Mechanisms of Butyrate in Diabetes Through the Metabolism‐Immunity Axis and Targeted Therapeutic Strategies

ABSTRACT

This review summarizes the impact of butyrate on the development of diabetes, particularly its mechanisms of action through the metabolism‐immunity axis. Butyrate, a short‐chain fatty acid produced by the fermentation of dietary fibers by gut microbiota, plays a crucial role in maintaining gut health and metabolic homeostasis. Recent studies have highlighted the significance of butyrate in regulating metabolic functions, including glucose metabolism, while also affecting immune responses. However, the precise mechanisms by which butyrate influences these pathways in the context of diabetes remain incompletely understood, and several challenges in translating these findings into clinical practice persist. This paper will provide a comprehensive overview of the current research status regarding butyrate's role in diabetes, discuss existing issues, and introduce potential targeted therapeutic strategies that could leverage butyrate's beneficial effects for diabetes management.

Overnutrition, lipotoxicity and hyperglycaemia induce metabolic stress and inflammation, driving insulin resistance, β‐cell dysfunction and persistent hyperglycaemia in a self reinforcing cycle. Butyrate may break this cycle via adipose immune resolution, intestinal barrier repair, β‐cell resilience, and Treg tolerance.

1. Introduction

Diabetes comprises heterogeneous disorders characterized by chronic hyperglycemia. Type 2 diabetes mellitus (T2DM) is dominated by insulin resistance and progressive β‐cell dysfunction whereas type 1 diabetes mellitus (T1DM) results from immune‐mediated β‐cell destruction. Despite these distinct initiating mechanisms both conditions involve reciprocal interactions among nutrient handling, tissue stress, inflammatory signaling, and immune‐cell function. This interface is commonly described as an immunometabolic axis.

The gut microbiota contributes to this axis by transforming dietary substrates into bioactive metabolites. Besides, the mechanism of action of gut microbiota is very complex because it often acts on multiple systems through the systemic circulation. It remains unknown whether these cross‐organ/system axes have cross‐dialogue (Figure 1). Metagenomic studies in T2DM have identified dysbiosis that includes reduced abundance of several butyrate‐producing taxa, although the taxonomic signature varies across cohorts and is influenced by medication and diet [1, 2]. Butyrate is therefore relevant not simply as a marker of a favorable microbiome, but as a candidate mediator linking microbial ecology to host metabolism and immunity.

FIGURE 1.

Bidirectional communication along the microbiota–gut–brain axis. Gut microbiota communicate with the brain through neural, immune, and endocrine pathways involving microbial metabolites, neurotransmitters, gut peptides, cytokines and hormones. Signals generated by intestinal epithelial, enteroendocrine, and immune cells reach the brain, whereas central neural and hypothalamic–pituitary–adrenal (HPA) axis activity reciprocally regulates intestinal function. Am, amygdala; Hy, hypothalamus; IC, insular cortex.

Currently, the molecular mechanism of butyrate in diabetes is still unclear. Previous discussions of butyrate in diabetes often list improvements in glucose metabolism, inflammation and gut integrity as parallel outcomes. This descriptive organization obscures the causal sequence connecting microbial production to host exposure, receptor or intracellular sensing, cellular metabolism, immune regulation and systemic phenotype. This narrative review addresses these gaps by proposing a unified butyrate—immunometabolic framework. This structure is intended to help doctors or researchers search for potential targets of butyrate in the treatment of diabetes and provide ideas for promoting the clinical translation of butyrate.

2. Microbial Production and Physiological Context

Butyrate, a short‐chain fatty acid (SCFA), is primarily produced through the fermentation of dietary fibers by specific gut microbiota, particularly those belonging to the Firmicutes phylum. The primary sources of butyrate in the human diet include resistant starches, inulin, and other fermentable fibers found in fruits, vegetables, and whole grains. Once these fibers reach the colon, they are metabolized by butyrate‐producing bacteria such as Faecalibacterium prausnitzii. The fermentation process not only yields butyrate but also other SCFAs like acetate and propionate, which play vital roles in gut health and overall metabolism.

