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Full Research Article

Innovative Potential of Lactococcus lactis D4 From Fermented Buffalo Milk (Dadiah) in Improving Fetal-maternal Outcomes in Hyperglycemic Animal Model

A
Ade Sukma1,*
0000-0001-9940-6518
N
Nadia Yulianti2
0009-0007-1493-6810
A
Almahdy Almahdy3
0000-0003-4311-6233
N
Najmiatul Fitria3
0000-0002-3255-1961
1Department of Livestock Product Technology, Faculty of Animal Sciences, Universitas Andalas, Kampus Unand Limau Manis, Padang, 25163, West Sumatera, Indonesia.
2Bachelor Program, Faculty of Pharmacy, Universitas Andalas, Kampus Unand Limau Manis, Padang, 25163, West Sumatera, Indonesia.
3Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Andalas, Kampus Unand Limau Manis, Padang, 25163, West Sumatera, Indonesia.

ABSTRACT

Background: Hyperglycemia in pregnancy, which can adversely affect both maternal and fetal outcomes. Sustainable strategies for its management are urgently needed. This study explores the therapeutic efficacy of Lactococcus lactis D4 (LD4), a probiotic strain isolated from traditional fermented buffalo milk (dadiah), as an innovative biofunctional approach to controlling hyperglycemia.

Methods: This experimental study involved 20 pregnant mice divided into four groups: K1 (control), K2 (10% glucose induction), K3 (10% glucose induction plus metformin) and K4 (10% glucose induction plus LD4). Blood glucose levels were measured at baseline. Laparotomy was performed on day 16 to assess maternal body weight, fetal number and fetal body weight. Data were analyzed using repeated-measures ANOVA followed by Duncan’s Multiple Range Test, with statistical significance set at p<0.05.

Results LD4 administration during pregnancy did not affect maternal body weight, fetal count, or fetal body weight (p>0.05). However, LD4 significantly influenced blood glucose levels in mice (p<0.05). LD4 demonstrates significant effects, indicating its potential as a probiotic-based strategy for managing hyperglycemia during pregnancy. Further studies are needed to confirm its long-term safety and efficacy in clinical settings.in improving glycemic control during pregnancy and shows strong potential to become an effective probiotic.

INTRODUCTION

Maternal hyperglycemia during pregnancy remains a major health concern affects both maternal and fetal outcomes (Murphy, 2020). Uncontrolled blood glucose levels can lead to adverse pregnancy complications such as fetal overgrowth, preterm birth and increased risk of metabolic disorders later in life for the offspring (Nicholas et al., 2013). Despite advances in clinical management, the search for effective and safe adjunct therapies to improve maternal-fetal health in hyperglycemic conditions is ongoing (Fitria et al., 2025).
       
Probiotics have emerged as a promising intervention for modulating metabolic and inflammatory pathways associated with hyperglycemia (Susmiati et al., 2023; Thorakkattu et al., 2022). Among the diverse probiotics, Lactococcus lactis, a member of lactic acid bacteria (LAB), has garnered interest due to its historical use in fermented dairy products and its potential therapeutic properties (Dahou et al., 2021; Hammadeche  et al., 2025; Kumari et al., 2021; Sukma et al., 2021).
       
Dadiah, a traditional fermented buffalo milk product from West Sumatra, Indonesia, is a rich source of indigenous LAB, including unique strains of Lactococcus lactis (Milfiadi et al., 2023; Syahriandra et al., 2022). It has been proved that the treatment with probiotic derived from fermented milk, such as dadiah, exerted beneficial effects on glucose metabolism and inflammation (Fitria et al., 2021; Sukma  et al., 2024). However, the specific efficacy of Lactococcus lactis strains isolated from dadiah in improving fetal-maternal outcomes under hyperglycemic conditions remains underexplored (Arnold et al., 2021; Sukma et al., 2018; Yadav et al., 2022).. To preserve dadiah as a traditional Minangkabau food with significant health benefits, this research tested the potential of Lactococcus lactis D4, an isolate from dadiah, as a candidate therapy for gestational diabetes in a pregnant animal model.

