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Gut microbiota encompasses a wide variety of commensal microorganisms consisting of trillions of bacteria, fungi, and viruses. This microbial population coexists in symbiosis with the host, and related metabolites have profound effects on human health. In this respect, gut microbiota plays a pivotal role in the regulation of metabolic, endocrine, and immune functions. Bacterial metabolites include the short chain fatty acids (SCFAs) acetate (C2), propionate (C3), and butyrate (C4), which are the most abundant SCFAs in the human body and the most abundant anions in the colon. SCFAs are made from fermentation of dietary fiber and resistant starch in the gut. They modulate several metabolic pathways and are involved in obesity, insulin resistance, and type 2 diabetes. Thus, diet might influence gut microbiota composition and activity, SCFAs production, and metabolic effects. In this narrative review, we discuss the relevant research focusing on the relationship between gut microbiota, SCFAs, and glucose metabolism.

Gallstones grow inside the gallbladder or biliary tract. These stones can be asymptomatic or symptomatic; only gallstones with symptoms or complications are defined as gallstone disease. Based on their composition, gallstones are classified into cholesterol gallstones, which represent the predominant entity, and bilirubin (‘pigment’) stones. Black pigment stones can be caused by chronic haemolysis; brown pigment stones typically develop in obstructed and infected bile ducts. For treatment, localization of the gallstones in the biliary tract is more relevant than composition. Overall, up to 20% of adults develop gallstones and >20% of those develop symptoms or complications. Risk factors for gallstones are female sex, age, pregnancy, physical inactivity, obesity and overnutrition. Factors involved in metabolic syndrome increase the risk of developing gallstones and form the basis of primary prevention by lifestyle changes. Common mutations in the hepatic cholesterol transporter ABCG8 confer most of the genetic risk of developing gallstones, which accounts for ∼25% of the total risk. Diagnosis is mainly based on clinical symptoms, abdominal ultrasonography and liver biochemistry tests. Symptoms often precede the onset of the three common and potentially life-threatening complications of gallstones (acute cholecystitis, acute cholangitis and biliary pancreatitis). Although our knowledge on the genetics and pathophysiology of gallstones has expanded recently, current treatment algorithms remain predominantly invasive and are based on surgery. Hence, our future efforts should focus on novel preventive strategies to overcome the onset of gallstones in at-risk patients in particular, but also in the population in general. Gallstones are masses in the gallbladder or biliary tract. This Primer by Lammert et al . focuses on the formation of gallstones, summarizes the current principles of treatment of the stones and their potential complications and envisions future approaches for this widespread disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and represents the hepatic expression of several metabolic abnormalities of high epidemiologic relevance. Fat accumulation in the hepatocytes results in cellular fragility and risk of progression toward necroinflammation, i.e., nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Several pathways contribute to fat accumulation and damage in the liver and can also involve the mitochondria, whose functional integrity is essential to maintain liver bioenergetics. In NAFLD/NASH, both structural and functional mitochondrial abnormalities occur and can involve mitochondrial electron transport chain, decreased mitochondrial β-oxidation of free fatty acids, excessive generation of reactive oxygen species, and lipid peroxidation. NASH is a major target of therapy, but there is no established single or combined treatment so far. Notably, translational and clinical studies point to mitochondria as future therapeutic targets in NAFLD since the prevention of mitochondrial damage could improve liver bioenergetics.

China faces the greatest challenge from stroke in the world. The death rate for cerebrovascular diseases in China was 149.49 per 100 000, accounting for 1.57 million deaths in 2018. It ranked third among the leading causes of death behind malignant tumours and heart disease. The age-standardised prevalence and incidence of stroke in 2013 were 1114.8 per 100 000 population and 246.8 per 100 000 person-years, respectively. According to the Global Burden of Disease Study 2017, the years of life lost (YLLs) per 100 000 population for stroke increased by 14.6%; YLLs due to stroke rose from third highest among all causes in 1990 to the highest in 2017. The absolute numbers and rates per 100 000 population for all-age disability-adjusted life years (DALYs) for stroke increased substantially between 1990 and 2017, and stroke was the leading cause of all-age DALYs in 2017. The main contributors to cerebrovascular diseases include behavioural risk factors (smoking and alcohol use) and pre-existing conditions (hypertension, diabetes mellitus, dyslipidaemia and atrial fibrillation (AF)). The most prevalent risk factors among stroke survivors were hypertension (63.0%-84.2%) and smoking (31.7%-47.6%). The least prevalent was AF (2.7%-7.4%). The prevalences for major risk factors for stroke are high and most have increased over time. Based on the latest national epidemiological data, 26.6% of adults aged ≥15 years (307.6 million adults) smoked tobacco products. For those aged ≥18 years, age-adjusted prevalence of hypertension was 25.2%; adjusted prevalence of hypercholesterolaemia was 5.8%; and the standardised prevalence of diabetes was 10.9%. For those aged ≥40 years, the standardised prevalence of AF was 2.31%. Data from the Hospital Quality Monitoring System showed that 3 010 204 inpatients with stroke were admitted to 1853 tertiary care hospitals during 2018. Of those, 2 466 785 (81.9%) were ischaemic strokes (ISs); 447 609 (14.9%) were intracerebral haemorrhages (ICHs); and 95 810 (3.2%) were subarachnoid haemorrhages (SAHs). The average age of patients admitted was 66 years old, and nearly 60% were male. A total of 1555 (0.1%), 2774 (0.6%) and 1347 (1.4%) paediatric strokes (age <18 years) were identified among IS, ICH and SAH, respectively. Over one-third (1 063 892 (35.3%)) of the patients were covered by urban resident basic medical insurance, followed by urban employee basic medical insurance (699 513 (23.2%)) and new rural cooperative medical schema (489 361 (16.3%)). The leading risk factor was hypertension (67.4% for IS, 77.2% for ICH and 49.1% for SAH), and the leading comorbidity was pneumonia or pulmonary infection (10.1% for IS, 31.4% for ICH and 25.2% for SAH). In-hospital death/discharge against medical advice rate was 8.3% for stroke inpatients, ranging from 5.8% for IS to 19.5% for ICH. The median and IQR of length of stay was 10.0 (7.0–14.0) days, ranging from 10.0 (7.0–13.0) in IS to 14.0 (8.0–22.0) in SAH. Data from the Chinese Stroke Center Alliance demonstrated that the composite scores of guideline-recommended key performance indicators for patients with IS, ICH and SAH were 0.77±0.21, 0.72±0.28 and 0.59±0.32, respectively.

