Effects of dietary intervention on human diseases: molecular mechanisms and therapeutic potential

Abstract

Diet, serving as a vital source of nutrients, exerts a profound influence on human health and disease progression. Recently, dietary interventions have emerged as promising adjunctive treatment strategies not only for cancer but also for neurodegenerative diseases, autoimmune diseases, cardiovascular diseases, and metabolic disorders. These interventions have demonstrated substantial potential in modulating metabolism, disease trajectory, and therapeutic responses. Metabolic reprogramming is a hallmark of malignant progression, and a deeper understanding of this phenomenon in tumors and its effects on immune regulation is a significant challenge that impedes cancer eradication. Dietary intake, as a key environmental factor, can influence tumor metabolism. Emerging evidence indicates that dietary interventions might affect the nutrient availability in tumors, thereby increasing the efficacy of cancer treatments. However, the intricate interplay between dietary interventions and the pathogenesis of cancer and other diseases is complex. Despite encouraging results, the mechanisms underlying diet-based therapeutic strategies remain largely unexplored, often resulting in underutilization in disease management. In this review, we aim to illuminate the potential effects of various dietary interventions, including calorie restriction, fasting-mimicking diet, ketogenic diet, protein restriction diet, high-salt diet, high-fat diet, and high-fiber diet, on cancer and the aforementioned diseases. We explore the multifaceted impacts of these dietary interventions, encompassing their immunomodulatory effects, other biological impacts, and underlying molecular mechanisms. This review offers valuable insights into the potential application of these dietary interventions as adjunctive therapies in disease management.

Fig. 1

Overview of the relationship between dietary interventions and diseases. The cellular microenvironment, including the tumor microenvironment (TME), plays a crucial role in disease biology, and diet serves as a vital source of nutrients that can influence these microenvironments. Metabolic reprogramming, a prominent feature associated with disease progression, can affect cell metabolism and immune function. Dietary interventions, such as caloric restriction (CR), fasting-mimicking diet (FMD), and ketogenic diet (KD), can modulate the progression and treatment sensitivity of various diseases, including cancer. Additionally, dietary interventions can alter the composition and functional capacity of the gut microbiome, thereby indirectly influencing the progression and treatment of diseases. These direct and indirect effects of dietary interventions can influence metabolic reprogramming, modulate immune responses, and potentially enhance the clinical efficacy of treatments for various diseases. This figure was created with BioRender.com

Fig. 2

Major metabolic pathways associated with different immune cell subtypes within the tumor microenvironment (TME). Summary of the main metabolic pathways of immune cells, highlighting the distinctive metabolic characteristics and requirements of different subsets of immune cells. This figure was created with BioRender.com