MATERIALS AND METHODS

Materials
 
All materials used in this study included female and male white mice (Mus musculus L.) provided with standard laboratory feed and water; Lactococcus lactis D4 isolated from dadiah;  10% glucose solution; metformin tablets (OGB Dexa®); sodium carboxymethyl cellulose (Na-CMC); distilled water and agar media for bacterial culture. Experimental procedures utilized plastic cages, oral gavage needles, analytical balances, an Easy Touch® glucometer.
 
Study design and setting
 
This experimental study was conducted from July - October 2025 at the Laboratory of Animal Product Technology, Faculty of Animal Sciences. Animal House Laboratory, Faculty of Pharmacy and the Laboratory of Pharmacology, Universitas Andalas, Padang, Indonesia. All experimental procedures complied with institutional ethical standards for animal research (Institutional Ethic Committee Faculty of Pharmacy Universitas Andalas No. 75/UN16.10.D.KEPK-FF/2025, date 2 September 2025).
 
Experimental Animals, acclimatization and mating procedure
 
A total of 25 female white mice and 5 male white mice (Mus musculus L.), weighing 20-25 g, were used in this study. Before experimentation, mice were acclimatized for 10 days in the Animal House Laboratory. Animals were housed in plastic cages with a wire cover under controlled environmental conditions with ad libitum access to standard laboratory feed and drinking water (Sukma  et al., 2024). Animals were eligible for the study if they exhibited normal behavior and body weight fluctuations of ≤10%. Mating was performed during the estrus phase using a female-to-male ratio of 4:1. Pregnancy was confirmed by the presence of a vaginal plug, indicating gestational day 0 (GD 0) (Gonzalez, 2016).
 
Probiotic LD4 isolation and preparation
 
Lactococcus lactis D4 was obtained from the fermentation of dadiah (traditional fermented buffalo milk). The selected dose of 109 CFU/mL, administered in 0.5 mL, was based on scientific evidence indicating that this concentration supports adequate bacterial viability (Anami et al., 2023).
 
Preparation of metformin suspension
 
A 0.5% Na-CMC solution was prepared by dispersing 0.5 g Na-CMC in 20 mL of hot distilled water until fully swollen, then diluting to 100 mL. Metformin (OGB Dexa®) 500 mg was then suspended in the Na-CMC solution to obtain a homogeneous suspension for oral administration. Metformin was used as a positive control and administered at 1.3 mg per 20 g of body weight, according to standard dosing guidelines (Wang et al., 2020).

Experimental grouping
 
Pregnant mice were randomly assigned to four experimental groups (n = 5 per group). The pregnant mice were randomly allocated into four experimental groups: a control group consisting of pregnant mice without any treatment (K1); 10% glucose group (K2); a positive control (10% glucose+metformin) (K3) and an intervention group (10% glucose+ Lactococcus lactis D4) (K4).
 
Surgical procedures and outcome measurement
 
Pregnant mice (45-47 g) underwent laparotomy under anesthesia to expose the uterus (Day 16). Primary outcomes comprised maternal blood glucose levels, maternal weight gain, fetal number and fetal weight. Secondary outcomes included comparative effects of LD4 administration under normoglycemic and hyperglycemic conditions, reflecting potential probiotic-mediated fetal-maternal benefits.
 
Data analysis
 
All data were analyzed using Statistical Product and Service Solutions (SPSS) software. Differences among groups were evaluated using one-way Analysis of Variance (ANOVA). When significant differences were observed, Duncan’s multiple range test (DMRT) was applied as a post-hoc analysis. Statistical significance was defined as p≤0.05.

RESULTS AND DISCUSSION

Observations of maternal weight gain during pregnancy were conducted to assess the nutritional status, health and the effect of LD4 on blood sugar levels in mice. Table 1 shows maternal weight data from day 0 to day 16 of pregnancy. Maternal body weight increased progressively throughout pregnancy in all experimental groups, reflecting normal gestational weight gain. Although the control group consistently exhibited slightly higher body weights than the hyperglycemic groups, no statistically significant differences were observed among the four groups at any observation point from gestational day 0 to day 16 (all p>0.05).

