Potential role of Limosilactobacillus fermentum as a probiotic with anti-diabetic properties: A review

Table 1 Characteristics of the studies testing the anti-diabetic effect of Limosilactobacillus fermentum strains

Ref.	Type of study	Experimental groups	Source of probiotics	Dosage of probiotic	Duration of treatment
Hartajanie et al[50], 2020	Experimental: 24 male Sprague-Dawley rats at 8 wk and weighing 170-200 g	Diabetic group; Diabetic group + acarbose; Diabetic group + bitter melon; Diabetic group + fermented bitter melon	L. fermentum LLB3 was isolated from the bamboo shoot pickle	1 × 107 CFU L. fermentum LLB3	4 wk
Hu et al[35], 2019	Experimental: 4-wk-old male Kunming mice (18 ± 2 g) were used	Normal control group; Diabetic group; Positive drug control group; Diabetic group + fructose 1 6-bisphosphatase (low dose); Diabetic group + 1-Deoxynojirimycin (middle dose); Diabetic group + 1-Deoxynojirimycin (high dose)	All probiotics were purchased from the Guangdong culture collection center	5 × 104 CFU/mL of each activated strain (L. plantarum + L. fermentum, L. plantarum + L. mesenteroides, L. plantarum + S. cerevisiae, L. fermentum + L. mesenteroides, L. fermentum + S. cerevisiae, and L. mesenteroides + S. cerevisiae)	4 wk
Chaiyasut et al[51], 2018	Experimental: male Wistar rats	Control group; Control group + L. fermentum; Control group + fermented H. erinaceus juice; Diabetic group; Diabetic group pretreatment and posttreatment treated with fermented H. erinaceus juice, L. fermentum, and insulin	L. fermentum HP3 was isolated from fermented Thai foods	L. fermentum HP3 in a concentration of 109 CFU/mL. L. fermentum HP3 was used with H. Erinaceus Juice	12 wk
Guilbaud et al[52], 2020	Experimental: 30 mice with 6 wk of age	Wild-type group;Wild-type group + L. fermentum;Diabetic group;Diabetic group + L. fermentum	Isolated from a fecal sample of one-year-old healthyEstonian child	L. fermentum ME-3 in a concentration of 1010 CFU per 400 μL H2O	12 wk
Archer et al[48], 2021	Experimental: 40 female Wistar rats	Control group; Diabetic group + high-fat diet; Diabetic group + high-fat diet + L. fermentum. MCC2759; Diabetic group + high-fat diet + L. fermentum. MCC2760	Isolated from fecal (L. fermentum. MCC2759) and from curd (L. fermentum. MCC2760)	Both isolated probiotics were offered in a concentration of 1 × 109 CFU/mL	4 wk
Ai et al[31], 2021	Experimental: 160 Male C57BL/6J mice with 6 wk of age	Control group; Diabetic group + high-fat diet; Diabetic group + defatted rice bran unfermented extracts; Diabetic group + pioglitazone; Diabetic group + high-dose of defatted rice bran fermentation extracts; Diabetic group + low-dose of defatted rice bran fermentation extracts	Isolated from Chinese rice noodle wastewater	The study evaluated the role of L. fermentum MF423. Dose of 100 μg/mL of defatted rice bran unfermented extracts	8 wk
Yadav et al[54], 2018	Experimental: 70 male Wistar rats with 8 ws old	Normal control group; Diabetic control group; Diabetic + normal diet supplemented with milk; Diabetic + L. rhamnosus MTCC5957; Diabetic + L. rhamnosus MTCC5897; Diabetic + L. fermentum MTCC 5898; Diabetic + L.rhamnosus 5957 and 5958 and L. fermentum MTCC 5898	The probiotics L. rhamnosus MTCC: 5957 and L. rhamnosus MTCC: 5897 were isolated from household curds. The probiotic L. fermentum MTCC: 5898 was isolated from the feces of breastfed human infants	All probiotic strains were offered in a dosage of 1 × 109 CFU	6 wk
Yousaf et al[55], 2016	Experimental: female mice of 6-8 wk, with an initial body weight of 21-23 g	Normal healthy mice; Diabetic mice; Diabetic mice + Momordica charanti; Diabetic mice + Eugenia Jambolana; Diabetic mice + L. Fermentum; Diabetic mice + L. Fermentum + Momordicacharanti + Eugenia Jambolana; Diabetic mice + Glucophage	L. fermentum fruit extracts of Eugenia Jambolana and Momordica charantia were isolated from local yogurt samples (Lahore, Pakistan)	Momordica charantia 200 mg/kg, and Eugenia Jambolana 100 mg/kg. The authors did not inform the concentration of L. fermentum (Gene Bank Accession KJ754019)	3 wk
Balakumar et at[49], 2018	Experimental: adult male C57BL/6J mice (age 8-10 wk)	Normal pellet diet; High-fat diet; High-fat diet + L. rhamnosus; High-fat diet + L. plantarum MTCC5690; High-fat diet + L. fermentum MTCC5689; High-fat diet + metformim; High-fat diet + vildagliptin	Isolated from Indian gut (Karnal, India)	Lactobacillus MTCC 5690 and MTCC 5689 in a concentration of 1.5 × 109 colonies/mouse/d	24 wk
Babadi et al[30], 2018	Clinical: primigravid women aged between 18 and 40 years, between the 24th and 28th week of gestation, diagnosed with gestational diabetes mellitus	Placebo group; Probiotic group	Probiotic supplements were produced by LactoCare®, Zisttakhmir Company (Tehran, Iran)	Probiotic capsule containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum and L. fermentum in a dosage of 2 × 109 CFU/g	6 wk

L. fermentum: Lactobacillus fermentum; L. rhamnosus: Lactobacillus rhamnosus; L. plantarum: Lactobacillus plantarum; S. cerevisiae: Saccharomyce cerevisae; L. mesenteroides: Leuconostoc mesenteroides; H. erinaceus: Hericium erinaceus.

