Gut microbes in metabolic disturbances. Promising role for therapeutic manipulations?

The prevalence of overweight, obesity, type 2 diabetes, metabolic syndrome and steatotic liver disease is rapidly increasing worldwide with a huge economic burden in terms of morbidity and mortality. Several genetic and environmental factors are involved in the onset and development of metabolic disorders and related complications. A critical role also exists for the gut microbiota, a complex polymicrobial ecology at the interface of the internal and external environment. The gut microbiota contributes to food digestion and transformation, caloric intake, and immune response of the host, keeping the homeostatic control in health. Mechanisms of disease include enhanced energy extraction from the non-digestible dietary carbohydrates, increased gut permeability and translocation of bacterial metabolites which activate a chronic low-grade systemic inflammation and insulin resistance, as precursors of tangible metabolic disorders involving glucose and lipid homeostasis. The ultimate causative role of gut microbiota in this respect remains to be elucidated, as well as the therapeutic value of manipulating the gut microbiota by diet, pre- and pro- synbiotics, or fecal microbial transplantation.

Metabolic dysfunction-associated gallstone disease: expecting more from critical care manifestations.

About 20% of adults worldwide have gallstones which are solid conglomerates in the biliary tree made of cholesterol monohydrate crystals, mucin, calcium bilirubinate, and protein aggregates. About 20% of gallstone patients will definitively develop gallstone disease, a condition which consists of gallstone-related symptoms and/or complications requiring medical therapy, endoscopic procedures, and/or cholecystectomy. Gallstones represent one of the most prevalent digestive disorders in Western countries and patients with gallstone disease are one of the largest categories admitted to European hospitals. About 80% of gallstones in Western countries are made of cholesterol due to disturbed cholesterol homeostasis which involves the liver, the gallbladder and the intestine on a genetic background. The incidence of cholesterol gallstones is dramatically increasing in parallel with the global epidemic of insulin resistance, type 2 diabetes, expansion of visceral adiposity, obesity, and metabolic syndrome. In this context, gallstones can be largely considered a metabolic dysfunction-associated gallstone disease, a condition prone to specific and systemic preventive measures. In this review we discuss the key pathogenic and clinical aspects of gallstones, as the main clinical consequences of metabolic dysfunction-associated disease.

Hepatokines, bile acids and ketone bodies are novel Hormones regulating energy homeostasis.

Current views show that an impaired balance partly explains the fat accumulation leading to obesity. Fetal malnutrition and early exposure to endocrine-disrupting compounds also contribute to obesity and impaired insulin secretion and/or sensitivity. The liver plays a major role in systemic glucose homeostasis through hepatokines secreted by hepatocytes. Hepatokines influence metabolism through autocrine, paracrine, and endocrine signaling and mediate the crosstalk between the liver, non-hepatic target tissues, and the brain. The liver also synthetizes bile acids (BAs) from cholesterol and secretes them into the bile. After food consumption, BAs mediate the digestion and absorption of fat-soluble vitamins and lipids in the duodenum. In recent studies, BAs act not simply as fat emulsifiers but represent endocrine molecules regulating key metabolic pathways. The liver is also the main site of the production of ketone bodies (KBs). In prolonged fasting, the brain utilizes KBs as an alternative to CHO. In the last few years, the ketogenic diet (KD) became a promising dietary intervention. Studies on subjects undergoing KD show that KBs are important mediators of inflammation and oxidative stress. The present review will focus on the role played by hepatokines, BAs, and KBs in obesity, and diabetes prevention and management and analyze the positive effects of BAs, KD, and hepatokine receptor analogs, which might justify their use as new therapeutic approaches for metabolic and aging-related diseases.

Ramadan intermittent fasting reduces visceral fat and improves gastrointestinal motility.

