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Background Several randomised clinical trials (RCTs) performing faecal microbiota transplantation (FMT) for the management of inflammatory bowel disease (IBD), particularly for ulcerative colitis, have recently been published, but with major variations in study design. These include differences in administered dose, route and frequency of delivery, type of placebo and evaluated endpoints. Although the overall outcomes appear to be promising, they are highly dependent on both donor and recipient factors. Objective To develop concensus-based statements and recommendations for the evaluation, management and potential treatment of IBD using FMT in order to move towards standardised practices. Design An international panel of experts convened several times to generate evidence-based guidelines by performing a deep evaluation of currently available and/or published data. Twenty-five experts in IBD, immunology and microbiology collaborated in different working groups to provide statements on the following key issues related to FMT in IBD: (A) pathogenesis and rationale, (B) donor selection and biobanking, (C) FMT practices and (D) consideration of future studies and perspectives. Statements were evaluated and voted on by all members using an electronic Delphi process, culminating in a plenary consensus conference and generation of proposed guidelines. Results and conclusions Our group has provided specific statements and recommendations, based on best available evidence, with the end goal of providing guidance and general criteria required to promote FMT as a recognised strategy for the treatment of IBD.

Background: Combining immunosuppressors has been proposed as a strategy to enhance treatment efficacy in Inflammatory Bowel Disease (IBD). Aim: To summarize current evidence on combinations of targeted therapies with traditional immunosuppressors or with other targeted therapies. Methods: A literature search on PubMed and Medline databases was performed to identify relevant articles. Results: Current evidence supports that the combination of infliximab and thiopurines is more effective than monotherapy with both agents in inducing remission in Crohn's Disease and Ulcerative colitis. Data on other combinations of other biologics and traditional immunosuppressors is lacking or show conflicting results. Vedolizumab seems a potentially effective maintenance regimen after calcineurin inhibitors-based rescue therapy in acute severe ulcerative colitis, as an alternative to thiopurines. Dual Targeted Therapy, which is the combination of 2 targeted therapies, might be a reasonable choice in patients with concomitant IBD and extraintestinal manifestations, or in patients with medical-refractory IBD who lack valid alternatives. Combinations with thiopurines are associated with an increased risk of infections and lymphoma. Data on other combinations is scarcer, but no specific safety issue has emerged so far. Conclusions: Combination therapies seem to be effective in selected patients, with an overall acceptable safety profile.

Obesity is a major health issue throughout the world and bariatric surgery plays a key role in its management and treatment. The role of microbiota in determining the pathogenesis of obesity has been widely studied, while its role in determining the outcome of bariatric surgery is an emerging issue that will be an outcome in near future studies. Studies on mice first showed the key role of microbiota in determining obesity, highlighting the fat mass increase in mice transplanted with microbiota from fat individuals, as well as the different microbiota composition between mice undergone to low-fat or high-fat diets. This led to characterize the asset of microbiota composition in obesity: increased abundance of Firmicutes, reduced abundance of Bacteroidetes and other taxonomical features. Variations on the composition of gut microbiome have been detected in patients undergone to diet and/or bariatric surgery procedures. Patients undergone to restricting diets showed lower level of trimethylamine N-oxide and other metabolites strictly associated to microbiome, as well as patients treated with bariatric surgery showed, after the procedure, changes in the relative abundance of Bacteroidetes, Firmicutes and other phyla with a role in the pathogenesis of obesity. Eventually, studies have been led about the effects that the modification of microbiota could have on obesity itself, mainly focusing on elements like fecal microbiota transplantation and probiotics such as inulin. This series of studies and considerations represent the first step in order to select patients eligible to bariatric surgery and to predict their outcome.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a direct impact on the gastrointestinal system, as up to 50% of fecal samples from coronavirus disease 2019 (COVID-19) patients contain detectable viral RNA despite a negative rhino-pharyngeal swab. This finding, together with an intestinal expression of angiotensin conversion enzyme 2 protein, suggests a possible fecal-oral transmission for SARSCoV-2. Furthermore, gastrointestinal (GI) symptoms are common in COVID-19 patients including watery diarrhea, vomiting particularly in children nausea, and abdominal pain. Pathogenesis of SARS-CoV-2 infection presents significant similarities to those of some immune-mediated diseases, such as inflammatory bowel diseases or rheumatoid arthritis, leading to the hypothesis that targeted therapies used for the treatment of immune-mediated disease could be effective to treat (and possibly prevent) the main complications of COVID-19. In this review, we synthesize the present and future impact of SARS-CoV-2 infection on the gastrointestinal system and on gastroenterology practice, hypothesizing a potential role of the "gut-lung axis" and perhaps of the gut and lung microbiota into the interindividual differential susceptibility to COVID-19 19 disease. Finally, we speculate on the reorganization of outpatient gastroenterology services, which need to consider, among other factors, the major psychological impact of strict lockdown measures on the whole population.