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/β-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.

China faces the greatest challenge from stroke in the world. According to results from the Global Burden of Disease Study 2019, there were 3.94 million new stroke cases, 28.76 million prevalent cases and 2.19 million deaths due to stroke in China in 2019. Furthermore, stroke is also the leading cause of disability-adjusted life-year (DALY) in China, the number of DALYs reached 45.9 million in 2019. Several recent large-scale epidemiological surveys have updated the data on pre-existing conditions contributed to stroke. The age-adjusted prevalence of overweight among Chinese adults aged 18–69 years was 34.4%, and the prevalence of obesity was 16.8% in 2018. 50.9% of Chinese adults ≥18 years of age without history of hypertension had prehypertension in 2018. The weighted prevalence of hypertension in adults was 27.5% in 2018. The weighted prevalence of total diabetes and pre-diabetes diagnosed by the American Diabetes Association criteria were 12.8% and 35.2%, respectively, among Chinese adults ≥18 years of age in 2017. The weighted atrial fibrillation prevalence was 1.8% among Chinese adults ≥45 years of age and equates to being present in an estimated 7.9 million people in China. Data from 1672 tertiary public hospitals in the Hospital Quality Monitoring System (HQMS) showed that 3 411 168 stroke cases were admitted during 2019. Of those, 2 818 875 (82.6%) were ischaemic strokes (ISs), 485 474 (14.2%) were intracerebral haemorrhages (ICHs), 106 819 (3.1%) were subarachnoid haemorrhages (SAHs). The average age was 66 years old, and 59.6% were male. A total of 1379 (<0.1%), 2604 (0.5%), 1250 (1.2%) paediatric strokes (age <18 years) were identified among IS, ICH and SAH, respectively. Over one-third (1 231 519 (36.1%)) of the stroke cases were covered by urban resident basic medical insurance, followed by urban employee basic medical insurance (891 103 (26.1%)) and new rural cooperative medical schema (543 108 (15.9%)). The leading risk factor was hypertension (57.3% for IS, 69.9% for ICH and 44.1% for SAH), and the leading comorbidity was pneumonia or pulmonary infection (10.4% for IS, 34.6% for ICH and 29.7% for SAH). In-hospital death/discharge against medical advice rate was 8.5%, ranging from 6.0% for IS to 20.6% for SAH. The median and IQR of length of stay was 9.0 (6.0–13.0) days, ranging from 10.0 (7.0–13.0) in IS to 14.0 (8.0–22.0) in ICH. Similar data from 2847 secondary public hospitals or private hospitals in the HQMS were also reported. Data from HQMS showed that higher proportions of interprovincial admission to other provinces were seen in Inner Mongolia, Anhui, Tibet and Beijing. Higher proportions of interprovincial admission from other provinces were seen in Beijng, Tianjin, Shanghai and Ningxia. Data from 323 601 strokes from 1337 hospitals in the Chinese Stroke Center Alliance during 2019 demonstrated that the composite scores of guideline-recommended key performance indicators for patients with IS, ICH and SAH were 0.78±0.20, 0.69±0.27 and 0.60±0.31, respectively.

The largest surface of the human body exposed to the external environment is the gut. At this level, the intestinal barrier includes luminal microbes, the mucin layer, gastrointestinal motility and secretion, enterocytes, immune cells, gut vascular barrier, and liver barrier. A healthy intestinal barrier is characterized by the selective permeability of nutrients, metabolites, water, and bacterial products, and processes are governed by cellular, neural, immune, and hormonal factors. Disrupted gut permeability (leaky gut syndrome) can represent a predisposing or aggravating condition in obesity and the metabolically associated liver steatosis (nonalcoholic fatty liver disease, NAFLD). In what follows, we describe the morphological-functional features of the intestinal barrier, the role of major modifiers of the intestinal barrier, and discuss the recent evidence pointing to the key role of intestinal permeability in obesity/NAFLD.