Gut microbiome: A revolution in type II diabetes mellitus

Abstract

Type II diabetes mellitus (T2DM) has experienced a dramatic increase globally across countries of various income levels over the past three decades. The persistent prevalence of T2DM is attributed to a complex interplay of genetic and environmental factors. While numerous pharmaceutical therapies have been developed, there remains an urgent need for innovative treatment approaches that offer effectiveness without significant adverse effects. In this context, the exploration of the gut microbiome presents a promising avenue. Research has increasingly shown that the gut microbiome of individuals with T2DM exhibits distinct differences compared to healthy individuals, suggesting its potential role in the disease’s pathogenesis and progression. This emerging field offers diverse applications, particularly in modifying the gut environment through the administration of prebiotics, probiotics, and fecal microbiome transfer. These inter-ventions aim to restore a healthy microbiome balance, which could potentially alleviate or even reverse the metabolic dysfunctions associated with T2DM. Although current results from clinical trials have not yet shown dramatic effects on diabetes management, the groundwork has been laid for deeper investigation. Ongoing and future clinical trials are critical to advancing our understanding of the microbiome’s impact on diabetes. By further elucidating the mechanisms through which microbiome alterations influence insulin resistance and glucose metabolism, researchers can develop more targeted interventions. The potential to harness the gut microbiome in developing new therapeutic strategies offers a compelling prospect to transform the treatment landscape of T2DM, potentially reducing the disease’s burden significantly with approaches that are less reliant on traditional pharmaceuticals and more focused on holistic, systemic health improvements.

Key Words: Type II diabetes; Gut microbiome; Probiotics; Prebiotics; Fecal microbiota transplantation

Core Tip: Type II diabetes mellitus (T2DM) has surged globally, driven by genetic and environmental factors. Amidst pharmaceutical options, exploring the gut microbiome stands out. Research reveals distinct microbiome differences in T2DM, suggesting its role in pathogenesis. Interventions such as prebiotics, probiotics, and fecal transfers aim to restore balance. While clinical trials have not shown dramatic effects yet, ongoing research holds promise. Understanding microbiome mechanisms could revolutionize T2DM treatment, emphasizing holistic health approaches.

INTRODUCTION

The human gut microbiome is a complex ecosystem, hosting thousands of bacterial species, each exerting a unique influence on host metabolism. This intricate interplay involves a variety of signaling molecules derived from dietary components that are metabolized by these microbiota. The role of the gut microbiome extends beyond digestion, as it actively engages with multiple bodily systems to maintain physiological homeostasis[1]. In the context of type II diabetes mellitus (T2DM), the gut microbiome exhibits notable changes, termed dysbiosis, where there is an increase in bacteria that negatively impact metabolic health and a decrease in beneficial bacteria[2,3]. This shift can lead to a cascade of health issues, including metabolic disorders, cardiovascular complications, neuronal diseases, and various inflammatory conditions, as depicted in Figure 1[4,5].

Figure 1 Communication channels of the gut with various systems of the body through metabolites produced by the gut microbiota. LPS: Lipopolysaccharides; SCFAs: Short-chain fatty acids.

Despite understanding the broad impacts of gut microbiome dysbiosis, specific pathways, and interactions that lead to T2DM remain underexplored. The mechanisms through which microbial products and toxins contribute to increased intestinal permeability and subsequent inflammation are not fully elucidated. Furthermore, the exact nature of changes in the production of short-chain fatty acids (SCFAs), lipopolysaccharides, and bile acids in diabetics requires detailed investigation[6-8]. These gaps in knowledge hinder the full exploitation of the gut microbiome as a target for therapeutic interventions. Understanding these pathways in greater depth could unveil novel strategies to manage or potentially reverse the effects of dysbiosis in diabetic patients. The primary objective of this review is to synthesize current understandings of the microbiome’s role in T2DM, with a particular focus on the pathophysiological changes associated with dysbiosis. We aimed to identify and discuss novel therapeutic strategies that target the microbiome to ameliorate the symptoms and complications associated with T2DM.

