A new strategy for enhancing S-Adenosyl-L-Methionine (SAMe) oral bioavailability: Preparation of SAMe loaded inulin nanoparticles for colon targeting with in vivo validation

Introduction

The gut-brain axis has become a focal point in contemporary neuroscience and psychiatry. Emerging evidence suggests a compelling connection between the composition of the gut microbiota and the development of depression. Recent studies have unveiled a bidirectional communication network between the gut and the brain, with the microbiota acting as a key mediator [1]. The gut-brain axis plays an important role in maintaining physiological homeostasis and influencing neurological health. Recent research has elucidated various mechanisms through which gut microbiota can affect brain function, including modulation of neurotransmitter systems [2], immune responses [3,4], and neuroinflammatory pathways [3]. Studies have indicated that alterations in the gut microbiome are associated with the occurrence of depression. Zhuang et al. found that modulation of gut microbiota through personalized diets or microbiota interventions could be a promising strategy for preventing or treating Alzheimer’s Disease and depressive symptoms [5]. This research implemented that specific bacterial taxa such as Actinobacteria, Bacteroidales, Ruminococcaceae, Selenomonadales, and Lachnoclostridium were altered in AD patients. This alteration in gut microbiota composition suggests a potential role of the microbiota-gut-brain axis in the pathogenesis of AD. Additionally, Lu et al. suggested that gut microbiota disorders are strongly related to the occurrence of depression [6].

Furthermore, Wingfield et al. provided strong evidence from preclinical animal models and clinical studies that depression is associated with the composition of the gut microbiome. The research utilized 16S rRNA gene-based next-generation sequencing to analyze saliva samples from 40 young adults diagnosed with depression according to DSM-IV criteria and 43 matched healthy controls. The study found significant differences in the alpha and beta diversity of the salivary microbiome between the depressed and control cohorts, with clear separation into distinct clusters. Specifically, 21 bacterial taxa were differentially abundant in the depressed cohort, with increased Neisseria spp. and Prevotella nigrescens and decreased abundance in 19 other taxa [7]. The exploration of gut microbiota having benefits for behavior and brain function can yield advances in depression treatment, as highlighted by Nanthakumaran et al. [8]. Furthermore, increasing evidence supports the theory presented by Li et al. [9] suggesting a correlation between structural modifications of the fecal microbiota and the onset of depression. Together, these data revealed the important role that the gut microbiota plays in regulating depression symptoms and offer insightful information on possible therapeutic approaches that focus on the gut-brain axis in the context of depression.
Depression is a complex and widespread mental health disorder that significantly impacts the quality of life. While conventional antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, remain the cornerstone of treatment, they often come with side effects and variable efficacy. In recent years, natural molecules derived from plants, fungi, and other biological sources have garnered attention as potential therapeutic agents. Among these, S-Adenosyl-L-Methionine (SAMe) has emerged as a promising candidate. S-adenosylmethionine, commonly called SAMe, is a naturally occurring compound found in all human tissues and bodily fluids. Produced within the body from essential nutrients, SAMe plays a vital role in numerous cellular processes. It is essential for methylation, a chemical process essential for DNA, RNA, protein, and fat function, transsulfuration, and aminopropylation [10,11]. SAMe exists in two molecular forms. The (S,S)-SAMe configuration is biologically active and essential for various cellular processes, including the modification of DNA, proteins, and lipids. In contrast, the (R,S)-SAMe form has minimal biological function [12].

Over the last two decades, a significant number of studies have demonstrated the effectiveness of SAMe in treating depression, osteoarthritis, and liver disease [10]. Research suggests that it may improve mood, similar to conventional antidepressants [13,14]. This effect is thought to stem from its role in producing neurotransmitters like dopamine and serotonin, which are vital for mood regulation [14]. Clinical studies have demonstrated SAMe’s efficacy in treating major depressive disorder, often with fewer side effects compared to traditional antidepressants [15]. However, its clinical application is hindered by low bioavailability (~1 %) due to poor stability, poor permeability, and extensive liver first-pass metabolism. Oral SAMe formulations are poorly absorbed and rapidly broken down, limiting their therapeutic effectiveness [10,12,16,17]. To enhance SAMe bioavailability, researchers have investigated various approaches, including enteric coating [17,18], encapsulation [19,20], synthesizing stable and lipophilic salts [21], and utilizing alternative administration routes [18].