The production of butyrate is influenced by various factors, including the composition of the gut microbiota, dietary intake, and the physiological state of the host. For instance, a diet rich in fibers promotes growth of butyrate‐producing bacteria, thereby enhancing butyrate production. Conversely, high‐fat diets and the use of antibiotics can lead to dysbiosis, characterized by a decrease in butyrate‐producing bacteria and subsequently lower butyrate levels.

In addition to its role as an energy substrate, butyrate is a potent anti‐inflammatory agent. It helps to regulate the immune response in the gut by promoting the differentiation of regulatory T cells (Tregs), which are critical for maintaining immune tolerance and preventing excessive inflammatory responses. Butyrate achieves this by inhibiting the production of proinflammatory cytokines and enhancing the secretion of anti‐inflammatory mediators. This immunomodulatory effect is particularly important in conditions such as inflammatory bowel disease, where dysregulated immune responses contribute to tissue damage [3].

In summary, butyrate is a vital metabolite produced by gut microbiota that plays multifaceted roles in maintaining gut health. Its functions extend beyond serving as an energy source, encompassing anti‐inflammatory properties, modulation of immune responses, and promotion of a healthy gut microbiome.

3. The Molecular Mechanism Between Butyrate and Diabetes

3.1. Receptor Signaling and Enteroendocrine Output

Some evidence indicate that butyrate can directly bind to FFAR2/GPR43, FFAR3/GPR41, and HCAR2/GPR109A (Figure 2, Table 1). In enteroendocrine L cells, short‐chain fatty acid (SCFA) sensing through FFAR2 contributes to glucagon‐like peptide‐1 secretion [4]. This route provides an indirect connection between microbial fermentation, insulin secretion, satiety, and glucose handling. In addition, adipocyte GPR43 signaling in mice can restrain insulin‐mediated lipid accumulation and redirect energy utilization [5], whereas HCAR2 (GPR109A) signaling in colonic epithelial and immune cells promotes anti‐inflammatory programs [6]. Importantly, several receptor studies examine mixtures of acetate, propionate, and butyrate rather than butyrate alone. In the future, it is necessary to further clarify the direct evidence of butyrate binding to receptors.

FIGURE 2.

Butyrate regulates the intestinal microecological immune system through histone modification (acetylation and methylation). Acetate and propionate signal predominantly through free fatty acid receptor 2 (FFAR2/GPR43), whereas intracellular butyrate inhibits histone deacetylases (HDACs). In CD4⁺ T cells, HDAC inhibition increases histone H3 acetylation at regulatory regions of the Foxp3 locus and favors the differentiation of Foxp3⁺ regulatory T cells. In intestinal epithelial and myeloid cells, SCFA‐dependent HDAC inhibits alters histone acetylation and modulates NF‐κB‐dependent transcription inflammatory mediator production, IL‐10 receptor α (IL‐10RA) expression antimicrobial peptide production, apoptosis and epithelial barrier function. SCFAs may also indirectly influence histone and DNA methylation and miRNA‐dependent post‐transcriptional regulation; miRNAs reduce target‐gene expression by promoting mRNA decay and/or translational repression. AC, acetylation; AMP, antimicrobial peptide; HDAC, histone deacetylase; IL‐10RA, interleukin‐10 receptor subunit α; Me, methylation; NF‐κB, nuclear factor κB; SCFAs, short‐chain fatty acids; Treg, regulatory T cell.

TABLE 1.

Mechanistic components of the butyrate–immunometabolic axis.