Fig. 3

Mechanisms by which diet modulates antitumor effects and cancer treatment via modulation of the gut microbiome. a Calorie restriction (CR) elevates IFNγ⁺CD8⁺ T cells in the tumor microenvironment (TME) by enriching Bifidobacterium bifidum and increasing acetate levels. b Ketogenic diet (KD) induces a shift from tolerogenic (Lactobacilli spp., Clostridium asparagiforme) toward immunogenic bacteria (such as Akkermansia muciniphila) driven by host production of ketone bodies, of which β-HB selectively inhibits the growth of bifidobacteria, resulting in KD-associated decreases in intestinal Th17 cell levels. c High-salt diet (HSD) increases the abundance of Bifidobacterium and leads to intratumoral localization of Bifidobacterium, further enhancing NK cell functions and tumor regression. HSD decreases the expression of IL-17A and iNOS and inhibits inflammation, which reduces enterotoxigenic Bacteroides fragilis (ETBF)-promoted colon carcinogenesis. HSD exacerbates Helicobacter pylori infection and promotes gastric carcinogenesis. d High-fat diet (HFD), through augmentation of queuosine-producing gut bacteria, can incite chemotherapy resistance in pancreatic cancer patients. HFD reduces SCFA-producing bacteria and SCFA production, leading to decreased levels of short-chain fatty acids (SCFAs) that activate the MCP-1/CCR2 axis, which promotes M2 TAM recruitment and polarization, ultimately contributing to colorectal cancer (CRC) progression. High bile salt hydrolase (BSH) enzyme activity in an HFD mouse model activates the β-catenin/CCL28 axis, further inducing immunosuppressive Tregs and accelerating CRC progression. e Dietary intake rich in tryptophan stimulates certain Bacteroides to produce the metabolite indole-3-acetic acid (3-IAA). Increased levels of 3-IAA enhance the efficacy of chemotherapy treatment. Dietary intake rich in tryptophan, through the action of the probiotic Lactobacillus reuteri (Lr), leads to the production of the metabolite indole-3-aldehyde (I3A). This metabolite promotes the production of IFNγ from CD8⁺ T cells, thereby enhancing antitumor immunity and the efficacy of immune checkpoint inhibitors (ICIs). f High-fiber diet enriches Akkermansia muciniphila which produces the microbiota-derived STING agonist c-di-AMP, inducing type I interferon (IFN-I) production by intratumoural monocytes, resulting in various TME modulation pathways, including reprogramming of mononuclear phagocytes into immunostimulatory monocytes and DCs, promoting macrophage polarization toward an antitumor phenotype and stimulating crosstalk between NK cells and DCs, further enhancing the therapeutic effect of immunotherapy. Dietary fiber inulin can enhance the effectiveness of anti-PD-1 therapy by increasing the abundance of beneficial commensal microbes (e.g., Akkermansia, Lactobacillus and Roseburia) and SCFAs, further increasing the number of stem-like T-cell factor-1 (Tcf1)⁺PD-1⁺CD8⁺ T cells numbers. Dietary fiber pectin can improve the effectiveness of anti-PD-1 therapy by increasing the abundance of butyrate-producing bacteria, further promoting T-cell infiltration and activation in the TME. This figure was created with BioRender.com

Fig. 4

Impact of different diets on neurodegenerative diseases. The ketogenic diet (KD) can enhance inhibitory neurotransmission and anti-inflammatory effects in epilepsy, influence the gut microbiota, and elevate beneficial metabolites. KD is particularly beneficial for treating pediatric drug-resistant epilepsy with elevated specific Bifidobacteria and TNF. In Alzheimer’s disease (AD) and Parkinson’s disease (PD), KD could counteract decreased β-HB levels, inhibit the NLRP3 inflammasome, reduce pathology, and alleviate symptoms by inhibiting microglial activation. Fasting mimicking diet (FMD) enhances the gut microbiota composition and metabolites, inhibiting neuroinflammation. This results in the attenuated loss of dopaminergic neurons in the substantia nigra in patients with PD. Caloric restriction (CR) may prevent AD by lowering serum tyrosine levels, reversing the exhaustion of tyrosyl-tRNA synthetase (TyrRS), and upregulating the sirtuin pathway, which attenuates the amyloidogenic processing of amyloid-β protein precursor (APP). Dietary restriction can increase brain-derived neurotrophic factor (BDNF) and chaperone heat-shock protein-70 (HSP70) levels in the striatum and cortex, which are relevant to Huntington’s disease (HD). High-fat diet (HFD) can accelerate recognition-memory impairment in an AD mouse model by increasing blood N-acetylneuraminic acid (NANA) levels, leading to systemic immune exhaustion. Conversely, the Mediterranean diet (MD) may protect against memory decline and mediotemporal atrophy by lowering amyloid-β protein and phosphorylated tau levels, reducing AD risk. This figure was created with BioRender.com