Inulin is a naturally occurring biological macromolecule in polysaccharide form and it is a widely recognized dietary fiber, primarily found in various plants such as Cichorium intybus (Chicory) and Dahlia pinnata Cav. (Dahlia). Its safety profile is well-established and it is categorized as a Generally Regarded As Safe (GRAS) polymer [22]. It is composed of fructose units linked by β (2 → 1) bonds and terminates with a glucose unit. Humans lack the enzyme necessary to digest the β (2 → 1) bond; however, inulin can be broken down by inulinase, an enzyme found in bifidobacteria and lactobacilli present in the human colon. Inulin has been shown to selectively stimulate the growth and activity of beneficial intestinal bacteria, thereby modulating the gut microbiota [23,24]. Inulin has received significant attention due to its potential colon-targeting properties [25]. Additionally, inulin provides a controlled release of therapeutic drugs into the colon by protecting the drug from the acidic environment of the stomach and allowing degradation in the colon in the presence of colonic microbiota. This property allows inulin to serve as a carrier for colon/tumor targeting, as it can be hydrolyzed by colon-specific enzymes. Additionally, the enzymatic breakdown of inulin specifically in the colon enhances its utility in colon-targeted drug delivery [26]. Studies have suggested that inulin may have a positive impact on mental health, including its potential role in alleviating depressive symptoms [27]. Prebiotic effects of inulin have been proven by numerous studies [28,29]. Inulin is a promising platform for drug delivery, particularly due to its biocompatibility, biodegradability, and ability to encapsulate a variety of therapeutic agents [26]. Furthermore, inulin has been reported to facilitate intestinal epithelial cell proliferation, inhibit colonic atrophy, reduce microbial invasion of the mucosa, and nourish the gut microbiota, thereby protecting against metabolic syndrome. The selective fermentation of inulin produces short-chain fatty acids (SCFAs), which are beneficial for colonic health and may enhance the absorption of certain drugs [30]. Due to these functions, inulin was used in the current study not only as a drug carrier but also as a promoter of colonic health.

The use of native inulin as a particulate drug delivery system is limited due to its hydrophilic nature, which increases the risk of premature release and agglomeration before reaching the absorption site [31]. In drug delivery systems, inulin is generally used after conjugation with hydrophobic functional groups such as acetylation [32,33], and octenyl-succinylation [34]. This approach enhances encapsulation efficiency, protects the drug molecule from body fluids, and enables targeted delivery with improved integrity [35,36]. The recent progress of inulin-based platforms provided in Table S1 encourages their usage in nanodrugs [25,[32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46]].

The objective of this research was to develop an efficient formulation for the treatment of depression. Endogenous antidepressant SAMe was incorporated in native inulin nanoparticles, which were then adhered to the microparticles to boost SAMe bioavailability via improved colonic uptake besides benefiting the prebiotic effects of inulin. The SAMe-loaded nanoparticles were spray-coated onto inert microcrystal cellulose (MCC) microspheres, followed by the re-coating with Eudragit L30D-55. Microcrystal cellulose (MCC) microspheres are used as inert drug carriers. This system produced as a nanoparticle-in-microparticle (NIM) is aimed to enhance the stability and handling of the nanoparticles. Eudragit L30D-55 is an enteric coating polymer targeting drug release specifically in the colon since it dissolves at a pH of 5.5 or higher. After the dissolution of the enteric polymer in the colon, the nanoparticles are released, and the drug is delivered from the nanoparticles. Formulation optimization studies were performed to investigate the effects of formulation parameters on the nanoparticles’ characteristics, and a spray-coating process was developed to produce NIMs. An in vivo pharmacokinetic study was carried out on the selected formulation in rats to evaluate the impact of the formulation on bioavailability.

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Materials

Inulin (from dahlia tubers), sodium lauryl sulfate, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) were purchased from Sigma-Aldrich (Milwaukee, WI, USA); S-adenosyl-l-methionine 1,4-butane disulfonate was purchased from Carbosynth NA (UK). Low viscosity hypromellose (hydroxypropyl methylcellulose – HPMC) (Pharmacoat® 606, DS 2910 6 mPa.san) was generously provided by Shin-Etsu (Tokyo, Japan). A copolymer dispersion of methacrylic acid and ethyl acrylate (1:1), 30 % (Eudragit® L30D-55) by Evonik

Ahmet Doğan Ergin, Zerrin Sezgin Bayindir, Mehmet Gümüştaş, Arif Tanju Özçelikay, Nilufer Yüksel, A new strategy for enhancing S-Adenosyl-L-Methionine (SAMe) oral bioavailability: Preparation of SAMe loaded inulin nanoparticles for colon targeting with in vivo validation, International Journal of Biological Macromolecules, 2024, 138818, ISSN 0141-8130, https://doi.org/10.1016/j.ijbiomac.2024.138818.

Read also our introduction article on Microcrystalline Cellulose here: