Microbiota-Gastric Cancer Interactions and the Potential Influence of Nutritional Therapies.

Gastric cancer (GC) is one of the most common causes of cancer deaths, and GC treatments represent a large area of research. Although initially regarded as a sterile organ and unsuitable for microbial communities, the discovery of Helicobacter pylori made us realize that some microbes can colonize the stomach. In recent years, growing interest in gastric bacteria has expanded to the gut microbiota and, more recently, to the oral microbiota. Indeed, the oral-gastric-gut microbiota axis may play a crucial role in maintaining homeostasis, while changes in microbiota composition in GC patients can influence clinical outcomes. On the one hand, the microbiota and its metabolites may significantly influence the progression of GC, while anti-GC treatments such as gastrectomy and chemotherapy may significantly impact the oral-gastric-gut microbiota axis of GC patients. In this context, the role of nutritional therapies, including diet, prebiotics, and probiotics, in treating GC should not be underestimated. Wit this review, we aim to highlight the main role of the gastric, oral, and gut microbiota in GC onset and progression, representing potential future biomarkers for early GC detection and a target for efficient nutritional therapies during the course of GC.

Liver Damage and COVID-19: At Least a "Two-Hit" Story in Systematic Review.

COVID-19 pandemic waves have hit on our lives with pulmonary and, also, gastrointestinal symptoms. The latter also includes acute liver damage linked to direct SARS-CoV-2 action and/or drug-induced (DILI) in the frame of pre-existing chronic liver disease. We aimed to review literature data regarding liver damage during COVID-19. We conducted a systematic search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials and case series using the following keywords and acronyms and their associations: liver disease, COVID-19, acute liver damage, drug-induced liver injury, antivirals. Acute liver damage due to SARS-CoV-2 infection is common among COVID-19 patients and is generally self-limiting. However, chronic hepatic diseases, such as metabolic-associated fatty liver disease (MAFLD), are associated with a less favorable prognosis, especially when alkaline phosphatases show a significant rise. Pathophysiology of COVID-19 liver damage is multifaceted and helps understand differences in liver derangement among patients. Thus, early recognition, monitoring and treatment of liver damage are crucial in these patients. In the frame of a not-ending pandemic sustained by SARS-CoV-2, it is crucial to recognize acute hepatic decompensation due to the virus and/or drugs used for COVID-19 treatment.

Ultrasound Prevalence and Clinical Features of Nonalcoholic Fatty Liver Disease in Patients with Inflammatory Bowel Diseases: A Real-Life Cross-Sectional Study.

Background and Objectives: Inflammatory bowel disease (IBD) is a condition characterized by chronic intestinal inflammation. We can identify two major forms: Crohn's disease (CD) and ulcerative colitis (UC). One of the extraintestinal manifestations of IBD is nonalcoholic fatty liver disease (NAFLD). IBD and NAFLD share common pathogenetic mechanisms. Ultrasound (US) examination is the most commonly used imaging method for the diagnosis of NAFLD. This cross-sectional observational retrospective study aimed to evaluate the US prevalence of NAFLD in IBD patients and their clinical features. Materials and Methods: A total of 143 patients with IBD underwent hepatic US and were divided into two different groups according to the presence or absence of NAFLD. Subsequently, new exclusion criteria for dysmetabolic comorbidities (defined as plus) were applied. Results: The US prevalence of NAFLD was 23% (21% in CD and 24% in UC, respectively). Most IBD-NAFLD patients were male and older and showed significantly higher values for body mass index, waist circumference, disease duration, and age at onset than those without NAFLD. IBD-NAFLD patients showed a significantly higher percentage of stenosing phenotype and left-side colitis. Regarding metabolic features, IBD-NAFLD patients showed a significantly higher percentage of hypertension and IBD plus dysmetabolic criteria. Also, higher values of alanine aminotransferase and triglycerides and lower levels of high-density lipoproteins are reported in these patients. Conclusions: We suggest performing liver US screening in subjects affected by IBD to detect NAFLD earlier. Also, patients with NAFLD present several metabolic comorbidities that would fall within the new definition of metabolic-associated fatty liver disease. Finally, we encourage larger longitudinal studies, including healthy controls, to provide further confirmation of our preliminary data.