Target	Cells and tissues	Principal event	Model	Limitation	Refs
FFAR2/FFAR3	Enteroendocrine and metabolic cells	GLP‐PYY release	Cell and mouse	SCFA mixtures, not a single butyrate mechanism	[4]
HCAR2/GPR109A	Colon epithelium and immune cells	Anti‐inflammatory signaling and Treg supportive programs	Cell and mouse	Strongest evidence is only from intestinal inflammation models	[6]
AMPK–PGC‐1α	Muscle, liver, and colon epithelium	Fat oxidation; energy expenditure	Cell and mouse	Systemic exposure after oral dosing may be insufficient	[7]
HDAC	T cells, macrophages, muscle and β cells	Treg differentiation; inflammatory transcription	Cell and mouse	Dose, duration, and cell state can reverse effects	[11, 12, 13]
NF‐κB/NLRP3	Adipocytes and immune cells	Reduced inflammatory mediators	Cell and mouse	Direct causal evidence in human diabetes is limited	[12, 13, 14]
AMPK–tight junctions/HIF	Colon epithelium	Barrier assembly; epithelial hypoxia and lower microbial translocation	Cell and mouse	Primarily a local intestinal mechanism	[15, 16]
Treg programming	Colonic and pancreatic immune compartments	Immune tolerance	Mouse	Translation to established human T1DM remains unproven	[6, 10, 11, 12]

3.2. Cellular Energetics, AMPK, and Mitochondrial Metabolism

Butyrate is both a signaling molecule and an oxidative substrate. In mice fed a high‐fat diet, supplementation improved insulin sensitivity and increased energy expenditure in association with greater mitochondrial function and activation of an AMP‐activated protein kinase (AMPK)– peroxisome proliferator‐activated receptor‐γ coactivator 1α (PGC‐1α) program in metabolic tissues [7]. Other mouse studies show that SCFAs can shift metabolism from lipogenesis toward fatty‐acid oxidation through a peroxisome proliferator‐activated receptor‐γ‐dependent mechanism [8].

These results provide a plausible route from microbial metabolite exposure to reduced ectopic lipid deposition and improved insulin action. However, pathway activation varies by tissue and dose. Skeletal‐muscle studies indicate that sodium butyrate can alter nucleosome positioning and mitochondrial adaptation during high‐fat feeding [9], but this preclinical evidence does not establish equivalent systemic exposure or pathway engagement after oral supplementation in humans.

3.3. HDAC Inhibition, Chromatin Regulation, and Inflammatory Signaling

At sufficient intracellular concentrations, butyrate inhibits class I and IIa histone deacetylases (HDACs). The resulting increase in histone acetylation can alter chromatin accessibility and transcription, but the downstream program depends on cell state. In T cells, butyrate promotes regulatory T (Treg) cell differentiation through enhanced acetylation at regulatory loci [10, 11]. In macrophages, HDAC inhibition changes antimicrobial and inflammatory programs [12]. In insulin‐resistant muscle cells, sodium butyrate restored elements of insulin signaling by epigenetically regulating insulin receptor substrate 1 [13].

Butyrate can restrain NF‐κB‐associated transcription and NLRP3 inflammasome‐related signaling in experimental systems. Macrophage studies link HDAC inhibition to reduced proinflammatory programs [12], whereas sodium butyrate reduced NLRP3 pathway activation and inflammatory mediator expression in adipocytes [14]. These changes can relieve cytokine‐mediated interference with insulin receptor signaling. Nevertheless, HDAC inhibition is not uniformly beneficial. Exposure concentration, duration and cell type can reverse the direction of effect, which is especially relevant to pancreatic β cells and therapeutic dosing.

3.4. Epithelial Barrier Function and Metabolic Endotoxemia

The intestinal barrier is a central bridge between local microbial metabolism and systemic inflammation. Butyrate activates AMPK‐dependent tight‐junction assembly in epithelial monolayers [15]. It also increases colonocyte oxygen consumption, helping to maintain epithelial hypoxia and hypoxia‐inducible factor‐dependent barrier programs [16]. These mechanisms can reduce the translocation of microbial products and thereby attenuate inflammatory stimuli reaching liver, adipose tissue and other organs. This model is consistent with experimental work linking gut permeability and metabolic endotoxemia to obesity and insulin resistance [17]. The evidence chain, however, is assembled across different studies: epithelial barrier effects are well supported locally, whereas direct demonstration that a butyrate‐induced barrier change causes improved glycemic control in humans remains limited. Therefore, it is necessary to further clarify the barrier function and metabolic outcomes together in a model.