Table 2 Primary outcomes of the studies testing the anti-diabetic effect of Limosilactobacillus fermentum strains

Ref.	Primary end-points
Hartajanie et al[50], 2020	↓ The fasting blood glucose; ↓ Postprandial blood glucose; ↑ In SOD concentrations
Hu et al[35], 2019	↓ Blood glucose levels; ↓ Insulin levels; Reversed insulin resistance; Improved serum lipid levels; Relieved gut dysbiosis
Chaiyasut et al[51], 2018	↓ Weight Gain; Improved insulin levels (↑ insulin); Recovery progress of hyperglycemia; ↓ HbA1c level (only with cointerventions); ↓ Inflammatory cytokines level
Guilbaud et al[52], 2020	↓ Weight Gain; ↓ Glycemic response 60-120 min; ↑ In HbA1c; ↓Weight of liver; ↓ FL-furosine levels in kidney ↓The expression of TNF-α; ↓The TG concentrations in liver; ↓ HDL and Non-HDL; Lower lipid droplets in liver.
Archer et al[48], 2021	↓ Blood glucose levels; Improved insulin levels (↑ insulin); ↓ levels of cholesterol, triglycerides, and LDL-C; ↓ The expression levels of TNF-α, and ↑ expression of IL-10; ↓ Expression of the TLR4 receptor, ↑ Expression of tight junction protein ZO-1, endocannabinoid receptor CB2 and GLP1, and ↑ Expression of GLUT4 in MAT and muscle tissue; Showed accumulation of neutrophils around the portal tracts in liver tissue, and reduction in the glomerular injury in kidney sections
Ai et al[31], 2021	Inhibit the degree of weight loss; ↓ The fasting blood glucose; ↓ Blood glucose levels; ↓ Levels of total cholesterol and LDL and ↑ HDL levels; Ameliorate the damage to liver cells and significantly reduced the accumulation of lipid droplets; Upregulated the levels of SOD, T-AOC and GSH-PX, and reversed elevation of MDA; ↓ Damage in composition of gut microbiota1
Yadav et al[54], 2018	Inhibit the degree of weight loss; ↓ The fasting blood glucose; ↓ Consumption of food and liquids; ↑ In oral glucose tolerance; ↑ In liver weight; Improved insulin levels (↑ Insulin); ↓ HbA1c level; ↑ CAT, SOD activity in kidney and liver; ↓ Serum levels of total cholesterol, LDL-C, VLDL-C and triglycerides; ↓ The serum inflammatory index, cytokine levels (IL-6 and TNF-α); ↓ In the expression of the genes G6Pase and pepck in the liver
Yousaf et al[55], 2016	↑ Body weight; ↓ Blood glucose levels; Lipid profile: no effect on cholesterol, ↓ tryglyceride, LDL, slight increase in the level of HDL
Balakumar et al[49], 2018	↓ Body weight; ↓ Blood glucose levels; ↑ In oral glucose tolerance; ↓ HbA1c level; Improved insulin levels (↓ Insulin); ↑ levels of GLP-1; ↓ Cholesterol, triglyceride and LDL levels; ↑ HDL level; ↓ Plasma DX-4000–FITC; ↑ mRNA expression of epithelial tight junction occludin and ZO-1; ↓ Serum levels of LPS; ↓ Proinflammatory gene expression profiles (IL6 and TNFα), ↑ adiponectin gene expression; ↓ Gene expression profiles of endoplasmic reticulum stress
Babadi et al[30], 2018	Downregulated gene expression of TNF-α; ↓ The fasting blood glucose; ↓ Serum insulin level; ↓ Insulin resistance; ↑ Insulin sensitivity; ↓ Levels of triglycerides, VLDL-cholesterol and total / HDL-cholesterol ratio, and ↑ levels of HDL-cholesterol; ↓ In plasma MDA; ↑ In plasma NO and total antioxidant capacity

¹These results were obtained by rice bran fermented with Lactobacillus fermentum MF423.

SOD: Superoxide dismutase; HbA1c: Glycayed hemoglobin A; TNF-α: Tumor necrosis factor-alpha; TG: Triglyceride; HDL- C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; VLDL-C: Very-low-density lipoprotein cholesterol; IL-6: Interleukin-6; IL-10: Interleukin-10; TLR4: Toll-like receptor 4; ZO-1: Zonula occludens-1; CB2: Cannabinoid receptor type 2; GLP1: Glucagon-like peptide-1; GLUT4: Glucose transporter type 4; MAT: Mesenteric adipose tissue; T-AOC: Total antioxidant capacity; GSH-PX: Glutathione peroxidase; MDA: Malondialdehyde; CAT: Catalase; G6Pase: Glucose 6-phosphatase; Pepck: Phosphoenolpyruvate carboxykinase; FITC: Fluorescein isothiocyanate-dextran; LPS: Lipopolysaccharide; NO: Nitric oxide.