Fig. 5

Impact of different diets on autoimmune diseases. Extravirgin olive oil (EVOO) can reduce joint inflammation and degradation in rheumatoid arthritis (RA) due to its phenolic compounds. However, the protective effects of a high-fiber diet can be reversed by Prevotella copri colonization, which promotes proinflammatory responses. Fish oil supplementation can suppress proinflammatory cytokines and cartilage degradation, improving RA outcomes. Vitamin D can inhibit the proliferation, differentiation, and function of B and T cells, potentially reducing inflammatory cytokine expression in systemic lupus erythematosus (SLE) patients. A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) can alleviate gut symptoms in quiescent inflammatory bowel disease (IBD) patients, possibly by regulating the immune response through reducing fecal microbial abundance. However, a high-fat diet (HFD) can exacerbate pre-IBD inflammation by impairing epithelial mitochondrial bioenergetics and triggering microbiota disruptions, especially when combined with antibiotics. High salt diet (HSD) can exacerbate autoimmune conditions such as multiple sclerosis (MS) by promoting the induction of pathogenic Th17 cells. Intermittent fasting (IF) can improve MS by reducing the number of IL-17-producing T cells, increasing the number of Tregs in the gut, and enhancing antioxidative microbial metabolic pathways. However, the Western diet can impair myelin-debris clearance in microglia, hindering lesion recovery after demyelination and potentially contributing to MS induction. This figure was created with BioRender.com

Fig. 6

Impact of different diets on cardiovascular diseases. Calorie restriction (CR) can reduce cardiac oxidative stress and inflammation, improve cardiac mitochondrial dynamics and maintain cardiac ion homeostasis, which may be protective against cardiovascular disease (CVD) in obese and/or insulin-resistant models. Fast-mimicking diet (FMD) increases cardiac vascularity and function and resistance to cardiotoxins in a high-fat, high-calorie diet (HFCD) mouse model. Alternate day fasting (ADF) improves cardiovascular markers, for example, reduced fat mass. Ketogenic diet (KD) inhibits the NLRP3 inflammasome and improves the blood lipid profile but may lead to impaired blood lipid profiles in healthy individuals. High-salt diet (HSD) can inhibit SIRT3 expression and induce persistent hepatic steatosis and inflammation, thereby contributing to cardiovascular damage. A diet lacking prebiotic fiber induces hypertension through inducing a deficiency in short-chain fatty acid (SCFA) production and GPR43/109A signaling. High branched-chain amino acid (BCAA) intake is associated with increased platelet activity and arterial thrombosis formation. This figure was created with BioRender.com

Fig. 7

Impact of different diets on metabolic disorders. High-fat diet (HFD) can directly increase caloric intake, induce inflammatory mediators such as JNK and IκB kinase (IKK) to promote hypothalamic inflammation, and contribute to adipose tissue hypoxia and inflammation, which all lead to the development of obesity and/or insulin resistance. Over-intake of fructose can also increase caloric intake and induce obesity by impairing hepatic insulin sensitivity. However, time-restricted feeding (TRF) with equivalent caloric intake from HFD can adjust various signaling pathways and rhythmic creatine-mediated thermogenesis and reverse excessive daytime sleepiness induced by paraventricular thalamic nucleus (PVT) dysfunction, resulting in a protective effect on HFD-induced obesity. High-fiber diet can reduce inflammation and insulin resistance by influencing the gut microbiota and associated molecules, for instance, SCFA-producing bacteria. Every-other-day fasting (EODF) regimen can also shift the gut microbiota composition and stimulate beige fat development within white adipose tissue to inhibit insulin resistance. Ketogenic diet (KD) is clinically beneficial for the glycemic control of type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). However, in experimental models, KD can decrease sensitivity to peripheral insulin by upregulating insulin receptors. Intermittent fasting (IF) alone or combined with exercise can reduce intrahepatic triglyceride (IHTG) levels and hepatic steatosis in NAFLD patients by downregulating hepatic inflammatory pathways, modifying lipogenic gene expression and inducing autophagy. Calorie restriction (CR) can be effective at reducing weight loss and reversing ovulatory/metabolic dysfunction in polycystic ovarian syndrome (PCOS) patients. This figure was created with BioRender.com