3.5. Immune‐cell Programming and Diabetes Subtype

Butyrate links metabolism and immunity by providing a carbon source, engaging cell‐surface receptors and changing chromatin. In the colon, these mechanisms favor Treg differentiation and can modify macrophage function [6, 10, 11, 12]. Reduced inflammatory tone may indirectly improve insulin signaling in T1DM. In a mouse model of autoimmune diabetes, butyrate‐induced Treg cells migrated from gut‐associated lymphoid tissue to the pancreas and contributed to restored immune tolerance [18]. Human supplementation trials have so far not shown comparable restoration of islet immune tolerance, underscoring the distance between a tractable immune mechanism in mice and treatment of longstanding human disease.

4. Overview of the Metabolism‐Immune Axis

Diabetes is accompanied by reciprocal disruption of metabolism and immunity. In type 2 diabetes mellitus (T2DM), chronic nutrient excess and tissue stress alter immune‐cell composition and inflammatory tone in adipose tissue, liver, intestine, skeletal muscle, and pancreatic islets (Figure 3); these immune changes, in turn, aggravate insulin resistance and beta‐cell dysfunction. In type 1 diabetes mellitus (T1DM), loss of immune tolerance directly drives beta‐cell destruction. The following sections first outline the major abnormal tissue and systemic metabolism‐immune axes in diabetes, with emphasis on T2DM, and then examine how butyrate may modify these responses and where the available evidence remains preclinical.

FIGURE 3.

Butyrate modulation of the metabolism–immune axis in diabetes. Overnutrition, lipotoxicity, and hyperglycaemia induce multitissue metabolic stress and activate inflammatory immune responses. Dysfunction of the adipose–immune, gut–immune–liver, islet–immune, and trained‐immunity axes converge on insulin resistance, β‐cell dysfunction and persistent hyperglycaemia, forming a self‐reinforcing cycle. Butyrate may interrupt this cycle by promoting adipose immune resolution, repairing the intestinal barrier, enhancing β‐cell resilience and supporting Treg‐associated immune tolerance. Arrows indicate proposed directional relationships; upward and downward arrows denote increased and decreased activity, respectively. HSPCs, haematopoietic stem and progenitor cells; LPS, lipopolysaccharide; Treg, regulatory T cell.

4.1. Importance of the Metabolism‐Immune Axis in Diabetes

The abnormal metabolism‐immune axis in diabetes is a self‐reinforcing network rather than a single inflammatory pathway. In T2DM, overnutrition, ectopic lipid deposition and hyperglycaemia change the abundance and functional state of tissue‐resident and recruited immune cells. The resulting inflammatory environment impairs insulin action and beta‐cell compensation, while worsening metabolic stress further sustains immune activation. The principal interconnected circuits are the adipose tissue‐immune‐peripheral insulin axis, the gut‐immune‐liver axis, the hepatic macrophage‐ hepatocyte axis, the islet‐immune axis and a systemic axis involving bone‐marrow‐ derived innate immune cells.

Adipose tissue is a major starting point for this network. As adipocytes enlarge and become metabolically stressed, monocytes are recruited and adipose tissue macrophages acquire lipid‐handling and inflammatory programmes that disturb adipocyte insulin responsiveness. Recent single‐nucleus analyses identified an ATF4‐high, PDIA3‐high inflammatory and metabolically activated macrophage population in obesity; suppressing PDIA3 reduced adipose inflammation and metabolic dysfunction in mice [19]. Complementary work showed that macrophage CREBZF expression was increased in adipose tissue from obese humans, correlated with insulin resistance, and causally promoted adipose inflammation and hyperglycaemia in diet‐induced insulin‐resistant mice [20]. In human subcutaneous adipose tissue from patients with T2DM, a 2026 single‐nucleus study further identified a maladaptive circuit between mitochondrially stressed adipocytes and lipid‐associated macrophages, although the small cohort requires independent validation [21]. Signals generated within inflamed adipose tissue are then propagated to other insulin‐responsive organs. In an interconnected human induced‐ pluripotent‐stem‐cell model, macrophage‐driven adipocyte inflammation was sufficient to induce hepatic lipid accumulation and system‐wide insulin resistance, supporting a functional adipose‐liver immune‐metabolic axis [22].

