interlinked with dysbiosis, particularly involving the gut-brain axis.

PD-1/PD-L1 immune checkpoint therapy demonstrates favorable safety profile in patients with autoimmune and cholestatic liver disease.

Introduction: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many malignancies in recent years. However, immune-related adverse events (irAE) are a frequent concern in clinical practice. The safety profile of ICI for the treatment of malignancies in patients diagnosed with autoimmune and cholestatic liver disease (AILD) remains unclear. Due to this uncertainty, these patients were excluded from ICI clinical trials and ICI are withheld from this patient group. In this retrospective multicenter study, we assessed the safety of ICI in patients with AILD. Methods: We contacted tertiary referral hospitals for the identification of AILD patients under ICI treatment in Europe via the European Reference Network on Hepatological Diseases (ERN RARE-LIVER). Fourteen centers contributed data on AILD patients with malignancies being treated with ICI, another three centers did not treat these patients with ICI due to fear of irAEs. Results: In this study, 22 AILD patients under ICI treatment could be identified. Among these patients, 12 had primary biliary cholangitis (PBC), five had primary sclerosing cholangitis (PSC), four had autoimmune hepatitis (AIH), and one patient had an AIH-PSC variant syndrome. Eleven patients had hepatobiliary cancers and the other 11 patients presented with non-hepatic tumors. The applied ICIs were atezolizumab (n=7), durvalumab (n=5), pembrolizumab (n=4), nivolumab (n=4), spartalizumab (n=1), and in one case combined immunotherapy with nivolumab plus ipilimumab. Among eight patients who presented with grade 1 or 2 irAEs, three demonstrated liver irAEs. Cases with grades ≥ 3 irAEs were not reported. No significant changes in liver tests were observed during the first year after the start of ICI. Discussion: This European multicenter study demonstrates that PD-1/PD-L1 inhibitors appear to be safe in patients with AILD. Further studies on the safety of more potent dual immune checkpoint therapy are needed. We conclude that immunotherapy should not categorically be withheld from patients with AILD.

Nonalcoholic Fatty Liver Disease (NAFLD) as Model of Gut-Liver Axis Interaction: From Pathophysiology to Potential Target of Treatment for Personalized Therapy.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide, affecting both adults and children and will result, in the near future, as the leading cause of end-stage liver disease. Indeed, its prevalence is rapidly increasing, and NAFLD is becoming a major public health concern. For this reason, great efforts are needed to identify its pathogenetic factors and new therapeutic approaches. In the past decade, enormous advances understanding the gut-liver axis-the complex network of cross-talking between the gut, microbiome and liver through the portal circulation-have elucidated its role as one of the main actors in the pathogenesis of NAFLD. Indeed, evidence shows that gut microbiota is involved in the development and progression of liver steatosis, inflammation and fibrosis seen in the context of NAFLD, as well as in the process of hepatocarcinogenesis. As a result, gut microbiota is currently emerging as a non-invasive biomarker for the diagnosis of disease and for the assessment of its severity. Additionally, to its enormous diagnostic potential, gut microbiota is currently studied as a therapeutic target in NAFLD: several different approaches targeting the gut homeostasis such as antibiotics, prebiotics, probiotics, symbiotics, adsorbents, bariatric surgery and fecal microbiota transplantation are emerging as promising therapeutic options.

Characterization of the gut-liver-muscle axis in cirrhotic patients with sarcopenia.

BACKGROUND & AIM: Sarcopenia is frequent in cirrhosis and is associated with unfavourable outcomes. The role of the gut-liver-muscle axis in this setting has been poorly investigated. The aim of this study was to identify gut microbiota, metabolic and inflammatory signatures associated with sarcopenia in cirrhotic patients. METHODS: Fifty cirrhotic patients assessed for the presence of sarcopenia by the quantification of muscle mass and strength were compared with age- and sex-matched controls. A multiomic analysis, including gut microbiota composition and metabolomics, serum myokines and systemic and intestinal inflammatory mediators, was performed. RESULTS: The gut microbiota of sarcopenic cirrhotic patients was poor in bacteria associated with physical function (Methanobrevibacter, Prevotella and Akkermansia), and was enriched in Eggerthella, a gut microbial marker of frailty. The abundance of potentially pathogenic bacteria, such as Klebsiella, was also increased, to the detriment of autochthonous ones. Sarcopenia was associated with elevated serum levels of pro-inflammatory mediators and of fibroblast growth factor 21 (FGF21) in cirrhotic patients. Gut microbiota metabolic pathways involved in amino acid, protein and branched-chain amino acid metabolism were up-regulated, in addition to ethanol, trimethylamine and dimethylamine production. Correlation networks and clusters of variables associated with sarcopenia were identified, including one centred on Klebsiella/ethanol/FGF21/Eggerthella/Prevotella. CONCLUSIONS: Alterations in the gut-liver-muscle axis are associated with sarcopenia in patients with cirrhosis. Detrimental but also compensatory functions are involved in this complex network.

Acute intramucosal dissection in eosinophilic esophagitis.

Acute intramucosal dissection of the esophagus (IED) is a rare complication of eosinophilic esophagitis (EoE). Only few of such IED cases have been described in the literature. We report the case of a 32-year-old man with a 4-months diagnosis of EoE who was referred to the Emergency Department complaining of dysphagia, epigastric pain and fever and who was diagnosed, after an urgent endoscopy, an IED. After careful evaluation and multidisciplinary assessment the patient was managed conservatively, with specific medical therapy-high-dose proton pump inhibitors, swallowed steroid, broad-spectrum antibiotic-and, after a period of absolute fasting, a diet regimen based on "six food elimination diet" with a stepwise increase of food consistency. The patient experienced a rapid and complete relief of symptoms, paralleled by a progressive healing of IED with no recurrence over a 6-month follow-up period. In EoE patients with a high clinical suspicion of an acute IED, we suggest an early execution of chest CT and a contrast esophagography, avoiding potentially dangerous endoscopic procedures in the acute phase that can contribute to enlargement of the dissection, or progression to perforation. Once the diagnosis of IED is confirmed, even in the presence of a contained perforation, a conservative treatment with a multidisciplinary management should always be considered.