Convergence in Nanomedicine: Integrating Brain-Targeted Delivery and Gut Microbiota Modulation for Neurological Protection

<p indent="0mm">Gut microbiota is closely related to host health. The interactions between gut microbiota and hosts are complex, including the relationships between microbiota and the immune system, gut-brain axis, gut-lung axis etc. Gut microbiota disorders are related to the occurrence and development of some diseases, and some microbial strains are identified to be the cause of some diseases. Moreover, gut microbiota has effects on drug metabolism, and the individual differences of gut microbiota might lead to the different individual effects of the same drug. Therefore, recovering individual gut microbiota is essential for the implementation of individual precision medical treatment. Gut microbiota is alterable, and gut microbiota can be modulated at healthy state by dietary regulation, probiotics/prebiotics/synbiotics supplement, and fecal microbiota transplantation. Besides, microbiota editing techniques and synthetic microbiota have been applied in the modulation of gut microbiota. Currently, modulation of gut microbiota has become one of the effective strategies to improve or cure some diseases. This review summarized the interactions between gut microbiota and hosts, the correlations and causal relationships between gut microbiota and diseases, the ways to improve human health by modulating gut microbiota, and gave insights into the application of microbiome and synthetic biology on the modulation and synthesis of gut microbiota.

Gut microbiota modulation by both Lactobacillus fermentum MSK 408 and ketogenic diet in a murine model of pentylenetetrazole-induced acute seizure

Gut microbiota affects the gut-brain axis; hence, the modulation of the microbiota has been proposed as a potential therapeutic strategy for cerebral ischemia/reperfusion injury (CIRI). However, the role and mechanism of the gut microbiota in regulating microglial polarization during CIRI remain poorly understood. Herein, using a middle cerebral artery occlusion and reperfusion (MCAO/R) rat model, we evaluated changes in the gut microbiota after CIRI and the potential effects of fecal microbiota transplant (FMT) on the brain. Rats underwent either MCAO/R or sham surgery, and then they received FMT (started 3days later; continued for 10days). 2,3,5-Triphenyltetrazolium chloride staining, neurological outcome scale, and Fluoro-Jade C staining showed that MCAO/R induced cerebral infarction, neurological deficits, and neuronal degeneration. In addition, immunohistochemistry or real-time PCR assay showed increased expression levels of M1-macrophage markers-TNF-α, IL-1β, IL-6, and iNOS-in the rats following MCAO/R. Our finding suggests that microglial M1 polarization is involved in CIRI. 16S ribosomal RNA gene sequencing data revealed an imbalance in the gut microbiota of MCAO/R animals. In contrast, FMT reversed this MCAO/R-induced imbalance in the gut microbiota and ameliorated nerve injury. In addition, FMT prevented the upregulation in the ERK and NF-κB pathways, which reversed the M2-to-M1 microglial shift 10days after MCAO/R injury in rats. Our primary data showed that the modulation of the gut microbiota can attenuate CIRI in rats by inhibiting microglial M1 polarization through the ERK and NF-κB pathways. However, an understanding of the underlying mechanism requires further study.

Oral rhein attenuate nonalcoholic steatohepatitis in mice through the modulation of gut microbiota and Th17 cell differentiation.