GUT MICROBIOTA AND ITS EFFECTS ON T2DM

Organisms with a positive correlation with the disease

The microbiome composition in individuals with diabetes, particularly T2DM, exhibits significant variations compared to non-diabetic individuals. Notably, the phyla Proteobacteria and Firmicutes[3] are predominantly observed in diabetics. Within Firmicutes, there is a noted increase in the genus Ruminococcus and a decrease in Clostridium species[3], as demonstrated in Figure 2, which outlines the microbiota profile variation in T2DM. However, observations in patients of different ethnicities may vary and needs further investigation.

Figure 2 Microbiota profile variation in type II diabetes mellitus. DM: Diabetes mellitus.

Research highlights that the Firmicutes-to-Bacteroides ratio, which is typically below 0.8 in healthy individuals, is elevated in those with T2DM and obesity. This altered ratio is indicative of microbial dysbiosis associated with these conditions[9-11]. Using a Predomics approach, three species have been identified as significant biomarkers for T2DM: Enterococcus faecium, Eubacterium linosum, and Absiella spp.[12]. Eubacterium linosum, an anaerobic acetogenic bacterium, is particularly noteworthy for its metabolic functions, including acetate production, sulfate reduction, and the degradation of urea and arginine. These metabolic activities contribute to chronic low-grade inflammation via pro-inflammatory cytokines and metabolites, a hallmark of T2DM[13,14]. Additionally, the production of acetate through the fermentation of galacto-oligosaccharides or inulin is linked to alterations in insulin sensitivity and weight gain[8,15]. Certain species within the Firmicutes phylum are recognized for their enhanced capacity to break down complex sugars and fatty acids, thereby potentially increasing the risk of obesity and T2DM[16]. On the other hand, some species within the Proteobacteria phylum, such as Fusobacterium spp., are implicated in protein fermentation and degradation, leading to dysbiosis. Fusobacterium spp. also contributes to pathogenicity by inducing inflammatory cytokines [interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-17, etc.], which further exacerbate the inflammatory state[17,18].

Organisms with a negative correlation with the disease

Several organisms exhibit a negative correlation with T2DM, primarily through mechanisms that involve the production of anti-inflammatory and immunoregulatory metabolites such as butyrate and propionate[14]. Among these, the genus Bifidobacterium is notably protective against T2DM, attributed to its cross-feeding mechanisms that enhance metabolic health[19]. Animal studies further corroborate the benefits of various species within this genus, demonstrating an increase in glucose tolerance[20-24].

Another significant genus negatively correlated with T2DM is Bacteroides. This group, which includes species like Bacteroides uniformis and Bacteroides acidifaciens, is known to improve glucose tolerance and insulin sensitivity, and is instrumental in managing metabolic diseases exacerbated by poor diet[25,26]. Despite their reduced presence in individuals with T2DM, other genera such as Faecalibacterium, Akkermansia, and Roseburia also exhibit similar negative correlations with the disease, though they are not as abundantly reported[27]. Lactobacillus species display variable associations with T2DM; however, species like Lactobacillus plantarum[28], Lactobacillus casei[29], and Lactobacillus reuteri[30] have been shown to improve symptoms when administered as probiotics. In synergy with Bifidobacterium, they confer a collective protective effect against the disease[31-37]. SCFAs such as butyrate play crucial roles beyond their metabolic functions; they regulate pancreatic beta-cell activity, reduce hepatic gluconeogenesis, and modulate immune system functions. The reduction in these critical microbiota directly contributes to the pathogenesis of T2DM.

Gut metabolites

The fermentation of nutrients by gut microbiota leads to the production of metabolites like SCFAs (butyrate, propionate, acetate), branched-chain amino acids, indoles, imidazoles, and succinates. These are predominantly produced by genera including Bacteroides, Akkermansia, Prevotella, Faecalibacterium, Lactobacillus, Clostridium, and Propionibacterium. These metabolites have diverse and significant interactions within the gut environment, as illustrated in Figure 3.

Figure 3 Metabolite breakdown products of gut microbiome. GLP-1: Glucagon-like peptide-1.

Pathogenesis of dysbiosis contributing to worsening T2DM

Alteration in permeability and steatosis: Changes in the gut microbiome composition have been associated with T2DM progression, particularly a decrease in species such as Bacteroides and Akkermansia. These microbes are crucial for the regulation of tight junction proteins including occludin and claudin, which maintain intestinal barrier integrity[4,38]. The disruption of these tight junctions leads to increased intestinal permeability. This, in turn, facilitates enhanced nutrient absorption and altered glycemic control, propelling the progression toward steatosis. Concurrently, the reduction in microbial populations that regulate hepatic gluconeogenesis exacerbates liver steatosis.

Inflammation and altered lipopolysaccharides: Increased intestinal permeability allows greater absorption of dietary products and bacterial endotoxins, such as lipopolysaccharides, into the bloodstream. This elevates the production of pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-17, and other cytokines linked to T helper (Th)1, Th2, and Th17 responses. This state of endotoxemia drives systemic inflammation and reactive oxygen species production, leading to the destruction of pancreatic beta cells and the onset of insulin resistance[4,38]. The absence of protective microbial effects due to altered microbiota composition, such as those from Roseburia intestinalis, Bacteroides fragilis, Akkermansia spp., and Lactobacillus casei, further compounds the problem. These species induce anti-inflammatory cytokines like IL-10, which may help mitigate low-grade inflammation and potentially improve insulin sensitivity. Roseburia intestinalis, for example, also promotes the production of IL-22, enhancing insulin sensitivity, and transforming growth factor-beta, inhibiting inflammatory processes.

Fatty acid metabolism: The altered composition of gut flora observed in T2DM patients may affect the production of SCFAs. These SCFAs, such as butyrate and propionate, are essential in promoting fatty acid oxidation by inhibiting the expression of peroxisome proliferator-activated receptor-gamma[39]. The absence of these regulatory mechanisms is evident in conditions like increased serum malonaldehyde, a marker for lipid oxidation, which is typically reduced by Lactobacillus casei and Akkermansia muciniphila in experimental models, but is elevated in diabetic subjects[40,41]. This disruption leads to enhanced fat accumulation in adipose tissue and the liver[42-44], triggering a modification in bile acid metabolism. Such alterations further propagate inflammation and microbial imbalance, perpetuating a cyclical exacerbation of T2DM pathogenesis[4]. Having discussed the potential associations between gut metabolites from microbiome dysbiosis and T2DM progression, specific targets to ameliorate their impact remains an area of future research.

Changes of the gut microbiome at different stages/complications of T2DM

The changes in the gut microbiome studied through various human and animal studies, a targeted replenishment of gut microbiota, can lead to delay or prevention in complications of diabetes through supplementation by probiotics, prebiotics, and fecal microbial transplantation, which in turn restores the stability of gut microbiota, as mentioned in Table 1.

Table 1 Dysbiosis observed in various stages of diabetes mellitus.

Complication/stage observed	Dysbiosis observed
	Decreased	Increased
Diabetic nephropathy	Lactobacillus, Bifidobacterium, Bacteroides, Prevotella, Roseburia, Ruminococcaceae, and Faecalibacterium	Enterococcus, Enterobacteriaceae, Clostridaceae, Klebsiella, and Parabacterides
Diabetic neuropathy	Bacteroides and Faecalibacterium	Escherichia, Blautia, Ruminococcus torques, and Lachnoclostridium
Diabetic retinopathy	Bacteroidetes and Actinobacteria	Escherihia, Enterobacter, and Acidaminococcus
Cerebrovascular disease	Lachnospiraceae, Ruminococcaceae, Bacteroidetes, Prevotella, and Faecalibacterium	Enterobacteriaceae, Veillonellaceae, Bifidobacterium, Lactobacillus, and Oscillobacter
Cardiovascular disease	Roseburia, Eubacterium spp, Bacteroides and Faecalibacterium	Collinsella, Escherichia-Shigella, Enterococcus, and the ratio of Firmicutes to Bacteroides
Peripheral vascular disease	-	Firmicutes, Actinobacteria, Verrucomicrobia, and Proteobacteria

Effects of diabetic medications on the gut microbiome

Metformin: Metformin is well-documented for its favorable modifications to the gut microbiome. According to Ismail and Evans-Molina[45], metformin treatment leads to changes in the composition of gut microbiota, enhancing the production of SCFAs and altering bile acids. These changes result in increased levels of glucagon-like peptide-1 (GLP-1), which promotes insulin secretion. Additionally, metformin helps normalize the altered microbial community by reversing the Firmicutes/Bacteroides ratio, which is often disrupted in diabetic conditions, thus restoring the microbiome toward a healthier state[4].

