npj Gut and Liver最新文献

Preterm infants born <32 weeks gestation have abnormal microbial colonisation and dysregulated inflammation within the gut. Preterm infant-derived intestinal organoids (PIOs) represent a valuable model for investigating gut microbiome-host interactions and inflammatory responses. We optimised an inflammation model in PIO monolayers incubated within an anaerobic co-culture system that recreates the physiological oxygen gradient of the intestinal epithelium. We trialled multiple stimuli, including live and heat-killed pathobiont consortia, lipopolysaccharide (LPS) and flagellin. We found that a combination of apical LPS and basolateral flagellin, incubated for 3 h, elicited the most robust response. This was characterised by enhanced pro-inflammatory cytokine secretion, the potential for chemokine-driven immune recruitment, TNFα and IL17C pathway signalling, shifts from NF-κB to AP-1-mediated responses, and signs of tissue remodelling. This provides a framework for appropriate study design to disentangle the impacts of microbiome-host interactions in health and disease using intestinal organoids.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by insulin resistance and impaired hepatic metabolism, which lead to steatosis and lipotoxicity. S100A11, an alarmin upregulated in MASH, promotes steatosis in vitro, but its role in vivo remains unclear. We hypothesized that S100A11 drives MASH by upregulating hepatic lipid synthesis. Using whole-body S100a11 knockout (S100a11 ^-/- ) mice on a MASH-inducing diet, we found S100a11 deficiency reduced steatosis, inflammation, and fibrosis. Hepatotropic AAV8-mediated silencing of S100a11 confirmed these findings. Bulk RNA sequencing with Ingenuity Pathway Analysis revealed dysregulated carbohydrate and lipid metabolism in S100a11 ^-/- livers, including downregulation of hexokinase 2 (Hk2). Since hexokinases regulate glucose flux into downstream metabolic processes, we overexpressed HK2 in S100a11 ^-/- mice, which was sufficient to increase steatosis. Further, palmitate-induced HK2 upregulation required S100A11 in a human hepatocyte cell line. These studies identify HK2 as a downstream target of S100A11, both of which are potential therapeutic targets for MASH.

Metabolic dysfunction-associated steatohepatitis (MASH) has become a global health issue associated with obesity and diabetes. It is becoming a leading cause of end-stage liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). Despite its increasing prevalence, effective pharmacotherapies for MASH remain limited, underscoring the urgent need for novel interventions. Amlexanox, an inhibitor of noncanonical IκB kinases, has demonstrated potential in restoring insulin sensitivity and glucose homeostasis in obese mice and human patients, as shown in our earlier studies. Here, we aimed to assess the therapeutic potential of amlexanox in dyslipidemia-associated diseases, particularly MASH and HCC, and to elucidate the underlying mechanism. We employed GAN diet-fed Ldlr ^-/- mice, which simultaneously develop obesity, MASH, and atherosclerosis, to recapitulate human metabolic syndrome and associated complications. Amlexanox was administrated orally to these mice after disease onset to examine its therapeutic efficacy. Our study demonstrates that even a low dose of amlexanox significantly reversed MASH and nearly completely prevented the progression from MASH to HCC. Both phenotypic and transcriptomic studies revealed that amlexanox markedly improved MASH-related dyslipidemia, hepatic steatosis, inflammation, liver injury, and hepatic fibrosis. Furthermore, multi-omics analysis revealed that amlexanox enhances hepatic bile acid synthesis and promotes fecal bile acid excretion. Notably, amlexanox reprogrammed gut microbiota, robustly increasing the abundance of Akkermansia muciniphila, a probiotic known to improve metabolic dysfunction. These findings uncover the multifaceted therapeutic potential of amlexanox in treating MASH and atherosclerosis by targeting bile acid metabolism, gut microbiota, hepatic inflammation, and fibrosis. Our study highlights amlexanox as a promising candidate for clinical applications.