The gut and liver form a second abnormal axis. Impaired intestinal integrity increases host exposure to microbial products, which can amplify systemic inflammation and hepatic insulin resistance. In a human case‐control study, obesity with T2DM was associated with reduced intestinal NLRP6 expression, greater gut permeability and increased inflammatory markers [23]. The liver normally limits this exposure through immune clearance. In obese mice, loss of CRIg‐positive Kupffer cells allowed microbial DNA to accumulate, whereas restoring the splicing factor SRSF3 in Kupffer cells recovered CRIg expression, reduced tissue inflammation and improved insulin sensitivity [24]. These observations connect intestinal barrier failure and defective hepatic immune surveillance to the persistence of insulin resistance rather than treating dysbiosis, endotoxaemia, and liver inflammation as separate abnormalities.

The pancreatic islet is another site where metabolic stress is converted into immune injury. During obesity and T2DM, stressed beta cells and nutrient‐derived signals expand and activate islet macrophages, creating a local inflammatory environment that progressively compromises insulin secretion. In diet‐induced obesity, palmitate‐driven mitochondrial stress activated STING in islet macrophages; these macrophages increased inflammatory cytokine production and engulfed insulin secretory granules, whereas genetic or pharmacological STING inhibition reduced islet inflammation and improved glucose‐stimulated insulin secretion [25]. This T2DM islet axis is dominated by chronic innate immune responses to metabolic stress and should be distinguished from the antigen‐specific lymphocyte‐mediated beta‐cell destruction that defines T1DM, although both ultimately reduce functional beta‐cell mass.

Finally, diabetes can imprint inflammation beyond individual organs. Hyperglycaemia alters haematopoietic stem and progenitor cells, generating myeloid progeny that remain hyper‐responsive after the initial metabolic stimulus has subsided. CD34‐positive haematopoietic progenitors from patients with T2DM displayed persistent inflammatory chromatin changes and produced proinflammatory intermediate monocytes [26]. Experimental diabetes similarly trained bone‐marrow‐derived macrophages and accelerated atherosclerosis after transfer into normoglycaemic recipients, with related transcriptional signatures detected in leukocytes and plaque macrophages from people with T2DM [27]. Thus, the abnormal metabolism‐immune axis in T2DM comprises linked local and systemic feedback loops: metabolic stress activates immune cells, immune‐derived inflammation impairs glucose and lipid handling, and hyperglycaemia and lipotoxicity stabilize this pathogenic state.

4.2. Effects of Butyrate on Immune Responses

Butyrate can influence diabetes‐related immunity at four closely connected levels: intestinal barrier integrity, innate immune‐cell activation, regulatory T‐cell tolerance and the resistance of beta cells to inflammatory injury. Its best‐established actions involve activation of HCAR2/GPR109A at the cell surface and inhibition of histone deacetylases (HDACs) after cellular uptake. However, the evidence is uneven. Direct links between these actions and diabetes are strongest in diabetic or diet‐induced‐obesity animal models and in ex vivo diabetic tissues, whereas clinical evidence for immune modulation remains limited.

The most direct T2DM evidence links butyrate to the gut‐adipose innate immune axis. In db/db mice, oral sodium butyrate reduced circulating lipopolysaccharide, inflammatory cytokines and HbA1c while restoring intestinal tight‐junction proteins and reducing inflammatory‐cell infiltration [28]. A separate db/db study showed that sodium butyrate decreased adipose CD68, interferon‐gamma and monocyte chemoattractant expression, suppressed the NLRP3‐interleukin‐1 beta programme and improved glucose tolerance and insulin sensitivity; similar effects of another HDAC inhibitor supported an HDAC‐dependent component [14]. Receptor‐dependent regulation has also been demonstrated in diet‐induced obesity. Tributyrin, a butyrate prodrug, reduced white‐adipose‐tissue inflammation, increased IL‐10, regulatory T cells and proresolving macrophages, and improved glucose metabolism in wild‐type mice, whereas these benefits were substantially lost in GPR109A‐deficient mice [29]. Together, these studies indicate that butyrate may interrupt T2DM progression by simultaneously limiting microbial inflammatory input and restraining adipose innate immune activation.

