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Journal of Drug Delivery and Therapeutics

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Open Access Full Text Article                                                                                 Review Article

Dietary Modulation of the Gut Microbiome: A Promising Approach for Management of Diabetes

Kingsley Ikechukwu Chukwudozie *¹, Izuchukwu Christopher Chukwudozie ², Chidimma Precious Onyeka ¹

1. Department of Microbiology, University of Nigeria
2. Department of Science Laboratory Technology, University of Nigeria

 

 

1. Introduction and Literature Review

The role of the microbiome, particularly the gut microbiome, in health cannot be overemphasized. The gut microbiome refers to the diverse community of microorganisms residing in the gastrointestinal tract and has emerged as a critical player in host metabolism and health ¹. Emerging evidence indicates that a symbiotic relationship exists between the host and its gut microbes. Studies have shown that the microbes of the gut microbiome impact the general physiology of the host ². The normal microbial community in the gut contributes to host nutrient metabolism, xenobiotic and maintenance of structural integrity of the gut mucosal barrier, immunomodulation, protection against pathogens and production of various bioactive compounds, thereby leading to overall improvement of host health ^3,4. On the other hand, an imbalance of this microbial community (dysbiosis) may result in any of various diseases, including metabolic diseases such as obesity and diabetes ^5–7 (Fig. 1)

Dysbiosis can impair the intestinal barrier, leading to increased gut permeability and the translocation of bacterial products like lipopolysaccharides (LPS) into the systemic circulation, triggering systemic inflammation, which promotes insulin resistance and impaired glucose metabolism ^8,9. This process can affect pancreatic beta-cell function, influence adipose tissue metabolism, and alter the production of beneficial microbial compounds like short-chain fatty acids (SCFAs), collectively contributing to the development and progression of diabetes ^10,11. Similarly, hematological parameters such as red and white blood cell counts and indices of anemia are often disrupted in diabetes, reflecting oxidative stress and impaired immune response ^12,13. Furthermore, the liver plays a central role in glucose homeostasis through processes like gluconeogenesis and glycogenolysis. In diabetes, the liver is often subjected to oxidative stress and metabolic strain, which can lead to hepatocellular damage and impaired function ^14,15. Elevated levels of liver enzymes such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), along with changes in total protein and albumin, are indicative of liver dysfunction and are commonly observed in diabetic patients ^16,17.

 

 

 

Figure 1: Dysbiosis in the gut microbiome can result to different diseases

 

 

There is a growing recognition of the role of diet in modulating the composition and metabolic activity of the human gut microbiota, which can impact health ^18–20. Several studies identified that changes in the quantity and diversity of gut microbiota have significant importance in the progression of many metabolic disorders, including diabetes and obesity ^4,21,22. The human gut microbiota is composed of different bacteria species taxonomically classified according to phyla, classes, orders, families, genera, and species. It is mostly composed by two dominant bacterial phyla, Firmicutes and Bacteroidetes that represent more than 90% of the total community, and by other subdominant phyla including Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia ^23,24.

Research has revealed that healthy individuals' gut microbiomes are more diverse and stable than individuals who developed autoimmunity and, eventually, diabetes. Diabetic individuals often have a gut microbial profile characterized by a reduction in beneficial bacteria populations and an increase in opportunistic or potential pathogenic bacteria ^25–27. Dietary interventions can modulate gut microbial composition to prevent and/or treat diabetes ²⁸. In the future, gut microbial signatures may serve as early diagnostic markers, and modulation of the gut microbiome may be widely applied to treat metabolic disorders such as diabetes. With more understanding of the gut microbiome and its relationship to health and disease, various interventions, including dietary interventions using prebiotics, probiotics and plant extracts, may restore the gut microbiota to health in patients with diabetes. 

Current therapeutic approaches for diabetes include insulin therapy and oral hypoglycemic agents. While effective, these interventions are often expensive, associated with adverse side effects, limited accessibility in resource-poor settings, and do not fully address the multi-systemic complications of the disease. These complications highlight the need for therapeutic strategies that address the systemic consequences of diabetes rather than focusing solely on glycemic control. Consequently, there is a growing need for alternative or complementary therapies that are affordable, safe, and capable of addressing the multifaceted complications of diabetes. Restoration of gut microbial balance in diabetic patients through dietary modulation of the gut microbiome is now being rapidly explored as an emerging promising novel therapeutic strategy for diabetes management and in the treatment of other ailments promoted by dysbiosis in the gut microbiome ^29–31. Promising results from several animal studies indicate a potential for gut microbiome modulation in preventing and treating diabetes. Restoring gut microbial balance in diabetic patients can be achieved through dietary modulation by increasing intake of high-fiber foods (fruits, vegetables, whole grains, legumes) and probiotic foods (yogurt, kimchi, sauerkraut) while reducing processed foods. These changes promote beneficial gut bacteria, which increase short-chain fatty acid (SCFA) production, improve gut barrier function, enhance insulin sensitivity, and reduce inflammation, leading to better glycemic control and metabolic health. 