Sulfonylureas: The effects of sulfonylureas on the gut microbiome are less clear, with studies presenting conflicting data. One study reports that the use of sulfonylureas is associated with increased levels of phenylalanine and tryptophan, suggesting a potential impact on the microbiome[46]. However, another study found no significant changes in the composition of the gut microbiota with sulfonylurea treatment[47]. This indicates that the influence of sulfonylureas on the gut microbiome may vary depending on other factors such as dosage, duration of treatment, and individual patient microbiome composition.

Alpha-glucosidase inhibitors: Alpha-glucosidase inhibitors prevent the breakdown of oligosaccharides in the small intestine, thereby increasing their availability as nutrients for gut bacteria. This alteration in nutrient availability promotes the growth of beneficial microbes such as Bacteroides, Lactobacillus, and Faecalibacterium, while reducing populations of potentially pathogenic bacteria like Ruminococcus and Butyricicoccus[48]. These microbial shifts are associated with changes in bile acid profiles and improvements in prognostic factors for T2DM.

GLP-1 agonists: GLP-1 agonists, which slow gastric emptying, induce significant shifts in the gut microbial community. Studies indicate a reduction in obesity-promoting organisms within the Firmicutes phylum and an increase in po-pulations of Verrucomicrobia and microbes from the orders Clostridiales and Bacteroidales[49]. These drugs also promote the growth of SCFA-producing bacteria such as Bifidobacterium and Bacteroides, further supporting glycemic control and metabolic health[50].

Sodium-glucose co-transporter type 2 inhibitors: Sodium-glucose co-transporter type 2 inhibitors, such as sotagliflozin, impact the gut microbiome by decreasing the Firmicutes/Bacteroides ratio and enhancing fatty acid production[51]. This alteration not only affects the microbial landscape but also has broader implications for energy metabolism and insulin sensitivity in T2DM patients. A summary of the effects of diabetic medications on the gut microbiome is tabulated in Table 2.

Table 2 Effects of diabetic medications on gut microbiome.

Medication	Effects on microbiome	Observed outcomes
Metformin[45]	Enhances SCFA production, normalizes Firmicutes/Bacteroides ratio	Increased GLP-1 levels, improved insulin secretion
Sulfonylureas[46,47]	Conflicting data on impact	Variable influence on microbiome, potential increase in phenylalanine and tryptophan levels
Alpha-glucosidase inhibitors[48]	Increases nutrient availability for beneficial bacteria	Growth of beneficial microbes like Bacteroides, improvement in T2DM prognostic factors
GLP-1 agonists[49,50]	Changes in gastric emptying rates influence microbiota	Reduction in obesity-promoting organisms, increase in beneficial microbes like Bifidobacterium
SGLT-2 inhibitors[51]	Alters microbial ratios favorably	Reduction in Firmicutes/Bacteroides ratio, enhanced fatty acid production

DM: Diabetes mellitus; GLP-1: Glucagon-like peptide-1; SCFA: Short-chain fatty acid; SGLT-2: Sodium-glucose co-transporter type 2.

Influence of diet and exercise on gut microbiome

The influence of diet and exercise on the gut microbiome has significant implications for the management of conditions such as T2DM. Various dietary patterns and physical activities have been shown to differentially affect the composition and functionality of the gut microbiota, with direct consequences on metabolic health (Table 3).

Table 3 Impact of diet and exercise on the gut microbiome in type 2 diabetes mellitus.

Factor	Description	Beneficial effects
Diet	High fiber plant-based foods[4,52]	Decrease in insulin resistance, stabilization of blood glucose levels, reduction in serum cholesterol
	High-fat and protein diets[53]	Increase in pro-inflammatory markers; variable effects based on protein source (plant vs animal)
	Mediterranean diet[54]	Improvement in SCFA production, enhanced insulin sensitivity, increased beneficial genera like Roseburia
Exercise	Low-intensity physical activity[55-57]	Favorable shifts in microbiota composition, improvement in metabolic health markers

SCFA: Short-chain fatty acid.