Lactobacillus M5 prevents osteoarthritis induced by a high-fat diet in mice

Wheat peptides (WP) have been claimed to have the potential to regulate metabolism and effectively prevent/mitigate gut microbiota dysbiosis. However, many studies into the effects of WP on hyperglycemia have provided conflicting findings, and the underlying mechanism has been elusive. In this study, WP intervention (50-1000 mg kg-1) dose-dependently attenuated high fat diet (HFD)-induced weight gain, fasting hyperglycemia, glucose intolerance and insulin resistance. WP suppressed systemic inflammation by normalizing serum levels of lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), while concurrently reducing adipocyte hypertrophy and hepatic steatosis. Serum lipid profiles were improved, with significant reductions in total cholesterol (TC) and triglycerides (TG), though low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels remained unaltered. Although gut microbiota α-diversity was unaffected, WP modulated microbial composition by decreasing the Firmicutes/Bacteroidota ratio and enriching beneficial genera, including Bifidobacterium and Lactobacillus. Metabolomic analyses further revealed that WP-restored metabolic homeostasis is associated with upregulating functional lipids [PE(18 : 1/20 : 3), PG(18 : 0/20 : 4), and PS(22 : 6/22 : 1)] and the tryptophan metabolite 5-HIAA, all of which exhibited inverse correlations with indices of metabolic dysfunction. Critically, the WP-derived peptides LPQ and LPQF, characterized by a proline residue at the second position (Pro2), exhibited potent dipeptidyl peptidase-IV (DPP-IV) inhibitory activity, mediated by high-affinity binding involving van der Waals forces, hydrogen bonding, and electrostatic interactions. Furthermore, in hyperglycemic zebrafish models, LPQ/LPQF (0.1-5 μg mL-1) normalized glycemic levels. Collectively, WP exerts hypoglycemic effects through potentially synergistic mechanisms: (i) suppression of inflammation, (ii) restoration of functional lipid and tryptophan metabolic pathways, (iii) modulation of the gut microbiota toward a beneficial profile, and (iv) DPP-IV inhibition by structurally optimized peptides. These findings highlight WP's therapeutic potential for metabolic syndrome, underscoring its utility as a multifaceted intervention for metabolic dysregulation.

Purpose of ReviewThe gut microbiota plays a crucial role in the pathogenesis of neuroinflammation and Alzheimer’s and Parkinson’s diseases. One of the main modulators of the gut microbiota is the diet, which directly influences host homeostasis and biological processes. Some dietary patterns can affect neurodegenerative diseases’ progression through gut microbiota composition, gut permeability, and the synthesis and secretion of microbial-derived neurotrophic factors and neurotransmitters. This comprehensive review critically assesses existing studies investigating the impact of dietary interventions on the modulation of the microbiota in relation to neurodegenerative diseases and neuroinflammation.Recent FindingsThere are limited studies on the effects of specific diets, such as the ketogenic diet, Mediterranean diet, vegetarian diet, and Western diet, on the progression of neuroinflammation and Alzheimer’s and Parkinson’s diseases through the gut-brain axis. The ketogenic diet displays promising potential in ameliorating the clinical trajectory of mild cognitive impairment and Alzheimer’s disease. However, conflicting outcomes were observed among various studies, highlighting the need to consider diverse types of ketogenic diets and their respective effects on clinical outcomes and gut microbiota composition. Vegetarian and Mediterranean diets, known for their anti-inflammatory properties, can be effective against Parkinson’s disease, which is related to inflammation in the gut environment. On the other hand, the westernization of dietary patterns was associated with reduced gut microbial diversity and metabolites, which ultimately contributed to the development of neuroinflammation and cognitive impairment.SummaryVarious studies examining the impact of dietary interventions on the gut-brain axis with regard to neuroinflammation and Alzheimer’s and Parkinson’s diseases are thoroughly reviewed in this article. A strong mechanistic explanation is required to fully understand the complex interactions between various dietary patterns, gut microbiota, and microbial metabolites and the effects these interactions have on cognitive function and the progression of these diseases.

