Montmorillonite restricts free fatty acid liberation and alters self-assembled structures formed during in vitro lipid digestion.

The global rise in obesity necessitates innovative weight loss strategies. Naturally occurring smectite clays, such as montmorillonite (MMT), offer promise due to their unique properties that interfere with free fatty acid (FFA) liberation, reducing systemic uptake. However, the mechanisms of MMT-FFA interactions and their implications for weight management are undefined. This study investigates these interactions by adding MMT (10 % w/w) to in vitro lipolysis media containing medium chain triglycerides (MCTs), and monitoring FFA liberation using pH-stat titration. Nanoparticle tracking analysis (NTA) and synchrotron-based small-angle X-ray scattering (sSAXS) observed time-dependent structural changes, while electron microscopy examined clay morphology during digestion. A 35 % reduction in FFA liberation occurred after 25 min of digestion with MCT + MMT, with digestion kinetics following a biphasic model driven by calcium soap formation. NTA revealed a 17-fold decrease in vesicular structures with MCT + MMT, and sSAXS highlighted a rapid lamellar phase evolution linked to calcium soap formation. This acceleration is attributed to MMT's adsorption to unionized FFAs via hydrogen bonding, supported by TEM images showing a decrease in d-spacing, indicating FFA intercalation is not the main adsorption mechanism. These findings highlight MMT's potential as a novel intervention for reducing dietary lipid absorption in obesity and metabolic diseases.

The Degree of Inulin Polymerization Is Important for Short-Term Amelioration of High-Fat Diet (HFD)-Induced Metabolic Dysfunction and Gut Microbiota Dysbiosis in Rats.

Inulin, a non-digestible polysaccharide, has gained attention for its prebiotic properties, particularly in the context of obesity, a condition increasingly understood as a systemic inflammatory state linked to gut microbiota composition. This study investigates the short-term protective effects of inulin with different degrees of polymerization (DPn) against metabolic health deterioration and gut microbiota alterations induced by a high-fat diet (HFD) in Sprague Dawley rats. Inulin treatments with an average DPn of 7, 14, and 27 were administered at 1 g/kg of bodyweight to HFD-fed rats over 21 days. Body weight, systemic glucose levels, and proinflammatory markers were measured to assess metabolic health. Gut microbiota composition was analyzed through 16S rRNA gene sequencing. The results showed that inulin27 significantly reduced total weight gain and systemic glucose levels, suggesting a DPn-specific effect on metabolic health. The study also observed shifts in gut microbial populations, with inulin7 promoting several beneficial taxa from the Bifidobacterium genera, whilst inducing a unique microbial composition compared to medium-chain (DPn 14) and long-chain inulin (DPn: 27). However, the impact of inulin on proinflammatory markers and lipid metabolism parameters was not statistically significant, possibly due to the short study duration. Inulin with a higher DPn has a more pronounced effect on mitigating HFD-induced metabolic health deterioration, whilst inulin7 is particularly effective at inducing healthy microbial shifts. These findings highlight the benefits of inulin as a dietary adjuvant in obesity management and the importance of DPn in optimizing performance.

Fibre-rich diet attenuates chemotherapy-related neuroinflammation in mice.