Perspective on the Role of Gut Microbiome in the Treatment of Hepatocellular Carcinoma with Immune Checkpoint Inhibitors.

Background and Objectives: Hepatocellular carcinoma (HCC) is the leading cause of liver cancer worldwide and has a high mortality rate. Its incidence has increased due to metabolic-associated liver disease (MAFLD) epidemics. Liver transplantation and surgery remain the most resolute measures. Despite the optimistic use of multi-kinase inhibitors, namely sorafenib, the co-existence of chronic liver disease made the response rate low in these patients. Immune checkpoint inhibitors (ICIs) have become a promising hope for certain advanced solid tumors and, also, for advanced HCC. Unfortunately, a large cohort of patients with HCC fail to respond to immunotherapy. Materials and Methods: We conducted a narrative search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials, and case series using the following keywords and acronyms and their associations: hepatocellular carcinoma, immunotherapy, checkpoint inhibitors, gut microbiota, and fecal microbiota transplantation. Results: ICIs are a promising and sufficiently safe treatment option for HCC. In detail, they have significantly improved survival and prognosis in these patients vs. sorafenib. Although there are several highlighted mechanisms of resistance, the gut microbiota signature can be used both as a response biomarker and as an effect enhancer. Practically, probiotic dose-finding and fecal microbiota transplantation are the weapons that can be used to increase ICI's treatment-response-reducing resistance mechanisms. Conclusion: Immunotherapy has been a significant step-up in HCC treatment, and gut microbiota modulation is an effective liaison to increase its efficacy.

The Role of Transjugular Intrahepatic Portosystemic Shunt (TIPS) in Treating Portal Hypertension in Patients with Hepatocellular Carcinoma.

Liver cancer is very frequent, and hepatocellular carcinoma (HCC) accounts for the majority of liver cancer cases. Its growing incidence has been greatly affected by the increasing prevalence of metabolic-associated fatty liver disease (MAFLD). The latter is a new epidemic in our era. In fact, HCC is often generated from noncirrhotic liver and its treatment benefits from surgical and nonsurgical approaches, potentially bridged by transjugular intrahepatic portosystemic shunt (TIPS) use. TIPS use is an effective treatment for portal hypertension complications, but its application in patients with HCC and clinically significant portal hypertension (CSPH) remains controversial due to concerns about tumor rupture, dissemination, and increased toxicity. The technical feasibility and safety of TIPS use in HCC patients have been evaluated in several studies. Despite concerns about intraprocedural complications, retrospective studies have shown high success rates and low complication rates in TIPS placement for HCC patients. TIPS use in combination with locoregional treatments, such as transarterial chemoembolization (TACE) or transarterial radioembolization (TARE), has been explored as a treatment option for HCC patients with portal hypertension. These studies have shown improved survival rates in patients undergoing TIPS in combination with locoregional treatments. However, the efficacy and toxicity of TACE in combination with TIPS use require careful evaluation, as changes in venous and arterial flow can affect treatment outcomes and complications. The results from studies evaluating the impact of TIPS on systemic therapy and surgical options are also promising. In conclusion, the TIPS is a sufficiently safe, useful item available for physicians treating complications of portal hypertension. Moreover, a TIPS can be used in combination with locoregional therapy in HCC patients. Systemic chemotherapy can also benefit of the use of TIPS placement. A complex interplay affects TIPS use with surgery. The latter needs further data. The TIPS is a useful and safe add-on treatment, changing the natural course of HCC progression. Its use is regulated by a sophisticated physiologic and pathophysiologic flow of evidence.

Metabolic-Dysfunction-Associated Fatty Liver Disease and Gut Microbiota: From Fatty Liver to Dysmetabolic Syndrome.