Butyrate also promotes immune tolerance through regulatory T (Treg) cells. Its classical intracellular action is HDAC inhibition, which increases histone acetylation at regulatory regions of the Foxp3 locus and favors the differentiation of colonic Treg cells [10]. The relevance to diabetes was tested directly in nonobese diabetic mice: a diet designed to increase colonic butyrate production expanded the number and function of Treg cells, improved gut integrity, reduced diabetogenic cytokines and protected against T1DM even when administered after loss of immunological tolerance had begun [30]. This provides direct evidence that butyrate can modify autoimmune diabetes by reinforcing regulatory immunity.

A further action occurs at the target tissue of diabetes‐related inflammation. Sodium butyrate preserved glucose‐stimulated insulin secretion in islets from human donors with T2DM and in cytokine‐exposed beta‐cell models. It restored stromal interaction molecule 1 expression and store‐operated calcium entry and reduced interleukin‐1 beta‐induced beta‐cell death [31]. This effect does not itself demonstrate suppression of an immune‐cell population, but it shows that butyrate can weaken the functional link between inflammatory cytokines and beta‐cell failure. Direct evidence in immune cells from patients with T2DM is less convincing. In peripheral blood mononuclear cells from individuals with poorly controlled T2DM, sodium butyrate produced a downward trend in LPS‐induced inflammatory cytokines, but the reductions were not statistically significant in the diabetic group [32]. Clinical findings therefore remain more limited than the experimental evidence. A randomized crossover trial in longstanding T1DM found that 1 month of oral sodium butyrate changed faecal short‐chain fatty acids but did not alter innate immune phenotypes, islet autoimmunity or beta‐cell function [33]. A 2026 proof‐of‐concept trial in adults with T2DM reported improved continuous‐ glucose‐monitoring time in range and lower triglycerides after oral sodium butyrate, but it did not measure immune endpoints and therefore cannot establish an immune mechanism [34]. Moreover, butyrate is not uniformly anti‐inflammatory: in TLR‐stimulated human macrophages it can activate NLRP3 and increase interleukin‐1 beta release through an HDAC‐dependent process [35]. Overall, direct diabetes studies support barrier repair, GPR109A‐dependent regulation of adipose immune cells, HDAC‐associated suppression of inflammatory programmes, promotion of Treg tolerance and protection of beta cells from cytokine injury. These mechanisms are biologically coherent, but their clinical relevance depends on dose, delivery, tissue exposure, and the pre‐existing inflammatory state.

5. Targeted Therapeutic Strategies for Butyrate

5.1. Existing Interventions

As we know, existing interventions targeting butyrate primarily focus on dietary modifications and supplementation aimed at enhancing butyrate production in the gut. Current strategies include the incorporation of prebiotics and probiotics into diets, which can stimulate the growth of butyrate‐ producing bacteria such as Faecalibacterium prausnitzii and Roseburia spp. For instance, dietary fibers like inulin and resistant starch have been shown to significantly increase fecal butyrate levels, thereby improving gut microbiota composition and enhancing gut barrier function [36]. Moreover, the therapeutic use of butyrate extends beyond gastrointestinal health. Research has indicated butyrate can exert neuroprotective effects, potentially benefiting conditions like depression and anxiety through modulating the gut‐brain axis [37]. This highlights the multifaceted therapeutic potential of butyrate, making it a promising candidate for various health interventions.

5.2. Emerging Drug Development

The emerging drug development strategies for butyrate focus on enhancing its bioavailability and therapeutic efficacy through new delivery systems and formulations. One promising approach involves the use of encapsulated butyrate or butyrate derivatives that can ensure targeted release in the colon, thereby maximizing its local effects while minimizing systemic exposure [38]. For instance, Butylated starch has been developed to enhance butyrate delivery specifically to gut, demonstrating significant anti‐inflammatory effects in preclinical models of colitis [39].