Dietary influences

A diet rich in plant-based fibers such as cellulose, inulin, pectin, and dextrin has been found to confer multiple health benefits, including reduced insulin resistance, lower serum cholesterol levels, and stable blood glucose levels. These effects are largely attributed to the enrichment of beneficial gut bacteria that negatively correlate with metabolic diseases. These bacteria produce SCFAs such as butyrates and propionates, which play a crucial role in reducing the production of pro-inflammatory cytokines, thereby mitigating inflammation associated with T2DM[4,52]. Conversely, diets high in fats and proteins, particularly from animal sources, tend to foster a pro-inflammatory gut environment. This is largely due to an increase in lipopolysaccharides, which are potent inflammatory agents. However, it is important to note that not all protein-rich diets have adverse effects. Diets rich in plant proteins can enhance the proliferation of beneficial microbes such as Lactobacillus spp. and Bifidobacterium spp. In contrast, diets high in animal proteins tend to increase levels of Bacteroides and Bilophila, which have mixed effects on health depending on the overall dietary context[53]. The Mediterranean diet, which is rich in vegetables, fruits, nuts, seeds, and whole grains, has been specifically noted for its positive alterations to the gut microbiota. Adherence to this diet enhances the production of SCFAs, thereby improving insulin sensitivity. Observational studies in obese patients have shown increases in beneficial genera such as Roseburia and Oscillospira, alongside a reduction in Prevotella spp., which are associated with dysbiosis and metabolic disturbances. The beneficial shifts in the gut microbiome are contingent upon strict adherence to the dietary regimen[54].

Exercise influence

Physical exercise also plays a critical role in modulating the gut microbiome. Low-intensity physical activities have been associated with favorable changes in the gut microbiota composition, including an increase in the Bacteroides/Firmicutes ratio[55-57]. This shift helps mitigate the adverse effects of an unhealthy diet and contributes to overall metabolic health. Exercise-induced modifications to the microbiome can enhance the resilience of the gut ecosystem, promoting a balance that favors metabolic health and potentially reducing the risk or severity of T2DM.

THERAPIES FOR T2DM BASED ON THE GUT MICROBIOME

Nutraceutical agents

Lactobacillus and Bifidobacterium are among the most extensively studied probiotics, known for their beneficial effects on glycemic control. Meta-analyses have demonstrated that supplementation with these microbes can significantly decrease hemoglobin A1c, fasting blood glucose, and markers of oxidative stress[58]. Additionally, the introduction of Akkermansia muciniphila, a recent focus in microbiome research, has shown promising results. In murine models, this bacterium has been found to increase GLP-1 levels in colon cells, enhance glucose tolerance, and maintain gut barrier integrity, thereby reducing inflammation and ameliorating liver damage[59]. Research indicates that Akkermansia muciniphila also modulates the Firmicutes/Bacteroides ratio, leading to increased butyrate production. These changes collectively contribute to reduced oxidative stress and improved lipid profiles and glucose tolerance[39].

Fecal microbiota transplantation

Beyond probiotics, fecal microbiota transplantation (FMT) represents a more direct method for altering the gut microbiome. Initially popularized through its efficacy in treating Clostridium difficile infections, which often arise from chronic antibiotic use and the resultant suppression of native flora, FMT has since broadened its clinical applications[60]. Data from various human studies suggest that FMT can decrease inflammatory markers and increase the production of secondary bile acids, although its effects on insulin resistance have been relatively mild[61]. This indicates that, while FMT holds potential, its full spectrum of therapeutic benefits in T2DM remains to be fully elucidated through additional clinical trials. Despite its potential, FMT carries risks, particularly the possibility of transferring a dysbiotic microbiome and infectious pathogens. Therefore, while FMT is a promising tool in the arsenal against metabolic diseases, its application must be approached with caution, ensuring rigorous screening and monitoring protocols to mitigate these risks. A summary of evidence of the role of the gut microbiome in T2DM is tabulated in Table 4.

Table 4 Summary of global studies of the gut microbiome in type 2 diabetes mellitus.

