Probiotics in the Management of Diabetes

Abstract

Gut microflora that has been present in our bodies since infancy are known to influence health, metabolism, and disease. Diabetes is a developing epidemic, and treatment that cures diabetes has yet to be discovered. Probiotics are living bacteria that may colonize the human gastrointestinal system and help to maintain a healthy microbiome and help normalize disrupted metabolism in diabetic patients. Lipopolysaccharides, trimethylamine, and imidazole propionate seem to hinder insulin signaling, whereas secondary bile acids, short-chain fatty acids (SCFAs), and tryptophan metabolites seem to enhance it. This chapter emphasizes the relationship between gut microflora and impaired glucose metabolism. This chapter also covers the mechanisms through which probiotics alleviate diabetes by addressing the gut microflora from the perspectives of amino acid metabolism, intestinal permeability, immunological responses, oxidative stress, and SCFAs.

1. Introduction

Diabetes mellitus (DM), often known as diabetes, is a metabolic syndrome caused by abnormalities in the body’s capacity to generate insulin and/or activate insulin, or both. Hyperglycemia and glucose intolerance are the symptoms of diabetes mellitus [1]. Hyperglycemia increases the complications in the microvascular system (neuropathy, retinopathy, and nephropathy) as well as in the macrovascular system (stroke, ischemic heart disease, and peripheral vascular disease). As a result, there is a marked increase in morbidity and a significant decline in the quality of life [2, 3, 4]. According to the World Health Organization (WHO), 420 million people worldwide have diabetes, and the prevalence was estimated to be 2.8% in 2000, rising to 4.8% by 2030. Over the last two decades, the disease has been more prevalent than expected [5]. DM is seen as a huge global health and economic burden in the aging population and is now the eighth biggest cause of mortality globally [6]. The number of diabetics in India alone is already over 40 million, and by 2030, the country will have the biggest diabetic population in the world with a population of over 90 million [7, 8].

Diabetes has three basic subtypes: type 1, type 2, and gestational diabetes [9, 10, 11]. About 10% of all cases of diabetes are type 1 diabetes (T1DM), which is characterized by the impairment of insulin-secreting B-cells and needs daily insulin therapy for survival [12, 13]. T1DM is becoming more common in the world as a result of ineffective preventative and treatment approaches. Therefore, a thorough understanding of T1DM’s pathophysiology is necessary. Environmental factors and genetic factors play a crucial role in the progression of T1DM [14, 15]. Most people with diabetes (90–95%) have type 2 diabetes (T2DM), which is defined by impaired lipid and glucose metabolism brought on by insufficient insulin production or by its insensitivity [1]. Although T2DM is mostly diagnosed in older persons, the frequency of the condition in youngsters has been shown to rise as a result of obesity and physical inactivity [16]. Smoking, hereditary factors, excessive calorie consumption, and sedentary lifestyle are the main risk factors for T2DM, with alteration in gut microbiota as one of the causes and associated comorbidities [17]. A common problem that affects roughly 2–5% of all pregnancies, gestational diabetes mellitus (GDM) is characterized by high glucose levels in the second and third trimesters of pregnancy. It may manifest as either type I or type II diabetes in persons who have an inherited tendency to have the disease [18]. In the future, T2DM is more likely to occur in women with GDM due to their increased risk of pregnancy problems and premature birth [19, 20].

As per epidemiological observations, one of the characteristics of diabetic patients is changes in the diversity of intestinal microflora. Additionally, there is increasing evidence that diabetes and intestinal microflora are closely related. The microflora, host cells, and nutrients make a complex ecosystem that creates up the human gut. The alimentary canal contains about 100 trillion bacteria, which together make up the intestinal flora [21]. The bacteria that make up the intestinal flora are numerous and diverse. Genus, family, order, and phylum classifications are used to taxonomically group these. In healthy adults, the six phyla Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, Fusobacteria, and Verrucomicrobia make up most of the intestinal microflora [22]. Researchers have shown that gut microbiota in diabetics is less reliable than in healthy individuals. In a sick condition functionality of gut microbiota changes, a human metagenome-wide association study conducted in Europe and China found surprising connections between specific bacterial genes, gut microbes, and the digestive system in T2DM patients [23]. These individuals showed greater levels of Lactobacillus spp. than nondiabetics, and fasting glucose and glycated hemoglobin (HbA1c) levels are positively connected with these levels [24]. Clostridium spp. had a negative relationship with fasting blood sugar and plasma triglycerides [25]. According to one investigation, it has been found that the number of Prevotella and Faecalibacterium decreased in diabetic conditions and demonstrated that the microbiome impacts both T1DM and T2DM [26]. In the mucous layer, there is an increase in Akkermansia muciniphila after metformin therapy [27]. It has been hypothesized that type 1 diabetes (T1DM) and autoimmune diabetes may both develop due to inflammation [28]. Autoimmune diabetes has been related to the microbiota of the gut because of the common receptors in the inflamed pancreas and the gut [29].