BackgroundThe human gut microbiota performs a variety of essential physiological homeostasis functions, including the development of the immune system, nutrient synthesis, vitamin production, and energy metabolism. Ginger's extensive pharmacological actions include anti-inflammatory, antioxidant, hypoglycemic, and lipid-lowering effects. This study aimed to investigate the beneficial effects of ginger on the prevention of obesity through the modulation of gut microbiota. MethodsThis study was carried out as a systematic review in 2024 by searching on the reliable databases of PubMed, Web of Sciences, and Scopus using the keywords "Obesity", "Gut-Microbiota", "Ginger" and their MeSH were analyzed with no time limit. Articles published in English that specifically focused on the beneficial effects of ginger in the prevention of obesity through the modulation of gut microbiota were included. s, letters to the editor, protocols, review articles and studies were inaccessible were excluded from consideration. To assess the quality of the included studies, a tool comprising 10 items was developed.FindingsGenerally, 3192 papers were retrieved from the above-mentioned databases and nine papers were considered for the present study after reading titles and abstracts and by considering the inclusion and exclusion criteria. In all these studies, the impact of ginger on gut microbiota has been examined, with a consistent focus on its effects on obesity. Overall, the existing evidence suggests that ginger not only positively influences gut microbiota but also serves as an effective agent in the prevention and management of obesity.ConclusionThese findings highlight the potential of ginger as a natural and effective option in obesity management programs and for improving overall health. Nonetheless, it is clear that the amount of ginger ingested may influence its effects, and more research is required to establish the proper dosage and understand the exact how ginger supplementation works.

Cardiac fibrosis is a prevalent characteristic of various cardiovascular diseases and poses a significant global health challenge. Recent research has established a robust correlation between gut microbiota and cardiovascular diseases. Hesperidin has been shown to possess cardioprotective properties to some extent. Furthermore, studies suggest that hesperidin may enhance overall health by regulating intestinal flora. However, there is a lack of reports regarding the effects of hesperidin on cardiac fibrosis. This study aimed to investigate the mechanisms by which hesperidin ameliorates cardiac fibrosis through the regulation of gut microbiota and associated metabolites. Cardiac fibrosis was induced in C57BL/6 mice via subcutaneous injection of isoproterenol (5 mg/kg per day) for a duration of 7 days. Echocardiography was used to assess cardiac function, while Masson staining, western blot analysis, and real-time polymerase chain reaction were used to evaluate fibrosis-related indicators. Changes in gut microbiota were analyzed through 16S ribosomal RNA gene sequencing. Our findings indicate that hesperidin significantly mitigates cardiac fibrosis in mice. These beneficial effects are associated with improvements in the dysbiosis of intestinal microbiota observed in fibrotic mouse models. The involvement of gut microbiota in cardiac fibrosis was further corroborated by administering hesperidin therapy to mice depleted of gut microbiota. To our knowledge, this study provides the first evidence that the modulation of gut microbiota by hesperidin contributes to improved outcomes in cardiac fibrosis. The use of traditional Chinese medicine to modulate gut microbiota presents a promising strategy for the treatment of cardiac fibrosis. SIGNIFICANCE STATEMENT: The work is extremely interesting because it acts on a frontier of science that relates the influence of the intestinal microbiota with human physiological systems and associated pathologies. This study provides the first evidence that the modulation of gut microbiota by hesperidin contributes to improved outcomes in cardiac fibrosis.

Cortex Phellodendri extract (CPE) has been used in China to treat diarrhea whereas the underlying mechanisms remain poorly understood. Given that dysbiosis of gut microbiota is a potential reason for diarrhea, and that oral CPE has a low absorption rate in intestine, we hypothesized that modification of gut microbiota is an important factor in CPE’s anti-diarrhea effect. To test this hypothesis, we established a diarrhea model by challenging post-weaning mice with oral Enterotoxigenic-Escherichia coli (ETEC), and then the mice were treated with two doses of CPE (80 mg/kg bodyweight and 160 mg/kg bodyweight) or the vehicle control (phosphate buffered saline). Diarrhea indices, inflammatory factors, morphology of jejunum, short-chain fatty acids (SCFAs), and serum endocrine were determined. Modification of gut microbiota was analyzed using 16S rDNA high-throughput sequencing. The changes in functional profiles of gut microbiota were predicted using software PICRUSt. We then explored the association between CPE-responding bacteria and the symptoms indices with the spearman’s rank correlation coefficient and significance test. Compared with diarrheal mice, CPE decreased Gut/Carcass ratio and water content of stool, increased goblet cell density and villus height/crypt depth of jejunum, as well as decreased inflammatory indices (Tumour Necrosis Factor-α, Myeloperoxidase and Interleukin-1α). CPE shifted the gut microbiota significantly by increasing alpha diversity (observed species, ace, Shannon, and Simpson) and restoring the gut microbiota. CPE increased Firmicutes and decreased Bacteroidetes. The reduced genus Prevotella, Acinetobacter, and Morganella were positively associated with the diarrhea indices, whereas increased genus Odoribacter, Rikenella, and Roseburia were negatively associated with the diarrhea indices. The abundance of carbohydrate metabolism-related gene and SCFAs-producing bacteria were increased, which was evidenced by increased butyric acid and total SCFAs concentration in the caecum. Consequently, endocrine peptides glucagon-like peptide-1, epidermal growth factor, and peptide tyrosine tyrosine in serum were elevated. ConclusionsCPE shows a shift function on the gut microbiota in alleviating the diarrhea of mice in a dose-dependent manner. In addition, the microbial metabolites SCFAs may mediate CPE’s anti-diarrhea effect by enhancing endocrine secretion in mice.