Ref.	Place of study	Probiotics used	Observed effects
Kumari et al[62], 2021	India	Lactobacillus spp.	Decreased HbA1C, insulin resistance, TNF-α, IL-1β
		Lactococcus spp.
		Propionibacterium spp.
		Bifidobacterium spp.
Zhao et al[63], 2020	China	Selenium enhanced	Decreased FG, HbA1C, and insulin levels and improves glucose tolerance and lipid profile
		Bifidobacterium spp.
Palacios et al[64], 2020	Australia	Lactobacillus plantarum	Decreased FG, HbA1C, and insulin resistance
		Lactobacillus bulgaricus
		Lactobacillus gasseri
		Bifidobacterium breve
		Bifidobacterium animalis sbsp. lactis
		Bifidobacterium bifidum
		S. thermophiles
		S. boulardii
Razmpoosh et al[65], 2019	Iran	Lactobacillus acidophilus	Decreased FG, insulin resistance, and increased HDL cholesterol
		Lactobacillus casei
		Lactobacillus rhamnosus
		Lactobacillus bulgaricus
		Bifidobacterium breve
		Bifidobacterium longum
		Streptococcus thermophilus
Madempudi et al[66], 2019	India	Lactobacillus salivarius	Decreased HbA1C and effects on lipid profile are not significant
		Lactobacillus casei
		Lactobacillus plantarum
		Lactobacillus acidophilus
		Bifidobacterium breve
		Bifidobacterium coagulans
Sabico et al[67], 2019	Saudi Arabia	Bifidobacterium bifidum W23	Decreased FG, insulin resistance, total cholesterol, and triglycerides
		Bifidobacterium lactis W52
		Lactobacillus acidophilus W37
		Lactobacillus brevis W63
		Lactobacillus casei W56
		Lactobacillus salivarius W24
		Lactobacillus lactis W19
		Lactobacillus lacis W58
Mazruei Arani et al[68], 2019	Iran	Bacillus coagulans T4	Decreased FG, insulin resistance, CRP, and improves lipid profile
Mohseni et al[37], 2018	Iran	Lactobacillus acidophilus	Decreased FG, insulin resistance, inflammatory markers, and improves lipid profile
		Bifidobacterium bifidum
		Lactobacillus casei
		Lactobacillus fementum
Kobyliak et al[61], 2018	Ukraine	14 probiotic strains of Lactobacillus	Decreased HbA1C and insulin resistance
		Lactococcus
		Bifidobacterium spp.
		Propionibacterium
		Acetobacter
Kassaian et al[69], 2018	Iran	Lactobacillus acidophilus	Decreased FG, HbA1C, and insulin resistance
		Bifidobacterium lactis
		Bifidobacterium bifidum
		Bifidobacterium longum
Mohseni et al[37], 2018	Iran	Bifidobacterium bifidum	Decrease FG, insulin resistance, total cholesterol, and increased GSH level
		Lactobacillus casei
		Lactobacillus acidophilus
Mofidi et al[35], 2017	Iran	Lactobacillus casei	Decreased FG and triglycerides
		Lactobacillus rhamnosus
		Streptococcus thermophilus
		Bifidobacterium breve
		Lactobacillus acidophilus
		Bifidobacterium longum
		Lactobacillus bulgaricus
Firouzi et al[36], 2017	Malaysia	Lactobacillus acidophilus	Decreased HbA1C and does not affect lipid profile
		Lactobacillus casei
		Lactobacillus lactis
		Bifidobacterium bifidum
		Bifidobacterium longum
		Bifidobacterium infantis
Tajabadi-Ebrahimi et al[33], 2017	Iran	Lactobacillus acidophilus	Decreased FG, increased insulin sensitivity, and does not affect lipid profile
		Lactobacillus casei
		Bifidobacterium bifidum
Ebrahimi et al[70], 2017	Iran	Lactobacillus spp.	Decreased FG, HbA1C, and no effect on lipid profile
		Bifidobacterium spp.
		Streptococcus thermophilus and fructo-oligosaccharide
