Type 2 diabetes (T2D) is a worldwide prevalent metabolic disorder defined by high blood glucose levels due to insulin resistance (IR) and impaired insulin secretion. Understanding the mechanism of insulin action is of great importance to the continuing development of novel therapeutic strategies for the treatment of T2D. Disturbances of gut microbiota have been widely found in T2D patients and contribute to the development of IR. In the present article, we reviewed the pathological role of gut microbial metabolites including gaseous products, branched-chain amino acids (BCAAs) products, aromatic amino acids (AAAs) products, bile acids (BA) products, choline products and bacterial toxins in regulating insulin sensitivity in T2D. Following that, we summarized probiotics-based therapeutic strategy for the treatment of T2D with a focus on modulating gut microbiota in both animal and human studies. These results indicate that gut-microbial metabolites are involved in the pathogenesis of T2D and supplementation of probiotics could be beneficial to alleviate IR in T2D via modulation of gut microbiota.

Irritable bowel syndrome with diarrhea (IBS-D) presents significant treatment challenges due to limited therapeutic options that effectively target the underlying pathophysiological mechanisms. In this study, we performed a multi-center, double-blind randomized placebo-controlled trial to investigate the efficacy and safety of herbal medicine JCM-16021 on IBS-D with a focus on its effects on gut microbiota. Our study assessed the clinical efficacy and safety of JCM-16021 in alleviating abdominal pain in IBS-D patients. The results suggested that JCM-16021 is both effective and safe, with its therapeutic effects closely linked to the modulation of short-chain fatty acid (SCFA) producers. Through fecal microbiota transplantation (FMT) experiments in mice, we showed that SCFA producers mediate the alleviation of abdominal pain symptoms by the JCM-16021 treatment. In a TNBS-induced mouse model of IBS, we showed that butyrate producers enriched by JCM-16021 significantly ameliorate abdominal pain. Importantly, baseline gut microbial profiles, such as the presence of Eubacterium rectale in IBS-D patients are predictive of their responses to JCM-16021 treatment. Our findings not only affirm the efficacy of JCM-16021 in mitigating abdominal pain in IBS-D patients but also highlight a microbiota-dependent mechanism, underscoring the therapeutic potential of gut microbiota modulation in treating gastrointestinal disorders. By combining clinical trials in humans with biological experiments in mice, this study establishes a translational approach to investigate the role of gut microbiota in the treatment of herbal medicine. gov no: NCT03457324.

Purpose of Review: Abdominal pain in constipation-predominant irritable bowel syndrome (IBS-C) and functional constipation (FC) remains a difficult clinical challenge due to unclear pathophysiological mechanisms and limited pain-targeted treatments. This review critically evaluates the evidence on the underlying pain mechanisms in IBS-C and/or FC and explores management strategies, their limitations, and future directions. Recent Findings: Most research on constipation-related pain is based on IBS-C patients or animal models, with limited studies focusing on FC. Visceral hypersensitivity, serotonin dysregulation, gut-brain axis dysfunction, and central/peripheral nervous system alterations are implicated in IBS-C pain, while FC pain is less studied and may be primarily linked to colonic distension and motility dysfunction. Management strategies include 5-HT4 agonists, GC-C agonists, chloride channel activators, psychological therapies, probiotics and complementary medicine. Summary: Despite available treatment options, managing abdominal pain in IBS-C and FC remains challenging due to heterogeneous pathophysiology and limited targeted therapies. While some interventions provide symptomatic relief, there is no universally effective treatment for abdominal pain across all patients. Future research should focus on identifying pain-specific biomarkers, refining diagnostic criteria, and integrating multi-omics data and neuroimaging techniques to better distinguish pain mechanisms in IBS-C versus FC and develop more precise, patient-centered interventions.

Functional constipation (FC), a common gastrointestinal disorder, poses significant therapeutic challenges due to the limited efficacy and durability of current therapies. A novel strategy for addressing FC involves the targeting of gut dysbiosis. Our previous study demonstrated that the botanical drug CDD-2101 alleviated bowel movement disorders in FC patients. Nevertheless, whether the alterations in gut microbiota composition affected by CDD-2101 are associated with improved bowel movements and the gut microbiota-mediated mechanisms of action of CDD-2101 are not yet fully comprehended. Here, we showed that CDD-2101 enriched aromatic trace amines and aromatic trace amines-producing gut bacteria in FC patients, which correlated with enhanced bowel function and increased peripheral serotonin levels. In preclinical studies, treatment with tyramine, one of the aromatic trace amines, improved constipation-like symptoms and upregulated serotonin production in mice. Consistent with these findings, the colonization of mice with tyramine-enriched fecal microbiota from CDD-2101-treated patients or administration of an aromatic trace amines-producing engineered Lactobacillus casei alleviated constipation-like symptoms and enhanced serotonin production. Mechanistically, we showed that aromatic trace amines improved gastrointestinal motility by activating the trace amine-associated receptor 1 (TAAR1)-serotonin biosynthesis axis. Our study provides mechanistic and therapeutic insights into aromatic trace amines as microbial-derived TAAR1 ligands that regulate serotonin production to improve defecation in FC. These results not only support the therapeutic potential of targeting gut microbiota for the treatment of FC but also identify the aromatic trace amines-serotonin axis, as promoted by CDD-2101, as a pivotal therapeutic target for the improvement of FC. Chinese Clinical Trial Registry (ChiCTR) no: ChiCTR2100043211.

Obesity has been linked to an increased risk of cognitive impairment and dementia in later life. Although aging and obesity are both associated with cognitive decline, it remains unclear how they interact to affect cognitive function across the lifespan and how brain function might mediate their relationship with cognition. Our previous findings and other studies have shown that membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14), which increases with age, regulates energy homeostasis. Inhibiting MT1-MMP improves insulin sensitivity, reduces body fat, and lowers serum cholesterol. Here, we demonstrate that MT1-MMP links neuroinflammation to cognitive decline in aging and obesity. Inflammatory responses in the brain increase MT1-MMP activation in the hippocampus of both mice and humans. Activation of hippocampal MT1-MMP alone can trigger cognitive decline and synaptic impairment independently of neuroinflammation. Conversely, ablation of MT1-MMP in the hippocampus reverses cognitive decline and improves synaptic plasticity in aging and obesity. Pharmacological inhibition of MT1-MMP, through an orally administered brain-penetrant inhibitor or targeted delivery of a neutralizing antibody to the hippocampus, improves memory and learning in aged and obese mice without toxicity. Mechanistically, MT1-MMP proteolytically inactivates G-protein-coupled receptor 158 (GPR158), a hippocampal receptor for osteocalcin (OCN) that is important for the maintenance of cognitive integrity, thus suppressing the ability of the OCN-GPR158 axis to promote cognition in aging and obesity. These findings suggest a new mechanism underlying hippocampal dysfunction and reveal the potential for treating multiple age-related diseases, including neurodegenerative disorders, obesity, diabetes, and atherosclerosis, with a single MT1-MMP-blocking agent.

The human gut microbiota exhibits significant diversity across populations, influenced by factors such as geography, diet, and lifestyle, particularly betw