Background/Objectives: Colorectal cancer (CRC) accounts for nearly 10% of global cancer cases and is the second leading cause of cancer-related mortality. While age and genetics are non-modifiable risk factors, nutrition and its impact on gut microbiota are emerging as key determinants in CRC prevention and management. We aimed to systematically evaluate recent evidence on the role of diet and microbiota-targeted interventions—including probiotics, prebiotics, synbiotics, and postbiotics—in modulating CRC risk and therapeutic outcomes. Methods: A structured literature search was performed in PubMed, ResearchGate, Scopus, and ScienceDirect up to July of 2025. Reference lists of relevant reviews and clinical trials were also screened. A total of 36 studies were selected according to PRISMA guidelines. Data were extracted on dietary exposures, microbiota modulation, metabolite profiles, and CRC-related outcomes. Evidence quality was assessed using appropriate appraisal tools for observational and interventional designs. Results: Western-type diets were consistently associated with microbiota dysbiosis, the enrichment of pro-inflammatory and genotoxic taxa, and elevated CRC risk. Diets rich in fiber and polyphenols enhanced commensals producing short-chain fatty acids (e.g., butyrate), with anti-inflammatory and antineoplastic effects. Probiotics, prebiotics, and postbiotics demonstrated potential to restore microbial balance, improve epithelial integrity, and enhance tolerance to conventional therapies. Conclusions: Current evidence supports a complex interplay between nutrition, the gut microbiota, and CRC, with strong translational potential. Microbiota-modulating nutritional strategies, particularly fiber-rich diets and synbiotics, show the most consistent microbiota-related benefits in CRC prevention and represent promising adjuncts to standard therapies. However, much of the available research is still based on preclinical models. Therefore, there is a pressing need for well-designed clinical studies in human populations to validate these findings and inform evidence-based guidelines.

Obesity (lipotoxicity) results from a chronic imbalance between energy intake and expenditure. It is strongly associated with type 2 diabetes mellitus (T2DM, glucotoxicity) and considered a major risk factor for the development of metabolic complications. Their convergence constitutes “diabesity”, representing a major challenge for public health worldwide. Limited treatment efficacy highlights the need for novel, multi-targeted therapies. Non-shivering thermogenesis (NST), mediated by brown and beige adipose tissue and skeletal muscle, has emerged as a promising therapy due to its capacity to increase energy expenditure and improve metabolic health. Also, skeletal muscle plays a central role in glucose uptake and lipid oxidation, further highlighting its relevance in diabesity. This review explores current and emerging knowledge on physiological stimuli, including cold exposure, physical activity, and fasting, as well as bioactive ingredients and drugs that stimulate NST in thermogenic tissues. Special emphasis is placed on melatonin as a potential regulator of mitochondrial function and energy balance. The literature search was conducted using MEDLINE and Web of Science. Studies were selected based on scientific relevance, novelty, and mechanistic insight; prioritizing human and high-quality rodent research published in peer-reviewed journals. Evidence shows that multiple interventions enhance NST, leading to improved glucose metabolism, reduced fat accumulation, and increased energy expenditure in humans and/or rodents. Melatonin, in particular, shows promise in modulating thermogenesis through organelle-molecular pathways and mitochondrial protective effects. In conclusion, a multi-target approach through the activation of NST by physiological, nutritional, and pharmacological agents offers an effective and safe treatment for diabesity. Further research is needed to confirm these effects in clinical practice and support their use as effective therapeutic strategies.

Background: Obesity is a multifactorial, chronic disease characterised by excessive fat accumulation, low-grade inflammation, and metabolic dysfunction. Emerging evidence suggests that the gut microbiome–mitochondria axis may play a significant role in the pathophysiology of obesity, particularly in regulating energy metabolism, inflammatory responses, and mitochondrial function. However, most mechanistic insights into this axis derive from preclinical animal studies, while human evidence remains limited and largely associative. Mitochondrial dysfunction disrupts cellular energy balance, increases reactive oxygen species production, and may exacerbate gut dysbiosis, further contributing to metabolic disturbances. In addition, factors such as micronutrient deficiencies also play a relevant role in obesity development and progression. Objectives: This review aims to examine the bidirectional interactions between the gut microbiome and mitochondrial systems in obesity, with a focus on the underlying molecular mechanisms and their potential as therapeutic targets. Methods: Evidence from experimental models and clinical studies was analysed to evaluate how modulation of the microbiome–mitochondria axis through probiotics, prebiotics, dietary strategies, and faecal microbiota transplantation influences mitochondrial function, inflammation, and metabolic regulation. Results: Preclinical studies indicate that the gut microbiome modulates mitochondrial activity through the production of bioactive metabolites, including short-chain fatty acids, secondary bile acids, and tryptophan-derived compounds, which influence mitochondrial efficiency, lipid metabolism, and glucose regulation. Dysbiosis reduces these beneficial metabolites, impairing mitochondrial signalling and promoting adiposity and insulin resistance. Interventions targeting this axis have shown potential in restoring metabolic balance, improving mitochondrial function, and mitigating obesity-related complications such as hyperlipidaemia and glucose intolerance. Conclusions: Targeting the microbiome–mitochondria axis represents a promising therapeutic strategy for obesity, with the evidence based largely on preclinical findings. However, further well-designed human studies are required to clarify causality, optimise interventions, assess long-term safety and efficacy, and establish standardised clinical protocols for implementation.