Asemi et al[71], 2016	Iran	Probiotic: Lactobacillus sporogenes	Decreased in serum insulin, insulin resistance, triglycerides and increased GSH levels
		Prebiotic: Inulin, beta-carotene
Madjd et al[72], 2016	Iran	Lactobacillus acidophilus LA5	Decreased HbA1C, 2-h postprandial glucose, insulin resistance, total cholesterol, and LDL levels
		Bifidobacterium lactis BB12
Karamali et al[73], 2016	Iran	Lactobacillus acidophilus	Decreased fasting glucose, insulin resistance, triglycerides, VLDL, and increased insulin sensitivity
		Lactobacillus casei
		Bifidobacterium bifidum
Ostadrahimi et al[74], 2015	Iran	Lactobacillus acidophilus	Decreased HbA1C, and FG and does not affect lipid profile
		Lactobacillus casei
		Bifidobacterium lactis
Eslamparast et al[75], 2014	Iran	Lactobacillus casei	Decreased FG, insulin resistance and has no effect on lipid profile
		Lactobacillus rhamnosus
		Streptococcus thermophilus
		Bifidobacterium breve
		Lactobacillus acidophilus
		Bifidobacterium longum
		Lactobacillus bulgaricus
Rajkumar et al[76], 2014	India	Bifidobacterium longum	Decreased FG, insulin resistance, total cholesterol, triglycerides, LDL, VLDL, and increased HDL levels
		Bifidobacterium infantis
		Bifidobacterium breve
		Lactobacillus acidophilus
		Lactobacillus paracasei
		Lactobacillus bulgaricus
		Lactobacillus plantarum
		Streptococcus thermophilus
Ivey et al[77], 2014	Australia	Lactobacillus acidophilus La5	Increased FG and insulin resistance
		Bifidobacterium lactis Bb12
Mohamadshahi et al[78], 2014	Iran	Bifidobacterium lactis Bb12	Decreased HbA1C
		Lactobacillus acidophilus
Asemi et al[79], 2014	Iran	Probiotic: Viable & heat-resistant Lactobacillus sporogenes	Decreased FG, HbA1C, insulin resistance, and inflammatory markers
		Prebiotic: Inulin
Asemi et al[34], 2013	Iran	Lactobacillus spp.	Decreased FG and increased insulin levels, total GSH levels, and LDL levels
		Bifidobacterium spp.
		Streptococcus spp. Fructo-oligosaccharide
Mazloom et al[80], 2013	Iran	Lactobacillus acidophilus	Decreased FG, insulin resistance, and improves fasting insulin
		Lactobacillus bulgaricus
		Lactobacillus bifidum
		Lactobacillus casei
Shavakhi et al[81], 2013	Iran	Lactobacillus acidophilus	Decreased FG, triglycerides, and total cholesterol
		Lactobacillus casei
		Lactobacillus rhamnosus
		Lactobacillus bulgaricus
		Bifidobacterium breve
		Bifidobacterium longum
		Streptococcus thermophilus
Asemi et al[82], 2013	Iran	Lactobacillus acidophilus LA5	Decreased insulin resistance
		Bifidobacterium animalis BB12
Asemi et al[34], 2013	Iran	Lactobacillus acidophilus	Decreased FG, increased insulin resistance, and LDL levels
		Lactobacillus casei
		Lactobacillus rhamnosus
		Lactobacillus bulgaricus
		Bifidobacterium breve
		Bifidobacterium longum
		Streptococcus thermophiles
Moroti et al[31], 2012	Brazil	Lactobacillus acidophilus	Decreased FG and increased HDL levels
		Bifidobacterium bifidum
Ejtahed et al[83], 2012	Iran	Lactobacillus acidophilus La5	Decreased FG and HbA1C and does not affect lipid profile
		Bifidobacterium lactis Bb12
Laitinen et al[84], 2009	Finland	Lactobacillus rhamnosus GG	Decreased FG, insulin resistance, and increased insulin sensitivity
		Bifidobacterium lactis Bb12