Metabolic-dysfunction-associated fatty liver disease (MAFLD) is the recent nomenclature designation that associates the condition of non-alcoholic fatty liver disease (NAFLD) with metabolic dysfunction. Its diagnosis has been debated in the recent period and is generally associated with a diagnosis of steatosis and at least one pathologic condition among overweight/obesity, type 2 diabetes mellitus, and metabolic dysregulation. Its pathogenesis is defined by a "multiple-hit" model and is associated with alteration or dysbiosis of the gut microbiota. The pathogenic role of dysbiosis of the gut microbiota has been investigated in many diseases, including obesity, type 2 diabetes mellitus, and NAFLD. However, only a few works correlate it with MAFLD, although common pathogenetic links to these diseases are suspected. This review underlines the most recurrent changes in the gut microbiota of patients with MAFLD, while also evidencing possible pathogenetic links.

Current Status and Future Therapeutic Options for Fecal Microbiota Transplantation.

The intestinal microbiota plays an important role in maintaining human health, and its alteration is now associated with the development of various gastrointestinal (ulcerative colitis, irritable bowel syndrome, constipation, etc.) and extraintestinal diseases, such as cancer, metabolic syndrome, neuropsychiatric diseases. In this context, it is not surprising that gut microbiota modification methods may constitute a therapy whose potential has not yet been fully investigated. In this regard, the most interesting method is thought to be fecal microbiota transplantation, which consists of the simultaneous replacement of the intestinal microbiota of a sick recipient with fecal material from a healthy donor. This review summarizes the most interesting findings on the application of fecal microbiota transplantation in gastrointestinal and extraintestinal pathologies.

Fecal Microbiota Transplantation in NAFLD Treatment.

Introduction: Gut microbiota is not only a taxonomic biologic ecosystem but is also involved in human intestinal and extra-intestinal functions such as immune system modulation, nutrient absorption and digestion, as well as metabolism regulation. The latter is strictly linked to non-alcoholic fatty liver disease (NAFLD) pathophysiology. Materials and methods: We reviewed the literature on the definition of gut microbiota, the concepts of "dysbiosis" and "eubiosis", their role in NAFLD pathogenesis, and the data on fecal microbiota transplantation (FMT) in these patients. We consulted the main medical databases using the following keywords, acronyms, and their associations: gut microbiota, eubiosis, dysbiosis, bile acids, NAFLD, and FMT. Results: Gut microbiota qualitative and quantitative composition is different in healthy subjects vs. NALFD patients. This dysbiosis is associated with and involved in NAFLD pathogenesis and evolution to non-acoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma (HCC). In detail, microbial-driven metabolism of bile acids (BAs) and interaction with hepatic and intestinal farnesoid nuclear X receptor (FXR) have shown a determinant role in liver fat deposition and the development of fibrosis. Over the use of pre- or probiotics, FMT has shown preclinical and initial clinical promising results in NAFLD treatment through re-modulation of microbial dysbiosis. Conclusions: Promising clinical data support a larger investigation of gut microbiota dysbiosis reversion through FMT in NAFLD using randomized clinical trials to design precision-medicine treatments for these patients at different disease stages.

Nutrient Drinking Test as Biomarker in Functional Dyspepsia.

INTRODUCTION: Functional dyspepsia (FD) is a prevalent condition with multifactorial pathophysiology, including impaired gastric accommodation (GA), hypersensitivity to gastric distention, and delayed gastric emptying. Drink tests (DT) have been proposed as a potential biomarker for the presence and severity of gastric sensorimotor dysfunction. Thus, we aimed to summarize the state of knowledge on different DT and their potential as a biomarker for FD. METHODS: A PubMed and MEDLINE search was conducted for English language articles, reviews, meta-analyses, case series, and randomized controlled trials, including also published meeting abstracts. RESULTS: Several DT have been described in literature (e.g., different type of liquid, number of calories used, pace of drinking, and subject's awareness of the amount of liquid drunk). FD patients ingest significantly less volume in the different variants of the tests. The slow nutrient ("satiety drinking") test (SDT) studies show the most consistent separation between health and FD and correlation with GA. However, sensitivity to distention may be correlated with rapid DT. SDTs were used to evaluate the effect of several pharmacological agents, often showing concordance between their effects on GA and tolerated nutrient volume. This correlation was not found mainly for agents with central actions. DISCUSSION: An SDT is a potential diagnostic biomarker in FD, reflecting GA. Additional studies are required to confirm its role as a predictive biomarker for treatment outcome in FD.