Diabetes interventions include medication [30], nutritional care [31, 32], physical activity [32], or weight control [33, 34]. They might also involve education, coaching, or social support [35]. As stated above, diabetes affects the gut microbiome; therefore, probiotics can be employed as one of the nutritional interventions. These are live bacteria that are given in sufficient amounts and continue to remain in the gut bionetwork to have a beneficial impact on one’s health [36]. Lilly and Stillwell used the word “probiotics” to refer to “organisms and substances which contribute to intestinal microbial balance” [37]. Probiotics are “organisms and compounds that help to gut microbial equilibrium,” according to Parker [38]. The International Scientific Association for Probiotics and Prebiotics (ISAPP), which was supported by the Food and Agriculture Organization of the United Nations/World Health Organization (FAO/WHO, 2001), defined probiotics as “Live microorganisms which, when administered in adequate amounts, confer a health benefit on the host” [39]. Probiotics are defined by the World Health Organization (WHO) as “products or preparations containing live, designated microorganisms in appropriate quantities that give positive effects on the host by altering its gut microbiota” [40].

Probiotics play an important role in immune system development, immune system homeostasis, and epithelial cell differentiation and proliferation [41]. Probiotics are not a recent discovery but have been present in many of our traditional foods for a long time, including drinks, salty fish, yogurt, various types of cheese, and so forth. Before the invention of the microscope, people were able to prepare a variety of milk products with various flavors and structures [42]. This is the result of various microbial reactions brought on by various microbes [43]. We really had no idea how probiotic-containing foods were first used, especially for therapeutic purposes. It is possible that Ilya Ilyich Metchnikoff, who won the Nobel Prize in Medicine in 1908, was the first to notice the effects of what is now known as probiotics while working at the Pasteur Institute. He correlated the consumption of yogurt’s microorganisms with good health. He proposed in 1907 that the bacteria Lactobacillus bulgaricus and Streptococcus thermophilus, which are involved in yogurt fermentation, block the putrefactive-type fermentations of the intestinal flora. He linked the consumption of yogurt containing the Lactobacillus species to the longevity and good health of Bulgarian peasants, and he presented his findings to the public in a manner that was easily understood [44].

The ISAPP consensus panel explained the concept that some probiotic mechanisms may be expressed by most strains of a larger taxonomic group, which is an evolving idea regarding the strain specificity of probiotic effects [45]. Lactic acid bacteria (LAB) are a group of predominant gut-friendly bacteria found in the digestive tract [46] and suppress pathogens through their secretions [47]. For instance, the majority of Bifidobacterium and Lactobacillus species both produce organic acids like lactate and acetate. There are several potential advantages for the gastrointestinal system. The inhibition of harmful microbes and the cross-feeding of other advantageous gut microbes result in the production of butyrate, which plays a significant role in cultivating a healthier gut environment [48]. The types of microbes from the genera Lactobacillus, Bifidobacterium, and Saccharomyces that are most frequently used as probiotics include these. Other genera of probiotics include Escherichia, Propionibacterium, Streptococcus, and Bacillus. Probiotics are poised to be an important tool for influencing the gut ecosystem’s function to enhance the nutritional status and health [49, 50]. The mechanisms of action that researchers have identified in various probiotic strains against diabetes are shown in Figure 1. However, there are still a lot of gaps in our understanding of the mechanisms underlying health benefits.

Figure 1.

Potential mechanisms linking probiotics to diabetes.