BACKGROUND: Ramadan is a model of intermittent fasting linked with possible beneficial effects. Scarce information, however, is available about the combined effects of Ramadan intermittent fasting (RIF) on anthropometric and metabolic indices, gastrointestinal symptoms, and motility. METHODS: In 21 healthy Muslims, we assessed the impact of RIF on caloric intake, physical activity, gastrointestinal symptoms and motility (gastric/gallbladder emptying by ultrasonography, orocaecal transit time by lactulose breath test), anthropometric indices, subcutaneous and visceral fat thickness (ultrasonography), glucose and lipid homeostasis. RESULTS: Mean caloric intake decreased from a median of 2069 kcal (range 1677-2641) before Ramadan to 1798 kcal (1289-3126) during Ramadan and increased again to 2000 kcal (1309-3485) after Ramadan. Although physical activity remained stable before, during, and after RIF, body weight, body mass index and waist circumference decreased in all subjects and in both genders, together with a significant decrease in subcutaneous and visceral fat thickness and insulin resistance. The postprandial gastric emptying speed was significantly faster after than before RIF. Fasting gallbladder volume was about 6% smaller after, than before Ramadan, with a stronger and faster postprandial gallbladder contraction. After RIF, lactulose breath test documented increased microbiota carbohydrate fermentation (postprandial H2 peak), and faster orocaecal transit time. RIF also significantly improved gastric fullness, epigastric pain and heartburn. CONCLUSIONS: RIF generates, in healthy subjects, multiple systemic beneficial effects in terms of fat burden, metabolic profile, gastrointestinal motility and symptoms. Further comprehensive studies should assess the potential beneficial effects of RIF in diseased people.

Contribution of the microbiome for better phenotyping of people living with obesity.

Obesity has reached epidemic proportion worldwide and in all ages. Available evidence points to a multifactorial pathogenesis involving gene predisposition and environmental factors. Gut microbiota plays a critical role as a major interface between external factors, i.e., diet, lifestyle, toxic chemicals, and internal mechanisms regulating energy and metabolic homeostasis, fat production and storage. A shift in microbiota composition is linked with overweight and obesity, with pathogenic mechanisms involving bacterial products and metabolites (mainly endocannabinoid-related mediators, short-chain fatty acids, bile acids, catabolites of tryptophan, lipopolysaccharides) and subsequent alterations in gut barrier, altered metabolic homeostasis, insulin resistance and chronic, low-grade inflammation. Although animal studies point to the links between an "obesogenic" microbiota and the development of different obesity phenotypes, the translational value of these results in humans is still limited by the heterogeneity among studies, the high variation of gut microbiota over time and the lack of robust longitudinal studies adequately considering inter-individual confounders. Nevertheless, available evidence underscores the existence of several genera predisposing to obesity or, conversely, to lean and metabolically health phenotype (e.g., Akkermansia muciniphila, species from genera Faecalibacterium, Alistipes, Roseburia). Further longitudinal studies using metagenomics, transcriptomics, proteomics, and metabolomics with exact characterization of confounders are needed in this field. Results must confirm that distinct genera and specific microbial-derived metabolites represent effective and precision interventions against overweight and obesity in the long-term.

Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling.

Bile acids (BA) are amphiphilic molecules synthesized in the liver (primary BA) starting from cholesterol. In the small intestine, BA act as strong detergents for emulsification, solubilization and absorption of dietary fat, cholesterol, and lipid-soluble vitamins. Primary BA escaping the active ileal re-absorption undergo the microbiota-dependent biotransformation to secondary BA in the colon, and passive diffusion into the portal vein towards the liver. BA also act as signaling molecules able to play a systemic role in a variety of metabolic functions, mainly through the activation of nuclear and membrane-associated receptors in the intestine, gallbladder, and liver. BA homeostasis is tightly controlled by a complex interplay with the nuclear receptor farnesoid X receptor (FXR), the enterokine hormone fibroblast growth factor 15 (FGF15) or the human ortholog FGF19 (FGF19). Circulating FGF19 to the FGFR4/ß-Klotho receptor causes smooth muscle relaxation and refilling of the gallbladder. In the liver the binding activates the FXR-small heterodimer partner (SHP) pathway. This step suppresses the unnecessary BA synthesis and promotes the continuous enterohepatic circulation of BAs. Besides BA homeostasis, the BA-FXR-FGF19 axis governs several metabolic processes, hepatic protein, and glycogen synthesis, without inducing lipogenesis. These pathways can be disrupted in cholestasis, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Thus, targeting FXR activity can represent a novel therapeutic approach for the prevention and the treatment of liver and metabolic diseases.

