Aug 2026· Biomedicines· Vol 14, pp. 1873· 0 citations· 236 references
Medicine
TL;DR
This narrative review synthesizes mechanisms through which diet influences ISC self-renewal, proliferation, differentiation, metabolic programming, and regenerative capacity.
Abstract
The intestinal epithelium is a dynamic tissue renewed by intestinal stem cells (ISCs) within the crypt niche. ISC behavior is regulated not only by intrinsic genetic programs but also by dietary composition, nutrient availability, microbial metabolites, and feeding rhythms. This narrative review synthesizes mechanisms through which diet influences ISC self-renewal, proliferation, differentiation, metabolic programming, and regenerative capacity. Dietary patterns exert context-dependent effects: caloric restriction, fasting, and structured feeding–fasting cycles may enhance epithelial regeneration through nutrient-sensing pathways, mitochondrial adaptation, and circadian regulation, whereas Western-type and high-fat diets may promote niche remodeling, inflammation, metabolic reprogramming, and tumorigenic risk. Macronutrients regulate ISC fate through carbohydrate metabolism, amino acid sensing, fatty acid oxidation, and lipid-derived signaling molecules. Micronutrients, including vitamins A, D, and B and minerals such as iron, zinc, selenium, and magnesium, contribute to epithelial differentiation, redox balance, and barrier integrity. Phytochemicals may modulate ISC function through Wnt/β-catenin, Nrf2, SIRT1, and epigenetic pathways or by stabilizing the epithelial microenvironment. The gut microbiota mediates diet–ISC interactions via short-chain fatty acids, bile acids, indole derivatives, and other metabolites. However, human evidence remains limited, and studies integrating human organoids, single-cell analyses, metabolomics, and chrononutrition are needed to inform personalized nutritional strategies for intestinal health.
The expanded microorganism-centered synthesis shows that dietary effects depend on microbial niche, substrate availability, community succession, metabolite production, and strain-specific probiotic or pathobiont activity.
Md. Hashibur Rahman, Hyuncheol Jeon, Haham Kim et al.· Microorganisms· 0 citations
The human microbiome is a complex ecosystem that produces a diverse repertoire of bioactive molecules essential for maintaining physiological homeostasis. Growing evidence indicates that microbiome-derived metabolites, including secondary bile acids, short-chain fatty acids (SCFAs), polyamines, vitamins, tryptophan-derived metabolites and microbial bioactive compounds, play vital roles not only in modulating immune responses and metabolic pathways but also in maintaining epithelial integrity and regulating systemic inflammation. Through their effects on host signaling pathways, these molecules act as key mediators in the development and progression of metabolic diseases and cancer. This review discusses how such molecules influence the tumor microenvironment, regulate epigenetic processes, such as histone deacetylase inhibition, and modulate metabolic pathways, including lipid homeostasis, adipogenesis, and insulin sensitivity. Emerging therapeutic approaches, including probiotics, postbiotics, and fecal microbiota transplantation, highlight the translational potential of microbiome-targeted interventions. Postbiotics comprise preparations of inanimate microorganisms and/or their components that confer health benefits and should be distinguished from purified microbial metabolites. Despite advancements in this field, challenges remain, including the standardization of metabolites and inter-individual variability in the microbiome, which can hinder widespread application. Future perspectives emphasize not only multi-omics technology but also the significant impact of personalized microbiome medicine, bioprospecting for novel metabolites, and computational modeling. Collectively, these findings highlight the therapeutic landscape of microbiome-derived molecules and their potential to transform interventional strategies for metabolic diseases and even cancer. This review synthesizes current knowledge on major classes of microbiome-derived metabolites, emphasizing their origins, mechanisms of action, and roles in disease modulation.
Tuayyeb Hussain Nadeem Hussain, Tuahir H. N. Hussain, Jyoti Bhagat et al.· Discover Molecules· 0 citations
Dietary macronutrients—proteins, lipids, and carbohydrates—influence the pathogenesis of inflammatory bowel disease (IBD) through distinct but interconnected metabolic pathways that extend beyond their roles as energy substrates. This narrative review synthesizes current evidence on how each macronutrient class modulates gut microbiota composition, intestinal barrier integrity, and mucosal immune responses. In the protein domain, the study examines how amino acid metabolism, particularly the tryptophan–kynurenine–indole axis and the arginine–inducible nitric oxide synthase–arginase balance, serves as a regulatory interface between microbial signals and immune cell function, and evaluates the clinical potential of targeted amino acid supplementation. In the lipid domain, a multi-level cascade is traced from phospholipid-dependent barrier structure through the pro-inflammatory/pro-resolving lipid mediator network to immune cell lipid reprogramming, and the study discusses how systemic lipoprotein abnormalities both reflect and amplify intestinal inflammation. In the carbohydrate domain, the study distinguishes between fermentable fiber and high-glycemic carbohydrates, and presents a dual-pathway model in which excess sugar drives IBD through two parallel routes: a microbiota-dependent pathway involving mucus depletion, barrier breach, and short-chain fatty acid deprivation; and a microbiota-independent pathway that directly impairs the metabolism of colonic epithelial stem cells. Throughout the study the emphasis is on the bidirectional nature of diet–inflammation interactions and identifies convergent mechanisms across macronutrient classes. The study concludes by outlining the translational challenges that must be addressed—cross-nutrient interactions, causal inference, and disease-stage-specific interventions—to move from generic dietary guidance toward mechanism-informed, personalized nutritional strategies for IBD, and highlights the need for well-designed intervention studies that test these strategies in defined patient subsets.