Modification of the gut microbiota’s composition is one alleged probiotic effect that has been challenging to prove in healthy humans. Although it is widely believed that probiotics “support a healthy intestinal flora,” [51], probiotic organisms seldom survive for longer than a few weeks after consumption [52]. Alpha diversity, richness, and evenness of the fecal microbiota were examined in a systematic review of studies looking at the effects of probiotics [51].

Research is still finding links between the microbiota and diabetes, and these seem to involve a variety of metabolic and immune response processes, most of which are linked to more specific mechanisms. Future investigations into the relationship between variations in the gut microbiota balance and diabetes may result in new interventional studies. This review provides an overview of the role of probiotics in diabetes management.

2. Probiotic interventions to ameliorate T1DM

Probiotics may, thus, be useful in T1DM prevention and management. By altering the gut microbiota, certain probiotic strains exhibit a positive impact on host health by boosting the synthesis of advantageous metabolites [53]. Additionally, by activating free fatty acid receptor 2 (FFAR2) and free fatty acid receptor 3 (FFAR3), which are involved in the regulation of the immune system and the pathogenesis of autoimmune diseases like T1DM, the administration of probiotic strains may increase the production of SCFAs (such as butyrate) and thereby balance the intestinal cellular homeostasis [54]. Additionally, intestinal L-cells’ ability to produce glucagon-like peptide-1 (GLP-1) might be improved by the activation of FFAR2/3 by SCFAs. The hormone GLP-1 is known as the “incretin effect” because it promotes the release of insulin from pancreatic beta-cells, lowering blood sugar levels [55, 56]. These findings show how probiotics may prevent or manage T1DM by preserving or re-establishing the gut microbiota-immune axis’ equilibrium. Figure 2 shows an overview of potential mechanisms of probiotics against type 1 diabetes.

Figure 2.

Potential mechanisms of probiotics against type 1 diabetes.

2.1 Animal studies

Lactobacillus brevis strains protect mice (streptozotocin [STZ]-induced T1DM) and lower blood glucose levels via the action of gamma-aminobutyric acid (GABA) [57]. It has been shown that probiotic strains from the families Bifidobacteriaceae and Lactobacillaceae and the genus Streptococcus thermophilus reduce intestinal inflammation, alleviate T1DM, and maintain gut immunological homeostasis by blocking IL-1 expression in nonobese diabetic (NOD) mice [58]. The feeding of a Lactobacillus lactis strain has also been demonstrated to have preventative benefits against T1DM development in NOD mice by the activation of the production of anti-inflammatory cytokines. Interestingly, the combination of the L. lactis strain with modest dosages of anti-CD3 boosted the production of IL-10. The intervention also led to the formation of antigen-specific Foxp3+ Tregs, which preserves pancreatic islets [59, 60]. Bifidobacterium species change the cytokine secretion pattern in gut-associated lymphatic tissue (GALT) from a proinflammatory condition to an anti-inflammatory. Controlling the preservation of the variety of B-cells and lowering insulitis reduced the likelihood of developing an islet-specific autoimmune disease and offered protection against autoimmune T1DM [61]. Table 1 shows an overview of important studies demonstrating the effect of probiotics on an animal model with type 1 diabetes mellitus.