The gastrointestinal microbiota has received increasing recognition as a key mediator of neurological conditions with neuroinflammatory features, through its production of the bioactive metabolites, short-chain fatty acids (SCFAs). Although neuroinflammation is a hallmark shared by the neuropsychological complications of chemotherapy (including cognitive impairment, fatigue and depression), the use of microbial-based therapeutics has not previously been studied in this setting. Therefore, we aimed to investigate the effect of a high fibre diet known to modulate the microbiota, and its associated metabolome, on neuroinflammation caused by the common chemotherapeutic agent 5-fluorouracil (5-FU). Twenty-four female C57Bl/6 mice were treated with 5-FU (400 mg/kg, intraperitoneal, i.p.) or vehicle control, with or without a high fibre diet (constituting amylose starch; 4.7 % crude fibre content), given one week prior to 5-FU and until study completion (16 days after 5-FU). Faecal pellets were collected longitudinally for 16S rRNA gene sequencing and terminal SCFA concentrations of the caecal contents were quantified using gas chromatography-mass spectrometry (GC-MS). Neuroinflammation was determined by immunofluorescent analysis of astrocyte density (GFAP). The high fibre diet significantly altered gut microbiota composition, increasing the abundance of Bacteroidaceae and Akkermansiaceae (p < 0.0001 and p = 0.0179) whilst increasing the production of propionate (p = 0.0097). In the context of 5-FU, the diet reduced GFAP expression in the CA1 region of the hippocampus (p < 0.0001) as well as the midbrain (p = 0.0216). Astrocyte density negatively correlated with propionate concentrations and the abundance of Bacteroidaceae and Akkermansiaceae, suggesting a relationship between neuroinflammatory and gastrointestinal markers in this model. This study provides the first evidence of the neuroprotective effects of fibre via dietary intake in alleviating the neuroimmune changes seen in response to systemically administered 5-FU, indicating that the microbiota-gut-brain axis is a targetable mediator to reduce the neurotoxic effects of chemotherapy treatment.

Self-emulsifying drug delivery systems (SEDDS) disrupt the gut microbiota and trigger an intestinal inflammatory response in rats.

Self-emulsifying drug delivery systems (i.e. SEDDS, SMEDDS and SNEDDS) are widely employed as solubility and bioavailability enhancing formulation strategies for poorly water-soluble drugs. Despite the capacity for SEDDS to effectively facilitate oral drug absorption, tolerability concerns exist due to the capacity for high concentrations of surfactants (typically present within SEDDS) to induce gastrointestinal toxicity and mucosal irritation. With new knowledge surrounding the role of the gut microbiota in modulating intestinal inflammation and mucosal injury, there is a clear need to determine the impact of SEDDS on the gut microbiota. The current study is the first of its kind to demonstrate the detrimental impact of SEDDS on the gut microbiota of Sprague-Dawley rats, following daily oral administration (100 mg/kg) for 21 days. SEDDS comprising a lipid phase (i.e. Type I, II and III formulations according to the Lipid Formulation Classification Scheme) induced significant changes to the composition and diversity of the gut microbiota, evidenced through a reduction in operational taxonomic units (OTUs) and alpha diversity (Shannon's index), along with statistically significant shifts in beta diversity (according to PERMANOVA of multi-dimensional Bray-Curtis plots). Key signatures of gut microbiota dysbiosis correlated with the increased expression of pro-inflammatory cytokines within the jejunum, while mucosal injury was characterised by significant reductions in plasma citrulline levels, a validated biomarker of enterocyte mass and mucosal barrier integrity. These findings have potential clinical ramifications for chronically administered drugs that are formulated with SEDDS and stresses the need for further studies that investigate dose-dependent effects of SEDDS on the gastrointestinal microenvironment in a clinical setting.

The impact of common pharmaceutical excipients on the gut microbiota.

INTRODUCTION: Increasing attention is being afforded to understanding the bidirectional relationships that exist between oral medications and the gut microbiota, in an attempt to optimize pharmacokinetic performance and mitigate unwanted side effects. While a wealth of research has investigated the direct impact of active pharmaceutical ingredients (APIs) on the gut microbiota, the interactions between inactive pharmaceutical ingredients (i.e. excipients) and the gut microbiota are commonly overlooked, despite excipients typically representing over 90% of the final dosage form. AREAS COVERED: Known excipient-gut microbiota interactions for various classes of inactive pharmaceutical ingredients, including solubilizing agents, binders, fillers, sweeteners, and color additives, are reviewed in detail. EXPERT OPINION: Clear evidence indicates that orally administered pharmaceutical excipients directly interact with gut microbes and can either positively or negatively impact gut microbiota diversity and composition. However, these relationships and mechanisms are commonly overlooked during drug formulation, despite the potential for excipient-microbiota interactions to alter drug pharmacokinetics and interfere with host metabolic health. The insights derived from this review will inform pharmaceutical scientists with the necessary design considerations for mitigating potential adverse pharmacomicrobiomic interactions when formulating oral dosage forms, ultimately providing clear avenues for improving therapeutic safety and efficacy.