Steatotic liver disease (SLD) prevalence in adults is estimated at 30%, but older populations are understudied. Here, SLD prevalence and associated risk factors were assessed 1,021 Whitehall II study participants (mean age 72.5) using transient elastography (FibroScan). SLD was present in 33.3% (CAP ≥ 275 dB/m), with most classified as metabolic dysfunction-associated SLD. Only 2.4% had significant fibrosis ( ≥ 7.9 kPa). Adjusted for age and sex, SLD was associated with low physical activity (OR 1.60, 95% CI 1.13-2.27), poorer motor function (SF-36 PCS OR 1.21, 95% CI 1.05-1.40), difficulties in activities of daily living (OR 3.19, 95% CI 1.17-8.64), and multimorbidity (OR 1.45, 95% CI 1.22-1.73). These associations persisted after adjustment for socioeconomic, behavioural, and cardiometabolic risk factors. Frailty was associated with SLD at higher CAP thresholds ( ≥ 290 dB/m). In this older adult sample, SLD is common and appears more as a marker of multimorbidity and low physical activity than significant fibrosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant cause of chronic liver disease globally, and the rising prevalence of MASLD is occurring in parallel with the global aging population. The use of non-invasive biomarker tools to rule-in or rule-out hepatic steatosis is important in large epidemiological studies in this field. While the Fatty Liver Index (FLI) is the best validated tool in older adults, not all studies will have the necessary parameters for steatosis identification. This retrospective post-hoc analysis of the ASPirin in Reducing Events in the Elderly (ASPREE) study involved 16,703 Australian adults aged ≥70 years. Using the FLI as the 'gold standard' index, we evaluated the correlation with other indices: the Dallas Steatosis Index (DSI), Framingham Steatosis Index, ZJU index (ZJU), Hepatic Steatosis Index (HSI), Lipid Accumulation Product (LAP), and Visceral Adiposity Index (VAI), as well as age- and sex-adjusted outcome measures including mortality, major adverse cardiovascular events (MACE), atrial fibrillation (AF), and persistent physical disability. Of the non-FLI indices, the DSI and FSI had the highest percentage of participants correctly classified as having MASLD (97.7% and 93.8% respectively). The FSI, LAP, and VAI were associated with MACE. The FSI and FLI were predictive of incident AF. The FLI, DSI, FSI, LAP and VAI were associated with physical disability. No MASLD score was associated with increased mortality. Indeed, MASLD defined by the ZJU and HSI were both inversely associated with mortality. As such, we've demonstrated that the FSI and DSI are the most accurate scores for identifying MASLD in older adults when compared to the FLI as the gold standard. The FSI is associated with MACE, AF, and persistent physical disability, lending support to its use in identifying older persons with MASLD when the FLI is unable to be calculated.

Dietary fiber is essential for health but remains under-consumed in Western diets. Fiber types differ in their physicochemical properties, which influence gastrointestinal function, bile acid (BA) metabolism, and gut microbiota composition. C57Bl/6 mice were fed control or 10% (w/w) fiber diets containing cellulose, chitin, resistant starch, pectin, inulin, β-glucan, psyllium, dextrin, or raffinose. All fibers reduced bacterial diversity, while most increased Akkermansia muciniphila abundance. Cellulose/chitin and inulin/β-glucan/raffinose formed distinct microbiome clusters. Rikenellaceae correlated positively with taurine-conjugated BAs levels. BA concentrations were reduced across tissues. Taurine conjugates showed inverse liver-intestine distribution. Inulin and β-glucan resulted in the highest taurine conjugate levels and reduced intestinal taurine-conjugated BAs concentrations, suggesting enhanced bile salt hydrolase (BSH) activity. Resistant starch had a minimal effect. Psyllium most strongly impacted BA- and taurine-related gene expression, cecum size and weight loss. Dietary fibers distinctly modulate BA metabolism and gut microbiota, with implications for metabolic health and targeted therapies.