Post-Coronavirus Disease 2019 Pandemic Antimicrobial Resistance.

BACKGROUND AND AIM: Antimicrobial resistance (AMR) is a chronic issue of our Westernized society, mainly because of the uncontrolled and improper use of antimicrobials. The coronavirus disease 2019 (COVID-19) pandemic has triggered and expanded AMR diffusion all over the world, and its clinical and therapeutic features have changed. Thus, we aimed to review evidence from the literature on the definition and causative agents of AMR in the frame of the COVID-19 post-pandemic era. METHODS: We conducted a search on PubMed and Medline for original articles, reviews, meta-analyses, and case series using the following keywords, their acronyms, and their associations: antibiotics, antimicrobial resistance, severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), COVID-19 pandemic, personal protective equipment. RESULTS: AMR had a significant rise in incidence both in in-hospital and outpatient populations (ranging from 5 up to 50%) worldwide, but with a variegated profile according to the germ and microorganism considered. Not only bacteria but also fungi have developed more frequent and diffuse AMR. These findings are explained by the increased use and misuse of antibiotics and preventive measures during the first waves of the SARS-CoV2 pandemic, especially in hospitalized patients. Subsequently, the reduction in and end of the lockdown and the use of personal protective equipment have allowed for the indiscriminate circulation of resistant microorganisms from low-income countries to the rest of the world with the emergence of new multi- and polyresistant organisms. However, there is not a clear association between COVID-19 and AMR changes in the post-pandemic period. CONCLUSIONS: AMR in some microorganisms has significantly increased and changed its characteristics during and after the end of the pandemic phase of COVID-19. An integrated supranational monitoring approach to this challenge is warranted in the years to come. In detail, a rational, personalized, and regulated use of antibiotics and antimicrobials is needed.

Nutrition and Disorders of Gut-Brain Interaction.

BACKGROUND: Disorders of gut-brain interaction (DGBIs) have a complex pathophysiology that is often characterized by a relationship between food ingestion and triggering of symptoms. Understanding of the underlying mechanisms and the role of nutrients as a therapeutic target are rapidly evolving. AIMS AND METHODS: We performed a narrative review of the literature using the following keywords, their acronyms, and their associations: nutrients, disorders of gut-brain interaction; functional dyspepsia; malabsorption; irritable bowel syndrome; diarrhea; constipation. RESULTS: Functional dyspepsia displayed a significant correlation between volume, fat and/or wheat abundance, chemical composition of ingested food and symptoms of early satiety, fullness and weight loss. Carbohydrate malabsorption is related to enzyme deficiency throughout the GI tract. Food composition and richness in soluble vs. non-soluble fibers is related to constipation and diarrhea. The elimination of fermentable oligo-, di-, monosaccharides and polyols (FODMAPs) has a significant and non-unidirectional impact on irritable bowel syndrome (IBS) symptoms. CONCLUSIONS: Food volume, nutritive and chemical composition, and its malabsorption are associated with symptom generation in DGBIs. Further multicenter, randomized-controlled clinical trials are needed to clarify the underlying pathophysiology.

Therapeutic success in primary biliary cholangitis and gut microbiota: a safe highway?