Probiotics	Model type	Mechanism of action	Major findings	References
Oral probiotics VSL#3	Nonobese diabetic mouse model	Producing more IL-33, indoleamine 2,3-dioxygenase (IDO); Decreasing the production of inflammatory cytokines; Encouraging differentiation of CD103+; Lowering Teff/Treg cell ratios in MLNs, PLNs, and gut mucosa	Alteration of the microbial ecology in the gut; Altering the pathophysiology of T1DM	[58]
Streptococcus salivarius, Lactobacilli, and Bifibobacteria	Nonobese diabetic mouse model	Slowing down the rate of cellular disruption; Pancreatic pseudocysts, the pancreas, and the spleen produce more IL-10.	Preventing autoimmune diabetes	[61]
Probiotic fermented milk with 1% of Lactobacillus species	Streptozotocin-induced albino Wistar rat model	A substantial reduction in the liver’s ability to express genes involved in gluconeogenesis; Significant reductions in IL-6 and TNF- levels in the serum; Declines in blood sugar levels, HbA1c, and blood lipid profiles.	Raising insulin levels while significantly lowering blood sugar levels; Enhancement of glucose metabolism; Reduction of oxidative stress, inflammation, and hepatic gluconeogenesis	[62]
Lactobacillus brevis	Streptozotocin-induced diabetic Mouse Model	High ability to produce GABA because of the gad gene; Significant reduction in plasma insulin levels or blood glucose levels	Preventing T1DM from developing in mice	[57]
Bifidobacterium spp.	Streptozotocin-induced diabetic Mouse Model	A dramatic drop in levels of blood sugar; Enhancing insulin receptor substrate, insulin receptor substrate 1, and expression of insulin receptor β; Reducing the expression of IL-6 and macrophage chemoattractant protein-1	Manage diabetes	[63]
Lactobacillus reuteri	Streptozotocin-induced diabetic Mouse Model	Inhibition of osteoblast TNF-signaling results in the development of anti-inflammatory properties	The administration of probiotics may help T1DM patients’ bones	[64]
Lactobacillus kefiranofaciens and Lactobacillus kefiri	Streptozotocin-induced diabetic Mouse Model	Pancreatic IL-10 level dramatically increased; More IL-10 prevents the production of TNF-α and TH1 and other pro-inflammatory cytokines	Capacity to induce GLP-1 release	[65]
Lactobacillus johnsonii N6.2	T1DM biobreeding diabetes-prone rats model	Modifications to the gut’s natural microbiome; Induced oxidative stress response and alterations in host mucosal protein; Lowering intestinal mucosal oxidative response protein; Reducing cytokines that are proinflammatory; Increasing expression of claudin and other tight junction proteins	Delaying or preventing the onset of T1DM.	[66]

Table 1.

Overview of important studies demonstrating the effect of probiotics on an animal model with type 1 diabetes mellitus.

Biobreeding diabetes resistant (BBDR) rats are more likely to develop T1DM when exposed to Kilham rat virus (KRV) infectious disease [67]. Similar results have also been seen in LEW.1WR1 rats that have had viral infections; these animals acquire autoimmune T1DM as a result of the infection of their cells. It has been shown experimentally that the oral administration of the Lactobacillus johnsonii strain develops resistance to the onset of T1DM in BBDR rats [67]. Consequently, L. johnsonii was linked to TH17 lymphatic cell predilection inside the mesenteric lymph nodes (MLNs) and might lower the incidence of T1DM in the bio-breeding diabetes-prone (BBDP) rat model. Increasing the level of the intestinal tight-junction protein claudin, L. johnsonii, also reduced the likelihood of developing T1DM [66]. In another experiment, probiotic-fermented milk was fed to diabetic rats induced by STZ. Consuming probiotic-fermented milk also reduced oxidative stress, inflammation, blood sugar levels, and the rate of gluconeogenesis [62]. Another investigation employing probiotic strain Lactobacillus plantarum in diabetic rats concluded that taking probiotics significantly decreased the serum α-amylase’s activity, favoring the glycemic index mechanism by limiting the digestion and hydrolysis of carbohydrates [68].

2.2 Human studies

Early exposure to probiotic supplements may reduce the incidence of islet-cell autoimmunity in relation to the increased risk of T1DM [69, 70, 71]. Additionally, probiotic usage has been linked to improved glucose control, increased GLP-1 production, and decreased TLR4 signaling in T1DM adults [72, 73, 74]. T1DM occurrences have reduced as a result of these modifications. Children with T1DM may benefit from taking Lactobacillus rhamnosus and Bifidobacterium lactis at a dosage of 10⁹ colony-forming units (CFUs) once a day for six months regulates gut microbiota disturbances. Results indicated the modification of immune cells in a positive way and maintaining the quantity and proliferation of pancreatic β-cells [75]. Additionally, it has been suggested that adult human subjects consuming Lactobacillus johnsonii N6.2 (10⁸ CFUs) in one capsule per day for eight weeks can control the natural killer cells and infiltration of monocytes. These modifications may help to prevent the development of T1DM. Furthermore, probiotic therapy has been linked to an increase in TH17 and TH1/TH17 cells. However, the probiotics-treated group showed a substantial rise in IgA concentration as compared to the placebo group [71]. Table 2 shows an overview of important studies demonstrating the effect of probiotics on human subjects with type 1 diabetes mellitus.