2. Functions of the Gut Microbiome

The gut microbiota plays an important role in the normal functioning of the host organism. The relationship between the gut microbiota and the host organism is mutual. The gut microorganisms are supported by the host's food and play a key role in keeping the host healthy. Growing evidence from several studies on humans and animal models have reported the beneficial role of gut microbiota in human health ^32,33. The gut microbiota has many important functions in the human host, including assisting in providing resistance to pathogens, modulating the immune system³⁴, and playing a role in digestion and metabolism ³⁵. 

2.1. Metabolic Function of the Gut Microbiome

The Gut microorganisms play a major role in energy extraction from food through a variety of mechanisms. The gut microbiota encodes some genes that are not encoded by their host, thereby enabling them to undertake various metabolic functions that the host is unable to perform, such as the digestion of substrates that the host cannot digest ³⁶. This ability results in the recovery of energy and absorbable substrates for the host and a supply of energy and nutrients for gut bacterial growth and proliferation. The gut bacteria can produce various vitamins, notably vitamin K, and a range of B group vitamins such as folate, riboflavin, biotin, niacin and thiamine, synthesize amino acids and short-chain fatty acids (SCFAs) such as butyrate, propionate and acetate ³⁷. Butyrate is the main energy source for colonocytes and helps strengthen the epithelial barrier against invasion and colonization by pathogenic microbes ³⁸. Butyrate can also activate intestinal gluconeogenesis and improve insulin sensitivity. It also has anti-inflammatory potential and potential anti-cancer activity via the ability to induce apoptosis of colon cancer cells ^39–41. Propionate is transferred to the liver, where it regulates gluconeogenesis and satiety signalling through interaction with the gut fatty acid receptors ⁴². Acetate is the most abundant SCFA and an essential metabolite for the growth of other bacteria. For instance, Faecalibacterium prausnitzii will not grow in pure culture in the absence of acetate ⁴³. After production, acetate is transported to the peripheral tissues, where it is used in cholesterol metabolism and lipogenesis and may play a role in central appetite regulation ⁴⁴. Some enzymes produced by gut microbes are involved in bile acid metabolism and generating secondary bile acids that act as signaling molecules and metabolic regulators to modulate important host pathways ⁴⁵.

2.2. Immuno-Protective Role of Gut Microbiota

The intestinal epithelium is the main interface between the immune system and the external environment. The development of a host’s immune system is affected by continuous and dynamic interactions with the intestinal microbiota and its metabolites. Gut bacteria are integral to the early development of the gut mucosal immune system, both in terms of its physical components and function 46. The intestinal microbiota co-evolved with the host in a symbiotic relationship. In addition to some metabolic benefits, the symbiotic gut microbiota provides the host with several functions that promote immune homeostasis, immune responses, and protection against pathogen attachment and colonization. The ability of symbiotic gut bacteria to inhibit pathogen invasion and colonization is accomplished through several mechanisms. Many intestinal bacteria produce antimicrobial compounds such as bacteriocins which can inhibit the growth of pathogenic bacteria ^47,48. Many studies have reported that some probiotic Lactobacillus species were able to protect the host from foodborne infections and this was dependent on the Lactobacillus bacteriocin ^49,50. Gut bacteria compete for nutrients and sites of attachment in the gut lining and outcompete pathogenic bacteria, thereby preventing their attachment and colonization. The gut microbiota influences the immune system, modulating effector and regulatory T cells' number and function. To achieve this aim, mutual regulation between the immune system and microbiota is achieved through several mechanisms, including the engagement of toll-like receptors (TLRs) ^51,52. TLRs are transmembrane receptors mostly present on the membrane of immune cells and epithelial cells, including intestinal epithelial cells. TLRs are capable of recognizing conserved molecular motives, generally divided into microbe-associated molecular patterns (MAMPS) expressed by resident commensal microbiota and pathogens-associated molecular patterns (PAMPS) produced or expressed by microbial invaders. TLRs' engagement with PAMPS induces several intracellular signalling cascades resulting in the activation of immune cells and the production of cytokines and chemokines while maintaining tolerance towards most members of commensal gut microbiota expressing MAMPS ⁵³. 