Primary biliary cholangitis (PBC) is a chronic, cholestatic, autoimmune disease, characterized by destruction of bile ducts. PBC predominantly affects women between 40 and 60 years of age. The presence of antimitochondrial antibodies (AMA) is a serological feature of PBC. These highly specific antibodies are found in about 95% of patients with the disease. The family of enzymes located in the inner membrane of the mitochondria, called the 2-oxo-acid dehydrogenase complex represents the target of the AMA. Ursodeoxycholic acid (UDCA) is a synthetic bile acid capable of protecting cholangiocytes from cholestatic damage caused by the accumulation of bile acids with a mechanism of action not yet well clarified. UDCA represents the gold standard therapy for PBC patients with recommended dose of 13-15 mg/kg/day. However, not every patient responds to therapy. On the other hand, the gut microbiota plays a key role in the onset of PBC through still unclear biochemical pathways. Less is known about its role as a potential biomarker after drug treatment. Actually, few studies analyzed the changes in gut microbiota composition before and after UDCA treatment. For this reason, this review represents an examination of the studies carried out on changes in gut microbiota composition in patients affected by PBC before and after treatment.

Gastrointestinal motility disorder assessment in systemic sclerosis.

OBJECTIVES: SSc is a clinically heterogeneous and generalized disease, characterized by thickness of the connective tissue of the skin and internal organs, such as the digestive tract, impairing gastrointestinal (GI) motility. Our aim is to evaluate retrospectively abnormalities of oesophageal motility, gastric emptying, oro-cecal transit time (OCTT) and small intestine bacterial overgrowth (SIBO) in a large cohort of SSc patients. METHODS: Ninety-nine SSc patients were included in the study. Forty-two patients underwent oesophageal conventional manometry, 45 performed a [(13)C]octanoic acid breath test to measure gastric emptying time and all 99 patients performed a lactulose breath test in order to evaluate OCTT and SIBO. Data were compared with healthy controls. RESULTS: In SSc patients, median lower oesophageal sphincter (LOS) pressure [14 mmHg (25th-75th; 8-19) vs 24 mmHg (19-28); P < 0.01] and median wave amplitude [30 mmHg (16-70) vs 72 mmHg (48-96); P < 0.01] were lower than in controls. Oesophageal involvement, defined as reduced LOS pressure and ineffective oesophageal motility pattern, was encountered in 70% of SSc patients. A delayed gastric emptying time was present in 38% of SSc patients: mean t½ was 141 ± 79 min vs 90 ± 40 min of controls (P < 0.01). Also, OCTT was significantly delayed in SSc: median OCTT was 160 min (25th-75th; 135-180) vs 105 min (25th-75th; 90-135) of controls (P < 0.01). SIBO was observed in 46% of SSc compared with 5% of controls (P < 0.01). CONCLUSION: GI involvement is very frequent in SSc patients. Oesophagus and small bowel are more frequently impaired, whereas delayed gastric emptying is less common.

Probiotics in non-alcoholic fatty liver disease: which and when.

Non-alcoholic fatty liver disease (NAFLD) is a common and serious disease. Literature reports the central role of the gut-liver axis in the pathogenesis of NAFLD, and recently suggests that the microbiota is a casual factor of the disease, involved in the interactions between intestinal lumen and liver. Probiotic are commensal bacteria, able to modulate the microbiota with benefits for the health of humans. Several data suggest a range of potentially beneficial medicinal uses for probiotics, in particular in NAFLD patients. However, the species with higher efficacy in this disease are not identified. The present review focuses on the role of gut-liver axis in the pathogenesis, and on the potential therapeutic role of probiotics in the managing of NAFLD.

Post-COVID-19 Gastro-Intestinal Disturbances.

BACKGROUND: Since the end of 2019, SARS-CoV-2 has been responsible for the multisystemic hyper-inflammatory disease, namely, COVID-19, as a majorly impactful pandemic. Gastrointestinal (GI) symptoms occurring during and after disease are gaining increasing attention among experts. METHODS: We briefly review and comment on preliminary and recent evidences on prevalence, pathophysiology, and perspective treatment options for GI disturbances during and after COVID-19. RESULTS: Several reports from the literature show a significant portion of COVID-19 patients suffering from GI symptoms both at the early stages of the disease and after the end of it, sometimes for several months, namely "long-COVID-19" patients, irrespective of vaccination. An unsolved issue regarding COVID-19 is the association between GI symptoms and the outcome of COVID-19 patients. Several studies and metanalyses suggest a worse evolution of COVID-19 in patients presenting with GI symptoms. However, these data have not been agreed. Indeed, only one uniform observation can be found in the literature: patients with chronic liver disease have a worse outcome from COVID-19 infection. Upper and lower GI symptoms have similarities with postinfectious functional dyspepsia (FD) and irritable bowel syndrome (IBS). FD and IBS following infection are recognize as pathophysiological factor the gut microbial, which is a gut microbial quali- and quantitative unbalance, namely dysbiosis. Furthermore, several preliminary reports and ongoing clinical trials have shown gut microbiota modulation by pre-, pro- and postbiotics to be effective in changing and preventing COVID-19 natural course. CONCLUSION: GI symptoms characterize both long- and non-long-COVID-19 with a potentially significant impact on its natural course. Gut microbiota modulation seems to be a sensible target for disease treatment and/or prevention.