Probiotics	Model type	Mechanism of action	Major findings	References
Lactobacillus johnsonii	Adult humans	Increasing tryptophan levels in the serum; Lowering the plasma kynurenine to tryptophan ([Kyn]/[Trp]) ratio; Delaying or lessening the memory of CD8+ T-cell apoptosis	Lowering the risk of developing T1DM.	[71]
Bifidobacterium lactis and Lactobacillus rhamnosus	Children (age range of 8–17)	Enhancing the barrier property of the gastrointestinal mucosa; Decreasing autoimmunity risk; Altering the local and systemic immunological responses	Retaining the function of the—β-cell while inhibiting the proliferation of infections	[75]
Probiotics and vitamin D	Children (age range of 4 to 10 years)	Reducing the risk of islet autoimmunity	Early probiotic supplementation may reduce the risk of islet autoimmunity	[70]
Probiotics	Adult human	Decreasing waist-to-hip ratio, body mass index, and obesity; Controlling triglyceride levels, HDL cholesterol, and blood pressure; Strongly linked to improve glycemic management	Beneficial impact on a range of variables connected to diabetes problems	[76]

Table 2.

Overview of important studies demonstrating the effect of probiotics on human subjects with type 1 diabetes mellitus.

By using probiotics products, T1DM adult patients might improve their glycemic control and manage symptoms associated with metabolic syndromes, such as hypertension, elevated level of triglyceride, and decreased HDL levels. These findings together imply that probiotic intake may lower the likelihood of T1DM progression. Other research on young children with a genetic risk of T1DM consumed a probiotic strain during the first two years of life and the risk of the onset of islet autoimmunity and progression of T1DM was increased [77]. This suggests that all probiotic strains do not have the same effects, although the cause of the results from these studies is still unknown.

3. Probiotic interventions to ameliorate T2DM

Currently, probiotics from the former genera of Lactobacillus and Bifidobacterium are the major focus of most therapeutic investigations. However, specific bacterial strains are linked to the amelioration of disorders linked with inflammation. It is anticipated that some of the newly identified strains will become probiotics in the future [78]. Figure 3 shows the overview of potential mechanisms of probiotics against type 2 diabetes. Numerous studies have utilized probiotics in T2DM patients to manage or treat the disease, but the number of studies is still less. When analyzing these studies, it is necessary to use caution because it is well known that the effectiveness of probiotics depends on various factors such as:

• The strain of microorganism (single or multistrain)

• Pathophysiology of the disease

• Subject of study

• Type and quantity of dosage

• Time period of intervention.

Figure 3.

Potential mechanisms of probiotics against type 2 diabetes.

3.1 Animal model study

Probiotics have been proven in studies to reduce insulin resistance (IR) in diabetic animal models (see Table 3). Probiotics like Lactobacillus spp. and Bifidobacterium spp. have been widely studied in diabetic animal models for their biological effects on glucose intolerance and insulin resistance (IR). Lactobacillus plantarum was given to the rats (which consume high-fat-diet [HFD]- and STZ-induced diabetes). It has been observed that L. plantarum reduces pancreatic beta-cell dysfunction, systemic inflammation, and insulin resistance [79]. L. plantarum reduced the weight and relieved IR in mice fed on the HFD [80]. In mice with diabetes generated by HFD, therapy with Lactobacillus fermentum has been demonstrated to reduce IR and stop the progression of diabetes [81]. The injection of Lactobacillus paracasei TD062 increased the insulin signaling pathway and improved glucose homeostasis, delaying the onset of T2DM [82]. In STZ-induced diabetic rats, a multiprobiotic formula, including Lactobacillus reuteri, Lactobacillus crispatus, and Bacillus subtilis, was studied. This research revealed that the daily consumption of probiotics may reduce glucose intolerance and increase insulin production [83]. By lowering fasting blood glucose (FBG), the oral glucose tolerance test (OGTT), and the HbA1c indices and increasing GLP-1 secretion, a composite probiotic made up of 10 Lactobacillus strains and four yeast strains were reported to improve T2DM in db/db mice [89]. Nano-selenium-enriched Bifidobacterium longum reduced the renal complication of T2DM in STZ-induced diabetes rats [84]. B. longum DD98 reduced the fasting blood glucose and HbA1c in HFD- and STZ-induced diabetic mice [90]. In diabetic rats caused by HFD and STZ, Bifidobacterium animalis administration increased oral glucose tolerance test and homeostatic model assessment for insulin resistance (HOMA-IR) indices and decreased proinflammatory cytokines [91].