Novel insights into the pathogenic impact of diabetes on the gastrointestinal tract.

Type 2 and type 1 diabetes are common endocrine disorders with a progressively increasing incidence worldwide. These chronic, systemic diseases have multiorgan implications, and the whole gastrointestinal (GI) tract represents a frequent target in terms of symptom appearance and interdependent pathophysiological mechanisms. Metabolic alterations linked with diabetic complications, neuropathy and disrupted hormone homeostasis can lead to upper and/or lower GI symptoms in up to 75% of diabetic patients, with multifactorial involvement of the oesophagus, stomach, upper and lower intestine, and of the gallbladder. On the other hand, altered gastrointestinal motility and/or secretions are able to affect glucose and lipid homeostasis in the short and long term. Finally, diabetes has been linked with increased cancer risk at different levels of the GI tract. The presence of GI symptoms and a comprehensive assessment of GI function should be carefully considered in the management of diabetic patients to avoid further complications and to ameliorate the quality of life. Additionally, the presence of gastrointestinal dysfunction should be adequately managed to improve metabolic homeostasis, the efficacy of antidiabetic treatments and secondary prevention strategies.

Obesity II: Establishing causal links between chemical exposures and obesity.

Obesity is a multifactorial disease with both genetic and environmental components. The prevailing view is that obesity results from an imbalance between energy intake and expenditure caused by overeating and insufficient exercise. We describe another environmental element that can alter the balance between energy intake and energy expenditure: obesogens. Obesogens are a subset of environmental chemicals that act as endocrine disruptors affecting metabolic endpoints. The obesogen hypothesis posits that exposure to endocrine disruptors and other chemicals can alter the development and function of the adipose tissue, liver, pancreas, gastrointestinal tract, and brain, thus changing the set point for control of metabolism. Obesogens can determine how much food is needed to maintain homeostasis and thereby increase the susceptibility to obesity. The most sensitive time for obesogen action is in utero and early childhood, in part via epigenetic programming that can be transmitted to future generations. This review explores the evidence supporting the obesogen hypothesis and highlights knowledge gaps that have prevented widespread acceptance as a contributor to the obesity pandemic. Critically, the obesogen hypothesis changes the narrative from curing obesity to preventing obesity.

Helicobacter pylori Infection and Extragastric Diseases-A Focus on the Central Nervous System.

Helicobacter pylori (H. pylori) is most known to cause a wide spectrum of gastrointestinal impairments; however, an increasing number of studies indicates that H. pylori infection might be involved in numerous extragastric diseases such as neurological, dermatological, hematologic, ocular, cardiovascular, metabolic, hepatobiliary, or even allergic diseases. In this review, we focused on the nervous system and aimed to summarize the findings regarding H. pylori infection and its involvement in the induction/progression of neurological disorders. Neurological impairments induced by H. pylori infection are primarily due to impairments in the gut-brain axis (GBA) and to an altered gut microbiota facilitated by H. pylori colonization. Currently, regarding a potential relationship between Helicobacter infection and neurological disorders, most of the studies are mainly focused on H. pylori.

Protocols for Mitochondria as the Target of Pharmacological Therapy in the Context of Nonalcoholic Fatty Liver Disease (NAFLD).

Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent metabolic chronic liver diseases in developed countries and puts the populations at risk of progression to liver necro-inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Mitochondrial dysfunction is involved in the onset of NAFLD and contributes to the progression from NAFLD to nonalcoholic steatohepatitis (NASH). Thus, liver mitochondria could become the target for treatments for improving liver function in NAFLD patients. This chapter describes the most important steps used for potential therapeutic interventions in NAFLD patients, discusses current options gathered from both experimental and clinical evidence, and presents some novel options for potentially improving mitochondrial function in NAFLD.

Multiplying effects of COVID-19 lockdown on metabolic risk and fatty liver.

BACKGROUND: Social containment measures imposed in Europe during the lockdown to face COVID-19 pandemic can generate long-term potential threats for metabolic health. METHODS: A cohort of 494 non-COVID-19 subjects living in 21 EU countries were interviewed by an anonymous questionnaire exploring anthropometric and lifestyle changes during 1-month lockdown. A subgroup of 41 overweight/obese Italian subjects with previously diagnosed nonalcoholic fatty liver (NAFLD) joined the study following a 12-month follow-up period promoting weight loss by healthy lifestyle. RESULTS: During the lockdown, body weight increased in 55% of subjects (average 2.4 ± 0.9 kg). Weight change increased with age, but not baseline body mass index. Subjects living in Italy had greater weight gain than those living in other European Countries. Weight gain during the lockdown was highest in subjects reporting no physical activity, and low adherence to Mediterranean diet. In the NAFLD group, weight gain occurred in 70% of cases. Subjects reporting weight loss during lockdown had decreased fatty liver score at 3 months before the lockdown, as compared with 1 year before. CONCLUSIONS: Strict measures of social containment-even short-term-pave the way to the increased risk of metabolic abnormalities in the medium-long term. In this context, adherence to Mediterranean diet and regular physical activity play a protective role both in terms of weight gain and fatty liver development/progression, with implication for primary and secondary prevention. When adopting measures imposing social containment, intensive educational campaigns must increase public awareness about beneficial effects of healthy lifestyles.

Helicobacter pylori Virulence Factors-Mechanisms of Bacterial Pathogenicity in the Gastric Microenvironment.

Gastric cancer constitutes one of the most prevalent malignancies in both sexes; it is currently the fourth major cause of cancer-related deaths worldwide. The pathogenesis of gastric cancer is associated with the interaction between genetic and environmental factors, among which infection by Helicobacter pylori (H. pylori) is of major importance. The invasion, survival, colonization, and stimulation of further inflammation within the gastric mucosa are possible due to several evasive mechanisms induced by the virulence factors that are expressed by the bacterium. The knowledge concerning the mechanisms of H. pylori pathogenicity is crucial to ameliorate eradication strategies preventing the possible induction of carcinogenesis. This review highlights the current state of knowledge and the most recent findings regarding H. pylori virulence factors and their relationship with gastric premalignant lesions and further carcinogenesis.

Bile Acids and GPBAR-1: Dynamic Interaction Involving Genes, Environment and Gut Microbiome.

Bile acids (BA) are amphiphilic molecules synthesized in the liver from cholesterol. BA undergo continuous enterohepatic recycling through intestinal biotransformation by gut microbiome and reabsorption into the portal tract for uptake by hepatocytes. BA are detergent molecules aiding the digestion and absorption of dietary fat and fat-soluble vitamins, but also act as important signaling molecules via the nuclear receptor, farnesoid X receptor (FXR), and the membrane-associated G protein-coupled bile acid receptor 1 (GPBAR-1) in the distal intestine, liver and extra hepatic tissues. The hydrophilic-hydrophobic balance of the BA pool is finely regulated to prevent BA overload and liver injury. By contrast, hydrophilic BA can be hepatoprotective. The ultimate effects of BA-mediated activation of GPBAR-1 is poorly understood, but this receptor may play a role in protecting the remnant liver and in maintaining biliary homeostasis. In addition, GPBAR-1 acts on pathways involved in inflammation, biliary epithelial barrier permeability, BA pool hydrophobicity, and sinusoidal blood flow. Recent evidence suggests that environmental factors influence GPBAR-1 gene expression. Thus, targeting GPBAR-1 might improve liver protection, facilitating beneficial metabolic effects through primary prevention measures. Here, we discuss the complex pathways linked to BA effects, signaling properties of the GPBAR-1, mechanisms of liver damage, gene-environment interactions, and therapeutic aspects.

Liver Steatosis, Gut-Liver Axis, Microbiome and Environmental Factors. A Never-Ending Bidirectional Cross-Talk.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide and parallels comorbidities such as obesity, metabolic syndrome, dyslipidemia, and diabetes. Recent studies describe the presence of NAFLD in non-obese individuals, with mechanisms partially independent from excessive caloric intake. Increasing evidences, in particular, point towards a close interaction between dietary and environmental factors (including food contaminants), gut, blood flow, and liver metabolism, with pathways involving intestinal permeability, the composition of gut microbiota, bacterial products, immunity, local, and systemic inflammation. These factors play a critical role in the maintenance of intestinal, liver, and metabolic homeostasis. An anomalous or imbalanced gut microbial composition may favor an increased intestinal permeability, predisposing to portal translocation of microorganisms, microbial products, and cell wall components. These components form microbial-associated molecular patterns (MAMPs) or pathogen-associated molecular patterns (PAMPs), with potentials to interact in the intestine lamina propria enriched in immune cells, and in the liver at the level of the immune cells, i.e., Kupffer cells and stellate cells. The resulting inflammatory environment ultimately leads to liver fibrosis with potentials to progression towards necrotic and fibrotic changes, cirrhosis. and hepatocellular carcinoma. By contrast, measures able to modulate the composition of gut microbiota and to preserve gut vascular barrier might prevent or reverse NAFLD.

Preoperative and Intraoperative Methods of Parathyroid Gland Localization and the Diagnosis of Parathyroid Adenomas.

Accurate pre-operative determination of parathyroid glands localization is critical in the selection of minimally invasive parathyroidectomy as a surgical treatment approach in patients with primary hyperparathyroidism (PHPT). Its importance cannot be overemphasized as it helps to minimize the harmful side effects associated with damage to the parathyroid glands such as in hypocalcemia, severe hemorrhage or recurrent laryngeal nerve dysfunction. Preoperative and intraoperative methods decrease the incidence of mistakenly injuring the parathyroid glands and allow for the timely diagnosis of various abnormalities, including parathyroid adenomas. This article reviews 139 studies conducted between 1970 and 2020 (49 years). Studies that were reviewed focused on several techniques including application of carbon nanoparticles, carbon nanoparticles with technetium sestamibi (99m Tc-MIBI), Raman spectroscopy, near-infrared autofluorescence, dynamic optical contrast imaging, laser speckle contrast imaging, shear wave elastography, and indocyanine green to test their potential in providing proper parathyroid glands' localization. Apart from reviewing the aforementioned techniques, this study focused on the applications that helped in the detection of parathyroid adenomas. Results suggest that applying all the reviewed techniques significantly improves the possibility of providing proper localization of parathyroid glands, and the application of indocyanine green has proven to be the 'ideal' approach for the diagnosis of parathyroid adenomas.

Aging and nutrition. Paving the way to better health.

Sufficient caloric intake is important to maintain the balanced health status, especially during the period of aging, as aging and sickness share paths. Maintaining adequate nutritional balance is the best preventive measure to counteract the risk of malnutrition. There are several causes for malnutrition in elderly people, and some techniques such as anthropometric measurements, laboratory and clinical parameters could help to diagnose malnutrition in these patients. The use of a simple validated questionnaire called the 'Mini Nutritional Assessment' measures the nutritional status of elderly patients. In this review, we discuss about the malnutrition in elderly people with and without a known cause and we present some of nutritional intervention. There are promising strategies that help overcoming malnutrition.

Physical Activity Modulating Lipid Metabolism in Gallbladder Diseases.

Physical activity encompasses a series of overall benefits on cardiovascular health and metabolic disorders. Research has recently focused on the hepatobiliary tract, as an additional target of the health-related outcomes of different types of physical exercise. Here, we focus on the global features of physical activity with respect to exercise modality and intensity, and on studies linking physical activity to lipid metabolism, gallbladder diseases (gallstones, symptoms, complications and health-related quality of life), gallbladder motor-function, enterohepatic circulation of bile acids, and systemic metabolic inflammation. Additional studies need to unravel the pathophysiological mechanisms involved in both beneficial and harmful effects of physical activity in populations with different metabolic conditions.