Background & aims: Alcohol use disorder (AUD) represents the most common cause of liver disease. The gut microbiota plays a critical role in the progression of alcohol-related liver damage. Aim of this study was to characterize the gut microbial composition and function in AUD patients with alcohol-associated liver disease (AALD). Methods: This study included 36 AUD patients (14 with cirrhosis) who were active drinkers and an equal number of matched controls. Stool microbial composition, serum levels of lipopolysaccharide, cytokines/chemokines and gut microbiota functional profile were assessed. Results: AUD patients had a decreased microbial alpha diversity as compared to controls (0.092 vs 0.130, P =.047) and a specific gut microbial signature. The reduction of Akkermansia and the increase in Bacteroides were able to identify AUD patients with an accuracy of 93.4%. Serum levels of lipopolysaccharide (4.91 vs 2.43, P =.009) and pro-inflammatory mediators (tumour necrosis factor alpha 60.85 vs 15.08, P =.001; interleukin [IL] 1beta 4.43 vs 1.72, P =.0001; monocyte chemoattractant protein 1 225.22 vs 16.43, P =.006; IL6 1.87 vs 1.23, P =.008) were significantly increased in AUD patients compared to controls and in cirrhotic patients compared to non-cirrhotic ones (IL6 3.74 vs 1.39, P =.019; IL8 57.60 vs 6.53, P =.004). The AUD-associated gut microbiota showed an increased expression of gamma-aminobutyric acid (GABA) metabolic pathways and energy metabolism. Conclusions: AUD patients present a specific gut microbial fingerprint, associated with increased endotoxaemia, systemic inflammatory status and functional alterations that may be involved in the progression of the AALD and in the pathogenesis of AUD.

The gut microbiota is a well-known prognostic factor and a modulator of treatment sensitivity in patients with cancers treated with immune checkpoint inhibitors. However, data on hepatocellular carcinoma (HCC) are lacking. This study aimed to evaluate the prognostic role of the gut microbiota and changes produced by immunotherapy on the intestinal environment in patients with cirrhosis and HCC. Eleven patients treated with Tremelimumab and/or Durvalumab were included in the analysis. All study participants underwent gut microbiota profiling, quantification of fecal calprotectin, serum levels of zonulin-1, lipopolysaccharide binding protein (LBP), and programmed death-ligand 1 (PD-L1) at baseline and at each treatment cycle until the third cycle, then every three cycles until treatment discontinuation or last visit. The 6 patients who achieved disease control (DC) showed lower pretreatment fecal calprotectin (median, 12.5; interquartile range [IQR], 5-29 vs. median, 116; IQR, 59-129 µg/g; P = 0.047) and PD-L1 serum levels (median, 0.08; IQR, 0.07-0.09 vs. median, 1.04; IQR, 0.17-1.95 ng/mL; P = 0.02) than nonresponders. The relative abundance of Akkermansia (log2 fold change [FC], 2.72; adjusted P [Padj] = 0.012) was increased, whereas that of Enterobacteriaceae (log2 FC, −2.34; Padj = 0.04) was reduced in the DC group. During treatment, fecal calprotectin showed a temporal evolution opposite to the Akkermansia to Enterobacteriaceae ratio and gut microbiota alpha diversity, but similar to zonulin-1 and LBP. Bifidobacterium had a stable behavior in patients with a long follow-up, while Akkermansia was more variable. Akkermansia and Bifidobacterium showed similar temporal patterns and causative relationships with Prevotella, Veillonella, Ruminococcus, Roseburia, Lachnospira, Faecalibacterium, and Clostridium. Conclusion: A favorable composition of the gut microbiota and low intestinal inflammation are associated with ac

