Exercise and diet are treatments for nonalcoholic fatty liver disease (NAFLD) and prediabetes, however, how exercise and diet interventions impact gut microbiota in patients is incompletely understood. We previously reported a 8.6-month, four-arm (Aerobic exercise, n = 29; Diet, n = 28; Aerobic exercise + Diet, n = 29; No intervention, n = 29) randomized, singe blinded (for researchers), and controlled intervention in patients with NAFLD and prediabetes to assess the effect of interventions on the primary outcomes of liver fat content and glucose metabolism. Here we report the third primary outcome of the trial—gut microbiota composition—in participants who completed the trial (22 in Aerobic exercise, 22 in Diet, 23 in Aerobic exercise + Diet, 18 in No Intervention). We show that combined aerobic exercise and diet intervention are associated with diversified and stabilized keystone taxa, while exercise and diet interventions alone increase network connectivity and robustness between taxa. No adverse effects were observed with the interventions. In addition, in exploratory ad-hoc analyses we find that not all subjects responded to the intervention in a similar manner, when using differentially altered gut microbe amplicon sequence variants abundance to classify the responders and low/non-responders. A personalized gut microbial network at baseline could predict the individual responses in liver fat to exercise intervention. Our findings suggest an avenue for developing personalized intervention strategies for treatment of NAFLD based on host-gut microbiome ecosystem interactions, however, future studies with large sample size are needed to validate these discoveries. The Trial Registration Number is ISRCTN 42622771.

Pathogenic viral infections represent a major challenge to human health. Host immune responses to respiratory viruses are closely associated with microbiome and metabolism via the gut-lung axis. It has been known that host defense against influenza A virus (IAV) involves activation of the NLRP3 inflammasome, however, mechanisms behind the protective function of NLRP3 are not fully known. Here we show that an isolated bacterial strain, Bifidobacterium pseudolongum NjM1, enriched in the gut microbiota of Nlrp3^−/− mice, protects wild-type but not Nlrp3 deficient mice against IAV infection. This effect depends on the enhanced production of type I interferon (IFN-I) mediated by NjM1-derived acetate. Application of exogenous acetate reproduces the protective effect of NjM1. Mechanistically, NLRP3 bridges GPR43 and MAVS, and promotes the oligomerization and signalling of MAVS; while acetate enhances MAVS aggregation upon GPR43 engagement, leading to elevated IFN-I production. Thus, our data support a model of NLRP3 mediating enhanced induction of IFN-I via acetate-producing bacterium and suggest that the acetate-GPR43-NLRP3-MAVS-IFN-I signalling axis is a potential therapeutic target against respiratory viral infections.

The management of metabolic disorder associated with polycystic ovary syndrome (PCOS) has been suggested as an effective approach to improve PCOS which is highly involved with gut microbiota, while the underlying mechanism is unclear. Here, we investigated the role of inulin, a gut microbiota regulator, in the alleviation of PCOS. Our findings showed that inulin treatment significantly improved hyperandrogenism and glucolipid metabolism in both PCOS cohort and mice. Consistent with the cohort, inulin increased the abundance of microbial co‐abundance group (CAG) 12 in PCOS mice, including Bifidobacterium species and other short‐chain fatty acids (SCFAs)‐producers. We further verified the enhancement of SCFAs biosynthesis capacity and fecal SCFAs content by inulin. Moreover, inulin decreased lipopolysaccharide‐binding protein (LBP) and ameliorated ovarian inflammation in PCOS mice, whereas intraperitoneal lipopolysaccharide (LPS) administration reversed the protective effects of inulin. Furthermore, fecal microbiota transplantation (FMT) from inulin‐treated patients with PCOS enhanced insulin sensitivity, improved lipid accumulation and thermogenesis, reduced hyperandrogenism and ovarian inflammatory response in antibiotic‐treated mice. Collectively, these findings revealed that gut microbiota mediates the beneficial effects of inulin on metabolic disorder and ovarian dysfunction in PCOS. Therefore, modulating gut microbiota represents a promising therapeutic strategy for PCOS.

This study aimed to develop a novel synbiotic composed of Lactiplantibacillus plantarum LLY-606 and galacto-oligosaccharides (GOS) to improve lipid metabolism in obesity. Design Through genome-wide analysis using COG and CAZy databases, we identified GOS as a specific growth substrate for Lactiplantibacillus plantarum LLY-606. The efficacy of this synbiotic (LP-GOS) was evaluated in both obese individuals and high-fat diet-induced obese mice. LP-GOS supplementation reduced visceral fat and waist circumference in humans and attenuated obesity in mice. It also improved gut microbiota composition and increased serum arginine levels. Metabolomic and microbiota analyses suggested that enhanced arginine production plays a key role. This was further confirmed by arginine synthesis inhibition, antibiotic treatment, and CRISPR-Cas9-mediated knockout of the Ass1 gene in Lactiplantibacillus plantarum LLY-606. These interventions demonstrated that LP-GOS improves lipid metabolism through arginine-mediated activation of the AMPK pathway. LP-GOS effectively alleviates obesity-associated lipid metabolism disorders by enhancing arginine production and activating the AMPK signaling pathway.

Poria cocos polysaccharides (PCP) are recognized as potential prebiotics with documented metabolic benefits in adults. However, their impact on the gut microbiota of children remains unclear. This study aimed to evaluate the effects of PCP versus inulin (INL) on the gut microbiota and bacterial metabolites in normal-weight children (CON) and obese children (OB). In vitro fermentation was conducted using fecal samples pooled from five normal-weight children and five obese children, respectively. The samples were incubated with PCP, INL, or a blank control under anaerobic conditions at 37 °C for 24 h. After fermentation, the effects of PCP and INL on gut microbiota were evaluated using 16S rRNA sequencing. Bacteria-derived metabolites were measured using targeted metabolic profiling. Single-strain validation was performed to confirm effects on key bacterial taxa. PCP supplementation promoted the growth of Bifidobacterium and Limosilactobacillus in both normal-weight and obese children, accompanied by a rise in acetic acid production, particularly in normal-weight children. Compared to INL, PCP showed similar but slightly weaker effects on Bifidobacterium growth and short-chain fatty acids (SCFAs) production, but more strongly stimulated Limosilactobacillus growth. Notably, PCP also stimulated the production of indolelactic acid in both obese and normal-weight children. Correlation analysis indicated that Bifidobacterium and Limosilactobacillus were positively associated with acetic acid, lactic acid, and indolelactic acid, and negatively associated with tryptophan. Single-strain fermentation supported the community-level findings. PCP and INL both modulate gut microbiota and metabolic profiles in children, with PCP demonstrating a distinct prebiotic profile. Notably, PCP increased health-associated metabolites such as acetic acid and indolelactic acid, which are implicated in gut barrier support, immune modulation, and metabolic regulation. These findings suggest PCP may be considered a functional food component for supporting gut health in children, warranting further research.