Probiotics	Model used	Mechanism	Outcomes	References
Lactobacillus plantarum	HFD- and STZ-induced T2DM mice	Reducing systemic inflammation and insulin resistance	Ameliorate T2DM	[79]
L. plantarum Ln4	Mice fed on HFD	Modifications in hepatic gene expression that control lipid and glucose metabolism (reduced CD36 and increased mRNA levels for IRS2, Akt2, AMPK, and LPL)	Reducing biomarkers for T2DM and obesity caused by diet	[80]
L. plantarum and Lactobacillus fermentum	Mice fed with HFD	Preventing the onset of insulin resistance and diabetes.	Seem to be effective against T2DM	[81]
Lactobacillus paracasei	HFD and STZ-induced T2DM mice	Controlling the levels of hepatic glycogen, lipid metabolism, glucose tolerance, postprandial blood glucose (PBG), and fasting blood glucose (FBG). Additionally, the antioxidant capability was enhanced	Preventing the development of T2DM	[82]
Lactobacillus reuteri, Lactobacillus crispatus, and Bacillus subtilis	STZ-induced diabetes	After the intervention period, Glut-4 and PPAR-γ gene expression improved; Considerable elevation in insulin levels and a large reduction in plasma glucose and HbA1c values	Probiotics may help to manage diabetes and its complications if taken regularly	[83]
Nano-selenium-enriched B. longum	Streptozotocin-induced diabetes	The expression of insulin signaling pathway-related proteins was upregulated in the Nano-Se-B longum-treated groups	Preventive effect of Nano-Se-B longum on the onset of diabetes and renal damage	[84]
Lactobacillus plantarum	Mice fed with HFD	Significantly reduced the mRNA expression of interleukin-1β in adipose tissue and serum levels of nonesterified fatty acids in mice	Significant reduction of blood glucose levels	[85]
Lactobacillus casei	HFD- and STZ-induced T2DM mice	Decreased levels of the inflammatory markers, tumor necrosis factor-α and interleukin-6 and increased intestinal glucagon-like peptide-1 (GLP-1) levels, which are associated with the production of short-chain fatty acids (SCFAs)	Modifying the gut microbiota, increasing the production of SCFAs, and ameliorating type 2 diabetes	[86]
Lactobacillus paracasei	HFD- and STZ-induced T2DM mice	Reducing the level of oxidative stress and insulin resistance, while also safeguarding beta-cell function and inhibiting the expansion of alpha-cell	Indicating that the pancreatic islets as the key target tissues for the probiotic strain’s ameliorative action against T2DM	[87]
Clostridium butyricum	HFD- and STZ-induced T2DM mice	Increased insulin signaling molecules, and peroxisome proliferator-activated receptor (PPAR), as well as altered intestinal flora diversity	Treating and preventing metabolic impairment caused by T2DM	[88]

Table 3.

Overview of important studies demonstrating the effect of probiotics on an animal model with type 2 diabetes mellitus.