Gut Microbiota According to the Metabolome.

The human gut microbiota is an ecosystem harboring trillions of microorganisms, encompassing bacteria, viruses, archaea, fungi, and protozoa [...].

Understanding and managing patients with overlapping disorders of gut-brain interaction.

Disorders of gut-brain interaction (DGBI) are frequently encountered in clinical practice, and recommendations for diagnosis and management are well established. In a large subset of patients, more than one DGBI diagnosis is present. This group of patients with more than one DGBI diagnosis have higher symptom severity and impact than patients with only one DGBI diagnosis, and the management approach is not well established for those with overlapping diagnoses. This Review aims to guide clinicians to understand, recognise, and manage overlapping DGBI by identifying causes and pitfalls of overlap conditions, and presenting potential practical approaches to diagnosis, treatment, and follow-up. Several clinical factors can contribute to finding overlapping DGBI, including the anatomical basis of the Rome diagnostic criteria, the potential confusion of symptom descriptors, and patients' biases towards higher symptom intensity ratings. Overlapping DGBI could also be caused by mechanistic factors such as pathophysiological mechanisms involving multiple gastrointestinal segments, and the effect of disorders in one segment on sensorimotor function in remote gastrointestinal parts, through neural or hormonal signalling. Key initial steps in the management of overlapping DGBI are detailed history taking, which can be facilitated using pictograms; carefully assessing the relative timing and cohesion of different symptoms; and recognising associated psychosocial dysfunction. Unnecessary technical investigations and complex combination treatment schedules should be avoided. Based on the identification of the dominant symptom pattern and putative underlying pathophysiological mechanisms, a single treatment modality should preferably be initiated, considering the efficacy spectrum of different therapies. Follow-up of the patient's condition allows the therapeutic approach to be adjusted as needed, while avoiding unnecessary additional technical investigations.

Human Genes Involved in the Interaction between Host and Gut Microbiome: Regulation and Pathogenic Mechanisms.

INTRODUCTION: The umbrella term "human gut microbiota" describes the complex ecosystem harboring our gut. It includes bacteria, viruses, protozoa, archaea, fungi, and yeasts. This taxonomic classification does not describe its functions, which encompass nutrients digestion and absorption, immune system regulation, and host metabolism. "Gut microbiome" indicates instead the genome belonging to these "microbes" actively involved in these functions. However, the interaction between the host genome and the microbial ones determines the fine functioning of our organism. METHODS: We reviewed the data available in the scientific literature on the definition of gut microbiota, gut microbiome, and the data on human genes involved in the interaction with the latter. We consulted the main medical databases using the following keywords, acronyms, and their associations: gut microbiota, gut microbiome, human genes, immune function, and metabolism. RESULTS: Candidate human genes encoding enzymes, inflammatory cytokines, and proteins show similarity with those included in the gut microbiome. These findings have become available through newer artificial intelligence (AI) algorithms allowing big data analysis. From an evolutionary point of view, these pieces of evidence explain the strict and sophisticated interaction at the basis of human metabolism and immunity regulation in humans. They unravel more and more physiopathologic pathways included in human health and disease. DISCUSSION: Several lines of evidence also obtained through big data analysis support the bi-directional role of gut microbiome and human genome in host metabolism and immune system regulation.