Multiple sclerosis (MS) is a progressive neuromuscular disorder characterized by demyelination of neurons of the central nervous system (CNS). The pathogenesis of the disorder is described as an autoimmune attack targeting the myelin sheath of nerve cell axons in the CNS. Available treatments only reduce the risk of relapse, prolonging the remissions of neurological symptoms and halt the progression of the disorder. Among the new ways of targeting neurological disorders, including MS, there is modulation of gut microbiota since the link between gut microbiota has been rethought within the term gut-brain axis. Gut microbiota is known to help the body with essential functions such as vitamin production and positive regulation of immune, inflammatory, and metabolic pathways. High consumption of saturated fatty acids, gluten, salt, alcohol, artificial sweeteners, or antibiotics is the responsible factor for causing gut dysbiosis. The latter can lead to dysregulation of immune and inflammatory pathways, which eventually results in leaky gut syndrome, systemic inflammation, autoimmune reactions, and increased susceptibility to infections. In modern medicine, scientists have mostly focused on the modulation of gut microbiota in the development of novel and effective therapeutic strategies for numerous disorders, with probiotics and prebiotics being the most widely studied in this regard. Several pieces of evidence from preclinical and clinical studies have supported the positive impact of probiotic and/or prebiotic intake on gut microbiota and MS. This review aims to link gut dysbiosis with the development/progression of MS, and the potential of modulation of gut microbiota in the therapeutics of the disease.

Gut microbiota plays a crucial role in regulating the response to immune checkpoint therapy, therefore modulation of the microbiome with bioactive molecules like carotenoids might be a very effective strategy to reduce the risk of chronic diseases. This review highlights the bio-functional effect of carotenoids on Gut Microbiota modulation based on a bibliographic search of the different databases. The methodology given in the preferred reporting items for systematic reviews and meta-analyses (PRISMA) has been employed for developing this review using papers published over two decades considering keywords related to carotenoids and gut microbiota. Moreover, studies related to the health-promoting properties of carotenoids and their utilization in the modulation of gut microbiota have been presented. Results showed that there can be quantitative changes in intestinal bacteria as a function of the type of carotenoid. Due to the dependency on several factors, gut microbiota continues to be a broad and complex study subject. Carotenoids are promising in the modulation of Gut Microbiota, which favored the appearance of beneficial bacteria, resulting in the protection of villi and intestinal permeability. In conclusion, it can be stated that carotenoids may help to protect the integrity of the intestinal epithelium from pathogens and activate immune cells.

Untangling the 2-Way Relationship Between Red Wine Polyphenols and Gut Microbiota

Targeting the Gut Microbiota in Coronavirus Disease 2019: Hype or Hope?

BackgroundAccording to TCM theory, ‘Spleen’ is associated with the functions of digestion, absorption and nutrition, differs from the function as an immune organ in modern medicine context. Being as one...