3.2 Human studies

Sabico et al. examined the effects of consuming 10¹⁰ CFU/day of a multistrain probiotic regarding metabolic endotoxemia levels and cardiometabolic parameters in adult patients recently diagnosed with T2DM. It has been found that the waist-hip ratio decreased across groups, while HOMA-IR was increased. The fasting blood glucose (FBG) level is less in the probiotic group when compared with the control group, while there are no substantial changes in the endotoxin levels [92]. In further research, the effect of the same probiotic mixture was examined for six months while using the same dosage and criteria as the earlier study. Again, a clinically substantial change in the HOMA-IR was noted, and the probiotic group’s insulin levels showed a borderline significant improvement [93]. When the flow of lipopolysaccharides (LPS) is decreased, it is anticipated that low-grade inflammation would decrease and insulin signaling will improve. Karczewski et al. assessed the effects of the probiotic Lactobacillus plantarum. The probiotic was injected directly into the duodenum of a group of people and followed by a tissue biopsy after 6 hours. According to the authors’ observations, zonula occludens-1 and occludin are translocated more often near tight junctions [94]. Similar results for various strains of the Lactobacillus genus were obtained in cell cultures [95]. In a nine-month double-blinded, randomized, placebo-controlled research, Hsieh et al. found that T2DM patients who consume capsules containing the probiotic Lactobacillus reuteri ADR-1 had lowered cholesterol and HbA1C level in their blood. The reduction in HbA1C was maintained even after three months of follow-up without probiotic treatment [96]. The effects of ingesting Lactobacillus reuteri for 12 weeks at various doses (low dose: 10⁸ CFU/day vs. high dose: 10¹⁰ CFU/day) were examined by Mobini et al.; however, they were unable to detect a reduction in HbA1C in T2DM patients. In the group consuming high-dosage of probiotic, insulin sensitivity index (ISI) was high [97]. Table 4 provides an overview of important studies demonstrating the effect of probiotics on human subjects with type 2 diabetes mellitus.

Probiotics	Model type	Mechanism of action	Major findings	References
Bifidobacterium animalis A6	28 type II diabetic patients	Significant decrease in fasting blood glucose, serum content of total cholesterol, the cardiovascular risk index (TC/HDL-C), the pro-inflammatory cytokines (IL-6, MCP-1) and adipokines (adiponectin, resistin, lipocalin-2, adipsin). Myokines (irisin, osteocrin) increased significantly, indicating possible improvement in skeletal muscle function	Probiotic camel milk powder twice a day for a consecutive four weeks can significantly decrease fasting blood glucose of type 2 diabetic patients	[98]
probiotic supplements including Bifidobacterium bifidum 2 × 10^9, Lactobacillus casei 2 × 10^9, Lactobacillus acidophilus 2 × 10^9 CFU/day (n = 30)	60 diabetic patients with CHD, aged 40–85 years	Decreasing inflammatory cytokines and suppressing the nuclear factor-κB pathway, their impact on gene expression and the activation of gut microbiota short-chain fatty acids (SCFA)-hormone axis	Probiotic supplementation for 12 weeks had beneficial effects on glycemic control, HDL-cholesterol, total-/HDL-cholesterol ratio, biomarkers of inflammation and oxidative stress in diabetic patients with CHD	[99]
Lactobacillus reuteri	68 T2DM patients	L. reuteri may influence changes in intestinal flora, which may lead to different outcomes after probiotic intake.	Significant reductions in HbA1c and serum cholesterol; Bifidobacterium spp. were significantly increased	[96]
Symbiter	53 patients	Significant reduction of HOMA-IR from 6.85 ± 0.76 to 5.13 ± 0.49 (p = 0.047), but remained static in the placebo group. With respect to our secondary outcomes, HbA1c	Modestly improved insulin resistance	[100]
Ecologic®Barrier	patients with type 2 diabetes mellitus	significant decrease in circulating levels of endotoxin by almost 70% over six months, as well as glucose (38%), insulin (38%), HOMA-IR (64%), triglycerides (48%), total cholesterol (19%), total/HDL-cholesterol ratio (19%), TNF-α (67%), IL-6 (77%), CRP (53%), resistin (53%), and a significant increase in adiponectin (72%) as compared with baseline	multistrain probiotics is a promising adjuvant antidiabetes therapy	[93]

Table 4.

Overview of important studies demonstrating the effect of probiotics on human subjects with type 2 diabetes mellitus.

A 12-week probiotic therapy that comprised a multistrain probiotic was administered to 101 adults with T2DM. This intervention revealed that the probiotic intake lowers insulin resistance, fasting blood glucose, and HbA1C levels [101]. In an randomized controlled trial (RCT) by Palacios et al., patients with prediabetes and T2DM were enrolled to examine the outcomes of a probiotic multistrain. The only thing that separated the intervention and placebo groups was an increase in butyrate levels. It is noteworthy that those taking both metformin and a probiotic had decreased levels of insulin resistance, FBG, and HbA1c [102]. In a trial utilizing a single-strain probiotic (10⁸ CFU/day of Lactobacillus casei for eight weeks), Khalili et al. discovered a decrease in FBG, insulin concentration, and insulin resistance [103].