CRP: C-reactive protein; FG: Fasting glucose; GSH: Glutathione; HbA1C: Hemoglobin A1c; HDL: High-density lipoprotein; IL: Interleukin; LDL: Low-density lipoprotein; TNF: Tumor necrosis factor; VLDL: Very low-density lipoprotein.

Challenges and limitations

One of the principal challenges in leveraging the gut microbiome for diabetes treatment is the inherent variability in microbial composition among individuals. Factors such as genetics, diet, age, and environment significantly influence the gut microbiota, creating a highly personalized microbial ecosystem. This variability can affect the efficacy of probiotic treatments, as the same probiotic strains may not produce identical effects in different individuals. The lack of standardization in probiotic formulations poses another significant challenge. Probiotics are available in various forms, from dietary supplements to fortified foods, with considerable differences in strain specificity, viability, and concentration. These discrepancies can lead to inconsistent study results and confusion about their clinical applicability. Moreover, the regulation of probiotics varies by region, affecting the quality and safety of available products.

While short-term studies have demonstrated the potential benefits of probiotics in managing T2DM, long-term safety and efficacy remain underexplored. Questions about the optimal duration of probiotic therapy, long-term side effects, and the sustainability of beneficial effects need to be addressed through longitudinal studies. A deeper mechanistic understanding of how probiotics interact with both the gut microbiota and the host is crucial. Current knowledge about the pathways through which probiotics influence metabolic health, including their effects on inflammation, insulin sensitivity, and lipid metabolism, is still rudimentary. Enhanced mechanistic insights would facilitate the development of more targeted and effective therapeutic strategies. Interactions between probiotics and other medications commonly used by diabetic patients pose another layer of complexity. The potential for probiotics to affect drug metabolism and efficacy needs thorough investigation to avoid adverse effects and ensure complementary therapeutic outcomes.

Future directions

Advancing a personalized medicine approach in microbiome research could significantly enhance the efficacy of treatments. By understanding individual microbiome profiles, treatments can be tailored to optimize microbial composition and functionality. This approach would involve integrating detailed genomic, metabolic, and dietary data to predict individual responses to specific probiotic strains. Research into next-generation probiotics, which are specifically engineered or selected based on their beneficial characteristics, is a promising direction. These could include not only bacteria but also other components of the microbiota such as beneficial viruses or fungi that play a role in metabolic regulation.

Combining probiotics with other therapeutic modalities, such as dietary interventions, pharmacotherapy, and lifestyle changes, could enhance overall treatment outcomes. For example, synchronizing probiotic supplementation with a fiber-rich diet might amplify the beneficial effects on the gut microbiome. Conducting more rigorous and comprehensive clinical trials that focus on various demographic groups and different stages of diabetes is crucial. These studies should aim to clarify optimal dosages, treatment durations, and combinations of probiotic strains. Moreover, trials should also assess the impact of probiotics on diabetes complications, offering a broader understanding of their potential benefits. Enhancing healthcare provider and patient education about the potential benefits and limitations of probiotics as part of diabetes management is essential. Increased awareness can lead to more informed decision-making and better clinical outcomes. The limitations and future directions in gut microbiome research for T2DM are summarized in Table 5.

Table 5 Limitations and future directions in gut microbiome research for type 2 diabetes mellitus.

Limitations	Description	Future directions
Variability in microbial composition	Individual differences in microbiome composition complicate standard treatment outcomes	Personalized microbiome interventions: Develop treatments based on individual microbiome assessments to optimize efficacy
Lack of standardization	Inconsistencies in probiotic formulations affect study comparability and clinical applicability	Standardization of products: Establish regulations and standards for probiotic formulations to ensure quality and consistency
Short-term focus	Most studies have short duration and do not address long-term safety and effectiveness	Longitudinal studies: Conduct long-term studies to assess the sustained effects and safety of microbiome-based interventions
Incomplete mechanistic understanding	The pathways through which the microbiome influences diabetes are not fully elucidated	Mechanistic research: Deepen research into the biochemical interactions within the gut microbiome that affect diabetes pathogenesis and treatment
Drug-microbiome interactions	Potential interactions between probiotics and anti-diabetic medications are not well understood	Interaction studies: Explore how probiotics interact with common diabetic medications to refine treatment protocols
Regulatory hurdles	The global regulatory landscape for probiotics and microbiome therapies varies significantly	Harmonize regulations: Work toward an international consensus on the regulation of microbiome therapies to facilitate global research and application

CONCLUSION

T2DM significantly impacts the gut microbiota, leading to dysbiosis, which in turn promotes inflammation and contributes to the development of insulin resistance. The evidence gathered from various trials and studies underscores the pivotal role of nutraceuticals in restoring a balanced gut flora, enhancing insulin sensitivity, and reducing insulin resistance. These beneficial effects have been consistently observed in animal models and, to a lesser extent, in human studies. Although the initial outcomes from human trials have not met all expectations, they lay a solid foundation for future research. Continued exploration and more targeted studies are essential to refine these interventions and fully assess their therapeutic potential. With ongoing advancements and deeper insights into gut microbiome interactions, nutraceuticals hold promise as a novel and effective treatment strategy to manage T2DM. As research progresses, these natural compounds will become an integral part of comprehensive diabetes management, potentially shifting current therapeutic paradigms.