Exercise and apulian hypocaloric diet affect adipokine changes and gastric banding-induced weight loss: A prospective study on severe obese subjects.

BACKGROUND: Adiponectin and Resistin correlate with insulin sensitivity and cardiovascular risk, respectively. This study aimed to identify lifestyle factors that modulate changes in Adiponectin and Resistin levels after gastric banding positioning (LapGB). MATERIALS AND METHODS: Before (T0), 3 months (T3), 6 months (T6), and 12 months (T12) after LapGB, serum Adiponectin and Resistin levels were evaluated in a single-centre prospective study including a cohort of 27 non-diabetic obese subjects (S-Ob, BMI ≥35 kg/m2). After surgery, a dietitian checked the adherence of S-Ob to an Apulian hypocaloric diet (aphypoD)/physical activity (phA) and, according to their high or low compliance to aphypoD/phA, S-Ob were included in group 1 (n = 14) or 2 (n = 13) respectively. Serum Adiponectin and Resistin were also measured in 10 healthy controls. RESULTS: At baseline, Resistin levels were significantly higher and Adiponectin levels significantly lower in S-Ob than in controls. After surgery, group 1 showed a 50.2% excess weight loss (%EWL), significantly decreased Resistin levels at T12 and increased Adiponectin levels at both T6 and T12 as compared with baseline. Group 2 showed 24.6 %EWL at T12, decreased Adiponectin levels at T6 and T12 as compared with baseline, but unaltered Resistin levels. After surgery, group 1 followed aphypoD/phA, while group 2 did not. CONCLUSIONS: LapGB fails to improve cardiovascular risk markers (Resistin) in S-Ob not improving lifestyle. Future studies might investigate these findings in a larger cohort and display whether aphypoD is more effective than other dietary intervention on cardiovascular risk in subjects undergoing LapGB or other Bariatric procedures.

Increased Colonic Permeability and Lifestyles as Contributing Factors to Obesity and Liver Steatosis.

Intestinal permeability (IP) is essential in maintaining gut-metabolic functions in health. An unequivocal evaluation of IP, as marker of intestinal barrier integrity, however, is missing in health and in several diseases. We aimed to assess IP in the whole gastrointestinal tract according to body mass index (BMI) and liver steatosis. In 120 patients (61F:59M; mean age 45 ± SEM 1.2 years, range: 18-75), IP was distinctively studied by urine recovery of orally administered sucrose (SO, stomach), lactulose/mannitol ratio (LA/MA, small intestine), and sucralose (SA, colon). By triple quadrupole mass-spectrometry and high-performance liquid chromatography, we measured urinary recovery of saccharide probes. Subjects were stratified according to BMI as normal weight, overweight, and obesity, and answered questionnaires regarding dietary habits and adherence to the Mediterranean Diet. Liver steatosis was assessed by ultrasonography. IP at every gastrointestinal tract was similar in both sexes and decreased with age. Stomach and small intestinal permeability did not differ according to BMI. Colonic permeability increased with BMI, waist, neck, and hip circumferences and was significantly higher in obese than in lean subjects. As determined by logistic regression, the odds ratio (OR) of BMI increment was significantly higher in subjects in the highest tertile of sucralose excretion, also after adjusting for age and consumption of junk food. The presence of liver steatosis was associated with increased colonic permeability. Patients with lower score of adherence to Mediterranean diet had a higher score of 'junk food'. Intestinal permeability tended to increase in subjects with a lower adherence to Mediterranean diet. In conclusion, colonic (but not stomach and small intestinal) permeability seems to be linked to obesity and liver steatosis independently from dietary habits, age, and physical activity. The exact role of these last factors, however, requires specific studies focusing on intestinal permeability. Results should pave the way to both primary prevention measures and new therapeutic strategies in metabolic and liver diseases.