4. Probiotic interventions to ameliorate gestational diabetes

Most of RCTs investigating the therapeutic benefits of probiotic supplementation in female GDM patients have been carried out in Iran; each study used a unique combination of microorganisms and examined a variety of outcomes in addition to glycemia such as gestational weight change [104], lipid profile [105], and inflammation [106]. Fasting blood sugar levels and insulin resistance dramatically decreased in the probiotic group in all these studies. Probiotics also decreased gestational weight gain, serum very-low-density lipoprotein (VLDL) cholesterol, and triglyceride levels [104, 105, 106]. Figure 4 shows an overview of potential mechanisms of probiotics against type 1 diabetes.

Figure 4.

Potential mechanisms of probiotics against gestational diabetes.

A recent study that randomly assigned GDM patients to receive probiotics (10⁹ colony-forming units (CFU) per day of Bifidobacterium bifidum and Lactobacillus acidophilus or a placebo for four weeks also found significant improvement in glucose metabolism in the probiotic group, including fasting glucose, insulin, and HOMA-IR. An RCT conducted in Ireland randomized 149 women (GDM sufferers) to receive either a probiotic (Lactobacillus salivarius, 10⁹ CFU per day) or a placebo, and the results showed no change between the two groups except for total cholesterol [107]. There was a considerable decrease in insulin resistance, which seemed to be primarily related to the species Bifidobacterium [108]. According to the findings, bigger, longer-term studies comparing various probiotic strains were required.

A modest number of RCTs have looked at probiotic supplementation’s potential to stop GDM. In the Finnish “Probiotics and Pregnancy Outcome Study, “ pregnant women were randomly assigned to receive dietary advice with probiotic supplementation (10¹⁰ CFU per day of Lactobacillus rhamnosus and Bifidobacterium lactis), dietary advice alone, or a placebo. In the probiotic group, the rate of GDM was much lower as compared to the other groups. There were no abnormalities in fetal development [109]. Table 5 provides an overview of important studies demonstrating the effect of probiotics on human subjects with gestational diabetes. Recently, a probiotic intervention study for women at risk of GDM in New Zealand has been carried out. At 14–16 weeks of gestation, the scientists randomly assigned women to take either a probiotic (Lactobacillus rhamnosus, 6 × 10⁹ CFU per day) or a placebo. They also noticed that the probiotic intervention dramatically reduced the occurrence of GDM [110]. Even though the results are encouraging, further research is required to decide if probiotic supplements should be widely utilized in early pregnancy to prevent GDM.

Probiotics	Model type	Major findings	References
Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12	Pregnant women; no chronic diseases apart from allergic diseases; less than 17 gw	Reducing prevalence of GDM	[109]
Lactobacillus salivarius UCC118	Women with GDM	No significant effect on the incidence of GDM	[107]
L. rhamnosus HN001	Pregnant women with a personal or partner history of atopic disease	Reducing the prevalence of GDM	[110]
myo-inositol 2 g + B. lactis and L. rhamnosus	Mexican women with three or more risk factors for developing GDM	Reducing the prevalence of GDM	[111]

Table 5.

Overview of important studies demonstrating the effect of probiotics on human subjects with gestational diabetes.

5. Conclusion

Our hypothesis is that the manipulation of the intestinal flora by probiotics may be useful for the prevention and treatment of diabetes. Experimental and clinical trials have shown the significant potential of probiotic strains in the management of diabetes. Probiotics may increase insulin signaling molecules and insulin sensitivity, reduce inflammation and inflammatory cytokines, suppress the nuclear factor-κB pathway, activate gut microbiota short-chain fatty acids (SCFAs)-hormone axis, and enhance the barrier property of the gastrointestinal mucosa by altering the intestinal flora. The studies discussed in this chapter provide insights into the impact of probiotics on diabetes, although further investigation is required to clarify the molecular processes involved in the regulation of intestinal flora by probiotic administration and their effects on the onset of diabetes.

Conflict of interest

The authors declare no conflict of interest.