Additionally, exploration of butyrate analogs and prodrugs is gaining traction. These compounds are designed to improve the pharmacokinetic properties of butyrate, enhancing its therapeutic potential in various clinical settings. For example, research is underway to develop butyrate‐based formulations that can be used in conjunction with existing therapies for conditions such as colorectal cancer, where butyrate's role as an HDAC inhibitor can be leveraged to enhance the efficacy of chemotherapeutic agents [40].

Furthermore, the integration of butyrate into combination therapies is being explored, particularly in the context of metabolic disorders and inflammatory diseases. Researchers aim to create synergistic effects that can lead to improved patient outcomes by combining butyrate with other agents such as probiotics or anti‐inflammatory drugs [33]. Multifaceted approach to drug development underscores the growing recognition of butyrate as a key therapeutic agent with the potential to address a wide range of health issues.

5.3. Dietary Interventions and Butyrate Supplementation

Dietary interventions play a pivotal role in enhancing butyrate production and overall gut health. A diet rich in fibers, particularly soluble fibers, is known to promote the growth of butyrate‐producing bacteria in the gut. Foods such as legumes, whole grains, fruits, and vegetables are excellent sources of dietary fibers that can lead to increased butyrate levels through fermentation by gut microbiota [41]. Studies have shown individuals adhering to high‐fiber diets exhibit higher fecal butyrate concentrations, which are associated with improved metabolic health and reduced inflammation [42].

In addition to dietary fibers, the incorporation of prebiotics and probiotics into the diet can further enhance butyrate production. Prebiotics, such as inulin, serve as substrates for beneficial gut bacteria, promoting their growth and activity. Probiotics, on the other hand, can directly contribute to the fermentation process, leading to increased butyrate synthesis [43]. Clinical trials have demonstrated supplementation with specific probiotic strains can significantly elevate butyrate levels and improve gut health markers in various populations, including those with obesity and metabolic syndrome [44].

Moreover, butyrate supplementation itself has gained attention as a therapeutic strategy for various health conditions. Sodium butyrate, in particular, has been studied for its potential benefits in managing IBD, diabetes, and cardiovascular diseases [45]. However, the efficacy of butyrate supplementation can vary among individuals, influenced by factors such as baseline gut microbiota composition and dietary habits. Therefore, personalized dietary interventions that consider individual microbiome profiles may enhance the effectiveness of butyrate supplementation strategies [46, 47].

In a word, targeted therapeutic strategies for butyrate encompass existing interventions, emerging drug developments, and dietary modifications. These approaches hold promise for enhancing gut health, managing the metabolic disorders, and improving overall well‐being. Continued research into the mechanisms of action and optimal delivery methods for butyrate will be crucial in realizing its full therapeutic potential.

6. Future Research Directions

6.1. Clinical Research and Trial Design

The design and execution of clinical research and trials focused on butyrate and its effects on diabetes management are essential for translating preclinical findings into therapeutic applications. Current clinical studies have begun to explore the efficacy of butyrate supplementation in various diabetic cohorts, but there remains a need for well‐structured trials that address several key factors, including dosage, duration, and patient‐specific characteristics [18].

One challenge in designing these trials is the heterogeneity of diabetes as a disease. Participants may exhibit varying degrees of insulin resistance, beta‐cell function, and gut microbiota composition, all of which can influence the outcomes of butyrate interventions. Therefore, stratifying patients based on these factors could enhance the precision of clinical trials and improve the likelihood of observing significant effects. T1DM and T2DM should be studied separately, and T2DM trials should report disease duration, residual β‐cell function, insulin resistance, obesity, and concomitant medication. Metformin and other glucose‐lowering therapies can alter the gut microbiome and may modify response. Baseline diet, habitual fiber intake, stool transit, and microbial functional capacity are also plausible effect modifiers. Randomized trials should prespecify dose, formulation, delivery site, and duration; distinguish primary from exploratory endpoints; and avoid interpreting post hoc subgroups as confirmatory. Repeated measurements of fecal and plasma SCFAs, microbial genes, inflammatory markers, enteroendocrine hormones and continuous glucose metrics could connect exposure to mechanism and clinical phenotype. Long‐term safety and durability remain essential, especially for live biotherapeutics.