Gut intestinal bacteria are also implicated in the prevention of allergy. Allergic infants and young children have been found to have a different composition of intestinal bacteria than those who do not develop allergies ^54,55. It is suggested that the intestinal microbiota stimulates the immune system and trains it to respond proportionately to all antigens. The altered composition of intestinal microbiota in early life can lead to an inadequately trained immune system that can often overreact to antigens ^56,57. There is growing evidence to show that short-chain fatty acids (SCFAs) play an important role in the modulation of host’s immunity and the development of several diseases ⁵⁸. Short-chain fatty acids SCFAs are end products of the microbial digestion of dietary fibre that humans cannot digest because the human genome does not encode the genes needed to produce the enzymes required for digestion of dietary fibre. These missing enzymes are provided by the gut microbiota. The luminal concentration of intestinal SCFAs is affected by the amount of fibre in the diet. In addition to acting as an energy source for the host, SCFAs also regulate host immune responses. SCFAs exert their signalling and immune-modulatory effects by binding to receptors such as G-protein-coupled receptors (GPCRs), FFA2, FFA3, and Olfr78 which are sensed by specific membrane-bound receptors on the surface of gut epithelial cells ⁵⁹. Studies have revealed that the binding of SCFAc to these receptors can lead to the regulation of metabolism, inflammation and other immune-modulatory effects. SCFAc such as butyrate exhibit anti-inflammatory effects by regulating the release of cytokines, and can modify the cytokine production profile of T-helper cells⁶⁰ and promote intestinal epithelial barrier integrity by serving as an energy source for gut epithelial cells ⁴⁴, which in turn can help to limit the exposure of the mucosal immune system to luminal microbes and prevent aberrant inflammatory responses. Several studies have also highlighted the role of SCFAs as a major player in maintaining gut and immune homeostasis ⁴⁶. 

A study showed the important role of acetate production in preventing infection with the enteropathogenic Escherichia coli (0157:H7) and this effect was attributed to acetate's ability to maintain the gut epithelial barrier function ^61, 62 investigated the therapeutic effect of administering butyrate orally to patients with Crohn’s disease CD. The result showed that the administration of 4g of butyrate daily for 8 weeks induced clinical improvement and remission in 53% of patients where butyrate successfully downregulated mucosal levels of NF-kB and IL-1b. ⁶³ and ⁶⁴ compared the production of SCFAs in allergic and non-allergic children and found that allergic children had lower levels of propionate, acetate, and butyrate in their faeces compared to non-allergic children. Mouse studies have also shown that SCFAs were beneficial in colitis as mice treated with butyrate had reduced inflammation in their colonic mucosa with reduced neutrophil infiltration ⁶⁵ and treatment with acetate had similar beneficial effects.  ⁶⁶ carried out a metagenomic analysis of the gut microbiota of type one diabetic subjects, and the 16S rRNA sequencing revealed a larger relative abundance of bacterial species capable of producing butyrate in controls than individual

3.0. Effect of Diet on Gut Microbiome

Dietary intake and eat­ing habits directly influence the composition and diversity of the gut microbiome. The intestinal microbiota rapidly responds to diet variations. Some gut bacteria can metabolize particular dietary components for energy, leading to their overgrowth in the gut when diets containing these particular dietary components are consumed. Furthermore, microbial metabolites such as short-chain fatty acids (SCFAs) produced from the consumption of complex carbohydrates promote the acidic environment in the gut, which in turn shapes the microbial composition ⁶⁷. Transient changes to the gut microbiota composition with a change in diets have been noted in several studies. Studies in mice have demonstrated that a high-fat diet decreases the number of bacterial species in the gut microbiome, and the gut microbiome of mice given a high-fat diet and those given a regular unpurified diet showed variations in microbial diversity ^68,69. Wu et al., 2011 investigated controlled feeding in 10 subjects and found that the microbiome composition changed within 24hrs of initiating a high-fat and low-fibre or low-fat and high-fibre diet and remained stable during the 10 days study ⁷⁰. Many dietary pat­terns such as the Western diet and Mediterranean diet have been shown to affect the gut microbiota's diversity, which may affect host metabolism ⁷¹ (Fig 2). The Western diet consists of a high intake of saturated fats, refined grains, sugar and a low fibre intake. It is highly associated with obesity and other metabolic diseases. The Western has also been shown to promotes inflammation, decrease the total gut bacteria diversity and the beneficial species in the gut ⁷². A Mediterranean diet is rich in dietary fibre, vegetables, grains and low in fat, contrasting with the Western diet. Abundant fi­bre in Mediterranean diets promotes stable gut microbiome profile and increases the presence of beneficial bacteria such as lactic acid bacteria ⁷³, ⁷⁴ reported that African children, who consume a low-fat and high-fibre diet, have less potentially pathogenic bacteria and exhibited a greater degree of diversity and microbial richness than European children consuming a high-fat diet (Western diet).