Background: Probiotics are defined as live, nonpathogenic bacteria that confer health benefits beyond their nutritional value. In particular, VSL#3 exhibits demonstrated efficacy in the management of diseases characterized by an increased intestinal permeability. Our study aimed to understand how VSL#3 promotes gut health by secreting bioactive factors and identify which human pathways are modulated by secretome derived from the VSL#3 formula. Methods: Two different lots of VSL#3 were used, and Caco-2 cell line was treated with conditioned media (CM) prepared using 1 g of the probiotic formula. We evaluated the effects of the probiotics on cellular proliferation and apoptosis by cytometry and the expression of tight junction proteins by western blotting. A proteomics analysis of both culture media and the whole proteome of Caco-2 cells treated with VSL#3-CM was performed by nano-ultra performance liquid chromatography - tandem mass (nUPLC MS/MS) spectrometry. Results: The probiotic formula increased cell proliferation, decreased cellular apoptosis cells, and increased re-epithelialization in the scratch assay. Several peptides specifically synthetized by all the species within the probiotic preparation were recognized in the proteomics analysis. Human proteins synthesized by CaCo-2 cells were also identified. Conclusions: To our knowledge, this manuscript describes the first evaluation of the probiotic secretome, and the results showed that the improvement in intestinal barrier functions induced by probiotics seems to be accompanied by the modulation of some human cellular pathways.

Research increasingly demonstrates the bidirectional communication between gut microbiota and the brain, enhancing the role of gut microbiota modulation in the treatment of central nervous system (CNS) disorders. The first five years of life are extremely important as it affects the development of gut microbiota, immune system and, consequently, the onset of psychometric alterations, particularly in genetically predisposed individuals. In this review, we focus on the link between specific microbial genera, gastrointestinal (GI) disorders, anxiety and depression and on the effects of different therapeutic strategies for mood disorders on gut microbiota.

Sarcopenia represents a major health burden in industrialized country by reducing substantially the quality of life. Indeed, it is characterized by a progressive and generalized loss of muscle mass and function, leading to an increased risk of adverse outcomes and hospitalizations. Several factors are involved in the pathogenesis of sarcopenia, such as aging, inflammation, mitochondrial dysfunction, and insulin resistance. Recently, it has been reported that more than one third of inflammatory bowel disease (IBD) patients suffered from sarcopenia. Notably, the role of gut microbiota (GM) in developing muscle failure in IBD patient is a matter of increasing interest. It has been hypothesized that gut dysbiosis, that typically characterizes IBD, might alter the immune response and host metabolism, promoting a low-grade inflammation status able to up-regulate several molecular pathways related to sarcopenia. Therefore, we aim to describe the basis of IBD-related sarcopenia and provide the rationale for new potential therapeutic targets that may regulate the gut-muscle axis in IBD patients.

Background: Combining immunosuppressors has been proposed as a strategy to enhance treatment efficacy in Inflammatory Bowel Disease (IBD). Aim: To summarize current evidence on combinations of targeted therapies with traditional immunosuppressors or with other targeted therapies. Methods: A literature search on PubMed and Medline databases was performed to identify relevant articles. Results: Current evidence supports that the combination of infliximab and thiopurines is more effective than monotherapy with both agents in inducing remission in Crohn's Disease and Ulcerative colitis. Data on other combinations of other biologics and traditional immunosuppressors is lacking or show conflicting results. Vedolizumab seems a potentially effective maintenance regimen after calcineurin inhibitors-based rescue therapy in acute severe ulcerative colitis, as an alternative to thiopurines. Dual Targeted Therapy, which is the combination of 2 targeted therapies, might be a reasonable choice in patients with concomitant IBD and extraintestinal manifestations, or in patients with medical-refractory IBD who lack valid alternatives. Combinations with thiopurines are associated with an increased risk of infections and lymphoma. Data on other combinations is scarcer, but no specific safety issue has emerged so far. Conclusions: Combination therapies seem to be effective in selected patients, with an overall acceptable safety profile.

Nutritional deficiencies are common in inflammatory bowel diseases (IBD). In patients, magnesium (Mg) deficiency is associated with disease severity, while in murine models, dietary Mg supplementation contributes to restoring mucosal function. Since Mg availability modulates key bacterial functions, including growth and virulence, we investigated whether the beneficial effects of Mg supplementation during colitis might be mediated by gut microbiota. The effects of dietary Mg modulation were assessed in a murine model of dextran sodium sulfate (DSS)-induced colitis by monitoring magnesemia, weight, and fecal consistency. Gut microbiota were analyzed by 16S-rRNA based profiling on fecal samples. Mg supplementation improved microbiota richness in colitic mice, increased abundance of Bifidobacterium and reduced Enterobacteriaceae. KEEG pathway analysis predicted an increase in biosynthetic metabolism, DNA repair and translation pathways during Mg supplementation and in the presence of colitis, while low Mg conditions favored catabolic processes. Thus, dietary Mg supplementation increases bacteria involved in intestinal health and metabolic homeostasis, and reduces bacteria involved in inflammation and associated with human diseases, such as IBD. These findings suggest that Mg supplementation may be a safe and cost-effective strategy to ameliorate disease symptoms and restore a beneficial intestinal flora in IBD patients.