Moreover, incorporating biomarkers of butyrate metabolism and gut microbiota composition as endpoints in clinical trials could provide valuable insights into the mechanisms of action and help identify which patient populations are most likely to benefit from butyrate supplementation. For instance, measuring levels of butyrate and its metabolites in plasma or stool samples could serve as a direct indicator of intervention's efficacy and help correlate clinical outcomes with metabolic changes [45]. In addition, the integration of technology, such as continuous glucose monitoring and telemedicine, could facilitate more comprehensive data collection and patient engagement throughout the trial process. This approach could enhance adherence to dietary interventions and allow for the real‐time monitoring of metabolic responses to butyrate supplementation [48].

Ultimately, future clinical research should aim to establish clear guidelines for the use of butyrate in diabetes management, supported by robust evidence from well‐designed trials that consider the multifactorial nature of diabetes and the individual variability in response to treatment.

6.2. Applications of Personalized Medicine in Diabetes Management

The application of personalized medicine in management of diabetes represents a transformative approach that tailors treatment strategies to individual patient characteristics, including genetic, phenotypic, and lifestyle factors. As the understanding of diabetes pathophysiology evolves, there is a growing recognition of the need for personalized interventions that go beyond traditional one‐size‐fits‐ all approaches [49].

Recent advancements in genomics and metabolomics have paved the way for more precise diabetes management strategies. Genetic screening can identify patients with monogenic forms of diabetes, such as Maturity Onset Diabetes of the Young (MODY), allowing for targeted therapies that address the underlying genetic defects [50]. Furthermore, pharmacogenomics can inform medication choices based on individual responses to specific drugs, optimizing treatment efficacy and minimizing adverse effects [51].

Incorporating lifestyle modifications into personalized care plans is also crucial. Understanding how individual behaviors, such as dietary choices and physical activity levels, interact with genetic predispositions can help the healthcare providers develop tailored interventions that promote better glycemic control and overall health [52]. Moreover, leveraging technology, such as mobile health applications and telehealth services, can facilitate ongoing patient monitoring and support, allowing for real‐time adjustments to treatment plans based on individual progress and feedback [48]. This dynamic approach to diabetes management not only enhances patient engagement but also fosters a collaborative relationship between patients and healthcare providers.

As research continues to uncover the complexities of diabetes and its interactions with various biological systems, the implementation of personalized medicine in diabetes care holds the promise of improving patient outcomes, reducing complications, and ultimately enhancing the quality of life for individuals living with diabetes. Future studies should aim to validate personalized approaches through rigorous clinical trials and real‐world evidence, ensuring that these strategies are both effective and accessible to diverse patient populations.

7. Conclusion

In conclusion, butyrate represents a promising avenue for enhancing diabetes treatment strategies through its intricate influence on metabolic‐immune axis. The ongoing exploration of its mechanisms and therapeutic applications holds the potential to improve patient outcomes significantly. However, achieving this goal will require a concerted effort to integrate various research perspectives, ensuring that the complexities of butyrate's role are fully understood and appropriately applied in clinical practice. As we look to the future, the focus must remain on innovative research that not only clarifies butyrate's benefits but also addresses the practical challenges of its application in diabetes management, ultimately aiming to enhance the quality of life for those affected by this chronic condition.

Author Contributions

Hong‐wei Yu: conceptualized and supervised the manuscript. Jian‐long Zhang: edited and revised the manuscript. Fang‐jie Liu, Ying Liu and Wan‐neng Yan: reviewed and edited the manuscript. Ze Yu: conceptualized, supervised, and drafted this manuscript, project administration and funding acquisition. All authors read and approved the final manuscript.

Funding

This study was supported by Zhejiang Provincial Administration of Traditional Chinese Medicine (2022ZB385, 2024ZL1228); Zhejiang Medical and Health Science & Technology Project (2022KY1369); and Clinical research fund project of Zhejiang Medical Association (2022ZYC‐A98).

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.