 

 

Figure 2: Many dietary pat­terns such as the Western diet and Mediterranean diet have been shown to affect the gut microbiota's diversity, which may affect host metabolism

 

4. Pathophysiology of Diabetes Mellitus

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both ⁷⁵. Prolonged hyperglycemia leads to disturbances in carbohydrate, fat, and protein metabolism, and long-term damage to blood vessels, nerves, kidneys, eyes, and other organs ⁷⁶. Insulin is a protein hormone secreted by the β cells of the islets of Langerhans of the pancreas under the influence of the blood glucose level. After secretion, insulin is deposited into the intracellular space from where it then passes into the bloodstream and proceeds through the circulation to the body's cells. At the cellular level, insulin interacts with a protein on the cell surface called an insulin receptor. This interaction stimulates a cascade of intracellular reactions, each catalyzed by a different enzyme, which ultimately results in another protein's production, called a glucose transporter (GLUT4) in cells. GLUT4 passes or migrates to the cell surface, facilitating the entrance of glucose. There are several forms or types of diabetes mellitus, but the vast majority of cases fall into two main categories: type 1 diabetes (TIDM) and type 2 diabetes (T2DM) ⁷⁷. TIDM is an autoimmune disorder usually due to immune-mediated destruction of insulin-producing pancreatic islet β -cells by immune cells. Consequently, the body produces little or no insulin. Without insulin, glucose cannot enter the body's cells to be used for energy. This leads to glucose building up in the bloodstream (hyperglycemia).

Type 2 diabetes is a more complex condition that develops over time. It is primarily characterized by two interconnected problems: insulin resistance and a progressive decline in beta-cell function. In the early stages, the body's cells (especially muscle, fat, and liver cells) become less responsive to insulin. This means that even though the pancreas is producing insulin, the cells aren't effectively taking up glucose from the blood. The pancreas initially compensates by producing more insulin to overcome this resistance, which keeps blood glucose levels in a normal range for a while. Over time, the pancreas's beta cells become exhausted from the hypersecretion of insulin and lose their ability to produce enough insulin to meet the body's demands. This progressive failure leads to insufficient insulin and persistent hyperglycemia. This process is often gradual and can take many years, which is why Type 2 diabetes is often diagnosed in adults. Factors such as genetics, obesity, a sedentary lifestyle, and poor diet significantly contribute to the development of insulin resistance and the eventual onset of Type 2 diabetes ^78,79. Resistance to insulin at the cellular level can be due to many causes. There can be genetic abnormalities of the insulin receptor so that insulin produced by the pancreatic islet β -cells cannot fit into the receptor and thus not activate the needed reactions within the cells. There can also be genetic abnormalities that result in a defect in any of the enzymes involved in any insulin actions within the cells.

5. Relationship Between Gut Microbiome and Diabetes

Various factors are involved in the development of diabetes, including genetic factors, diet, lifestyle and intestinal microbiota ⁸⁰. Several studies have shown that the gut microbial composition differs between healthy hosts and hosts with diabetes or at risk of diabetes, suggesting that the gut microbiota play a role in the aetiology of diabetes ^81–83. Several alterations of gut microbiota composition were described both in animal model and in humans. The decrease of Firmicutes/ Bacteroides ratio was the most frequent pattern described, in particular, in human studies. At the phyla level, it was well documented that the relative abundance of Firmicutes phyla decreased in T1DM patients compared to the healthy individual group, while Bacteroidetes abundance increased successively ^53,54.

In a case-control study that included sixteen (16) children with type1 diabetes and sixteen (16) healthy children, their gut microbial composition showed significant differences between the healthy children and the children with type1 diabetes. At the phyla level, the abundance of Firmicutes and Actinobacteria and the ratio of Firmicutes to Bacteroidetes were all significantly lower in the children with type1 diabetes than the healthy children ⁸³. At the genus level, the healthy children had greater numbers of Bifidobacterium, Lactobacillus, Blautia coccoides/Eubacterium rectale group, and Prevotella specie in the gut whereas children with type1 diabetes contained greater numbers of Veillonella, Clostridium and Bacteroides, ⁸³. also reported that compared with healthy control subjects, type 1 diabetes was associated with a significantly lower microbiota diversity, a significantly higher relative abundance of Veillonella, Ruminococcus, Blautia, Bacteroides and Streptococcus genera, and a lower relative abundance of Faecalibacterium, Bifidobacterium, Roseburia and Lachnospira. From the above discussion, it can be deduced that diabetic patients’ gut microbiota is characterized by an increased level of opportunistic pathogens and decreased level of probiotics. Furthermore, Firmicutes are negatively associated with diabetes, while Bacteroidetes is a positive factor at the phyla level. However, conflicting results have been reported on the difference between healthy individuals and diabetic patients at the genus level.