Ying Wang, Yin-Ying Wang, Yu-Qi Fu et al.· Frontiers in Nutrition· 0 citations
Innate lymphoid cells (ILCs) are innate-like lymphocytes that contribute to tissue homeostasis, barrier immunity, inflammation, and host defense. In metabolic syndrome (MetS), a condition estimated to affect more than 1.5 billion adults worldwide, dietary patterns and gut microbial metabolites are increasingly recognized as regulators of immune and metabolic dysfunction [1-8]. This review critically summarizes mainly experimental and preclinical evidence, with selected human observations where available, linking dietary components, gut microbiota-derived metabolites, and ILC subsets to obesity, insulin resistance, type 2 diabetes mellitus (T2DM), and related metabolic complications. Current evidence suggests that dietary fibers, short-chain fatty acids, lipids, vitamins, and fermented foods can modulate ILC1, ILC2, and ILC3 responses in a context-dependent manner. However, most mechanistic data derive from mouse models, and direct translation to human MetS remains limited. Through integrating diet-microbiota interactions, ILC subset biology, and metabolic inflammation, this review highlights candidate pathways and biomarkers that may guide future therapeutic studies rather than established clinical interventions.
The gut microbiota produces a wide variety of metabolites that are essential for host-microbe communication and play a critical role in regulating host physiology, metabolism, and immunity. Among the most important of these metabolites are Short-Chain Fatty Acids (SCFAs), bile acid derivatives, tryptophan metabolites, polyamines, vitamins, and polyphenol-derived compounds. These bioactive metabolites regulate energy homeostasis, glucose and lipid metabolism, intestinal barrier integrity, immune signaling, and gene expression. Moreover, they influence systemic physiological processes, including cardiovascular and neuroendocrine functions, while playing a pivotal role in regulating hepatic and adipose tissue metabolism and maintaining intestinal homeostasis. Dysbiosis-induced alterations in microbial metabolic activity have been associated with the development of several chronic diseases, including obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, cardiovascular diseases, cancer, autoimmune disorders, and neurological conditions. Consequently, therapeutic strategies aimed at modulating microbial metabolism, such as probiotics, prebiotics, postbiotics, dietary interventions, faecal microbiota transplantation, and synthetic biology-based approaches, are being extensively investigated, with microbial metabolites emerging as promising pharmacological targets. Despite these advances, significant challenges remain regarding their mechanistic understanding, standardisation, safety, and successful translation into clinical practice. The integration of multi-omics technologies, artificial intelligence, and precision microbiome-based interventions is expected to accelerate the development of personalized therapeutic strategies and enhance the clinical applicability of microbial metabolite research.
Amit Kumar, Phool Chandra, Prakhar Varshney et al.· Current pharmaceutical desig...· 0 citations
Intestinal barrier dysfunction, intestinal flora disorder and systemic chronic low-grade inflammation are key pathological processes that drive the progression of a variety of metabolic diseases (including obesity, type 2 diabetes and osteoporosis). Natural polyphenols have the ability to regulate intestinal microecology and regulate multi-target signal transduction, so they show significant metabolic regulation potential in dietary intervention strategies. In view of this, this review takes the pig model (which is highly similar to humans in terms of anatomy, physiology, immunology and intestinal microenvironment) as the research object to explore the intervention effect of polyphenols on metabolic diseases and its transformation clinical value. This review first explains the unique advantages and transformation application prospects of pigs as an ideal large animal model for human metabolic research. Subsequently, the system summarized the molecular mechanism of polyphenols to maintain intestinal homeosta by reshaping the core intestinal flora and promoting the production of short-chain fatty acids (SCFAs). In addition, this review also analyzes the regulatory effect of polyphenols in enhancing systemic antioxidant defense by activating the Nrf2/Keap1 pathway and inhibiting the release of pro-inflammatory factors by blocking the TLR4/NF-κB signaling pathway. By integrating the polyphenol intervention effect observed in the pig model and its potential molecular mechanism, this review provides reliable scientific evidence and theoretical reference for the development of dietary intervention strategies based on natural polyphenols and their subsequent clinical transformation.
Ying Zhou, Xin-Li Zhou· Frontiers in Microbiology· 0 citations
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