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.

Compositional and functional alterations of the gut microbiota are involved in the pathogenesis of several gastrointestinal diseases. Rifaximin is often used to induce disease remission due to its eubiotic effects on the gut microbiota. To investigate the correlation between changes in the gut microbiota composition and symptoms improvement in patients who present a clinical response to rifaximin treatment. Patients with ulcerative colitis (UC), Crohn’s disease (CD), irritable bowel syndrome (IBS) and diverticular disease (DD) undergoing rifaximin treatment for clinical indication were enrolled in the study. Rifaximin was administered at the dose of 1,200 mg/day for 10 days. Faecal samples were collected at baseline and at the end of treatment; clinical improvement was assessed by Mayo score for UC, CD Activity Index (CDAI) for CD, IBS severity scoring system (IBS-SSS) for IBS and global symptomatic score (GSS) for DD. Twenty-five patients were included in the analysis and a clinical improvement was recorded for 10/25 (40%) of them. Microbial alpha diversity showed a slight increase in clinical responders (P=0.271), while it decreased in patients who did not improved (P=0.05). A significant post-treatment increase in Faecalibacterium abundance was observed in patients with a positive response (log2FC 1.959, P=0.042). Roseburia abundance decreased in both groups, whereas Ruminococcus decreased only in patients who clinically improved. Clinical improvement consequent to rifaximin treatment is associated with an increase in Faecalibacterium abundance. Achieving a positive shift in the gut microbiota composition seems a key event to obtain a clinical benefit from treatment.

Osteoarthritis (OA) is considered one of the most common joint disorders worldwide and its prevalence is constantly increasing due to the global longevity and changes in eating habits and lifestyle. In this context, the role of gut microbiota (GM) in the pathogenesis of OA is still unclear. Perturbation of GM biodiversity and function, defined as ‘gut dysbiosis’, might be involved in the development of inflammaging, one of the main risk factors of OA development. It is well known that physical exercise could play a key role in the prevention and treatment of several chronic diseases including OA, and it is recommended by several guidelines as a first line intervention. Several studies have shown that physical exercise could modulate GM composition, boosting intestinal mucosal immunity, increasing the Bacteroidetes–Firmicutes ratio, modifying the bile acid profile, and improving the production of short chain fatty acids. Moreover, it has been shown that low intensity exercise might reduce the risk of gastrointestinal diseases, confirming the hypothesis of a strict correlation between skeletal muscle and GM. However, up to date, there is still a lack of clinical trials focusing on this research field. Therefore, in this narrative, we aimed to summarize the state-of-the-art of the literature regarding the correlation between these conditions, supporting the hypothesis of a ‘gut–joint axis’ and highlighting the role of physical exercise combined with adequate diet and probiotic supplements in rebalancing microbial dysbiosis.

Objectives Cytokines play a pivotal role in inflammatory bowel disease (IBD). We investigated the expression of inflammatory and regulatory cytokines in inflamed and uninflamed mucosal samples of ulcerative colitis patients. Methods Twenty-five ulcerative colitis patients were enrolled. Bioptic samples from inflamed and not inflamed intestinal areas were obtained. Multiplex analysis for inflammatory and regulatory cytokines was performed. Serum C-reactive protein (CRP) was assessed. Endoscopic Mayo score and histological simplified Geboes score were calculated. Results Interleukin (IL)-1Ra, IL-6, IL-8, IL-17, induced Protein (IP)-10, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1a, MIP-1b resulted increased in ulcerative colitis inflamed vs ulcerative colitis not inflamed areas. No differences were registered between conventional and anti-tumor necrosis factor-a regimens. No difference with CRP levels was found. IL-7 resulted reduced in patients with endoscopic Mayo score ≥2. All the not inflamed samples had a Geboes score <2A, while all the inflamed specimens had a Geboes score ≥2B. IL-1Ra resulted increased in the group with a Geboes score ≥4. Conclusions Inflamed and adjacent not inflamed mucosal areas in ulcerative colitis patients share detailed inflammatory molecular pathways, but can be differentiated endoscopically and histologically on the basis of specific cytokines levels. This underlines the complexity of the mucosal cytokine network in ulcerative colitis and highlights the major limitations of a single proinflammatory target therapeutic strategy in IBD.

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