The mechanisms by which altered gut microbiota and diabetes interact are complex and are likely to proceed through a cascade of events primarily driven by how microbial activity impacts host metabolism and inflammation. The Gut microbiota contribute to the regulation of host glucose homeostasis through multiple mechanisms, including the synthesis of metabolites during fermentation of dietary fibre and their resulting secondary effects ⁸⁶. Butyrate, acetate, and propionate represent the principal short-chain fatty acids (SCFAs) produced through the microbial fermentation of dietary fibers in the intestine ^87,88. Among these, acetate and propionate are mainly synthesized by members of the phylum Bacteroidetes, whereas butyrate is predominantly produced by Firmicutes ⁵⁸. SCFAs may be directly utilized by intestinal epithelial cells as an energy substrate or absorbed into the systemic circulation, where they constitute an important energy source for the host and act as bioactive signaling molecules ^90,91. Even though SCFAs share some similarities in their mechanisms, they can exert different physiological effects due to variations in their chemical structure, receptor binding, cellular targets, and the specific metabolic pathways and tissues they influence. Butyrate has been reported to be the most effective short-chain fatty acid (SCFA) for improving diabetic conditions, with evidence showing it significantly reduces fasting blood glucose levels and improves insulin sensitivity in animal models ^92,93.

When the gut microbiota is in dysbiosis, as in the cases of diabetes, it is directly related to alteration of SCFA production ^94,95. According to ⁹⁶, the main characteristics of the microbiota of diabetic patients are reduced butyrate-producing bacteria population, dysbiosis, proinflammatory environment, increased intestinal permeability and increased serum lipopolysaccharide (LPS) concentration ^66,67. Butyrate improves insulin sensitivity and secretion by stimulating the secretion of glucagon-like peptide1 (GLP-1) from enteroendocrine L-cells ^98–100. GLP-1 intensifies glucose-induced insulin release from β-cells, suppresses glucagon secretion, protects β-cells from apoptosis, promotes β-cell proliferation ^70,71. Butyrate also serves as a primary energy source for colonic epithelial cells, essential for maintaining their integrity. Insufficient levels of butyrate have been linked to increased gut permeability due to weakened colonic epithelial cells ^103–105.

Thus, the decrease in relative abundance of Firmicutes and the corresponding increase in the level of Bacteroidetes in diabetic individuals could be linked with metabolic endotoxemia ^106,107. Bacteroidetes are gram-negative bacteria containing lipopolysaccharides in their outer membranes. Dysbiosis can compromise the integrity of the intestinal barrier, leading to a condition known as "leaky gut." This increased permeability allows bacterial components, such as lipopolysaccharides (LPS) from the cell walls of Gram-negative bacteria, to leak into the bloodstream. This translocation of LPS triggers a state of chronic, low-grade systemic inflammation, which is a major contributor to insulin resistance ¹⁰⁸. This inflammation disrupts insulin signaling pathways, making the body's cells less responsive to insulin and impairing glucose uptake ¹⁰⁹. Chronic Inflammation may lead to the activation of T-cells that mistakenly target and destroy the insulin-producing beta cells in the pancreas especially in genetically predisposed individuals.

Despite extensive research on the relationship between diabetes and the gut microbiome, the precise role of the intestinal microbiome in the pathogenesis of both Type 1 and Type 2 diabetes remains to be fully elucidated. The existing evidence is insufficient to definitively establish a causal relationship, leaving an open question as to whether dysbiosis is a cause or merely a consequence of the metabolic changes associated with the disease.

Conclusion

Dietary modulation of the gut microbiome represents a compelling and evidence-based strategy for the prevention and management of diabetes. Accumulating research demonstrates that nutrient composition, food diversity, and bioactive dietary components can reshape gut microbial communities, enhance short-chain fatty acid production, and reduce systemic inflammation, thereby improving insulin sensitivity and glycemic control. While promising, the clinical application of these findings requires further large-scale, long-term studies to identify optimal dietary patterns, individualize interventions, and elucidate host–microbe interactions that drive therapeutic benefits. Integrating dietary strategies with existing pharmacological and lifestyle approaches offers a holistic framework for diabetes management, paving the way for personalized nutrition and microbiome-targeted therapies.

Conflict of Interest: The authors declare no conflict of interest concerning the contents, authorship, and/or publication of this article.

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