Table 1: Maternal body weight progression (Days 0-16) in pregnant mice receiving glucose, metformin, or Lactococcus lactis D4.


       
Table 2 shows the number of fetuses in pregnant rats for each treatment group. The control group showed the highest average fetal number, no statistically significant differences were observed among the groups (p = 0.209). These findings suggest that glucose induction, metformin treatment and LD4 administration did not significantly influence fetal number under the experimental conditions. The effects of Metformin and Lactococcus lactis D4 on Blood Glucose Levels were presented in Table 3. Blood glucose levels differed significantly among the treatment groups throughout the observation period. Both metformin and LD4 treatments progressively reduced glucose levels. By gestational day 16, the LD4-treated group had blood glucose levels comparable to those of the metformin-treated group and markedly lower than those of the untreated hyperglycemic group, indicating that LD4 effectively improved glycemic control during pregnancy (p<0.05).

Table 2: Number of fetuses and fetal growth parameters in maternal mice from each group.



​

Table 3: Effects of metformin and Lactococcus lactis D4 on blood glucose levels in hyperglycemic pregnant mice.


       
Table 4 shows that the four groups can be divided into two similar groups based on their blood glucose levels. Pregnant mice given 10% glucose and those given 10% glucose plus metformin had similar, relatively low blood glucose levels. Post-hoc analysis using Duncan’s multiple range test further confirmed significant differences in blood glucose levels among the treatment groups. The untreated hyperglycemic group consistently showed the highest glucose concentrations, whereas both the metformin and LD4 groups formed homogeneous subsets with significantly lower glucose levels. These findings indicate that LD4 produced a glucose-lowering effect comparable to that of metformin in hyperglycemic pregnant mice.

​

Table 4: Comparison of mean blood glucose levels across treatment groups using duncan’s multiple rank test.


       
Maternal weight gain tended to increase from day 11 to day 16 of pregnancy due to fetal development and increased volumes of amniotic fluid, placenta and amniotic membranes. The research findings reveal a significant difference in maternal weight gain from the beginning of the treatment until the end of the study period (p=0.0279). This is consistent with data on maternal weight gain from day 0 to day 4 after induction and from day 16 before laparotomy (p=0.036). The effect of metformin on lower maternal weight is to inhibit intestinal glucose absorption, reduce hepatic glucose production (gluconeogenesis) and increase insulin sensitivity in peripheral tissues. This suppresses the accumulation of excess fat and calories during pregnancy so that maternal weight does not increase as much as in other test groups and prevents maternal obesity (Salomäki  et al., 2013). The LD4 test group experienced slight weight gain because probiotics can reduce insulin resistance and stabilize weight gain without causing absolute weight loss by modulating the gut microbiota to increase insulin sensitivity and reduce inflammation. This increase is consistent with the physiology of mouse pregnancy. Maternal hyperglycemia is transferred to the fetus, reducing maternal fat deposition, resulting in absolute weight loss in the mother (Mahdizade Ari  et al., 2022).
       
Probiotics, including Lactococcus lactis, can modulate the gut microbiota, increasing the production of short-chain fatty acids (SCFAs). These SCFAs play a crucial role in regulating energy metabolism, improving insulin sensitivity and reducing systemic inflammation (Diana and Fitria, 2022). Other studies in mice have shown that maternal weight gain is closely correlated with fetal and conceptus weight gain (Putri et al., 2020). Maternal obesity affects fetal growth and pregnancy outcomes and weight loss before conception may improve fetal growth, but some effects of prior obesity persist on the offspring phenotype (Panchenko et al., 2016).
       
Statistical analysis revealed a highly significant difference in the number and/or weight of fetuses among the treatment groups (p=0.000), indicating a strong effect of LD4 on fetal development. The control group had the highest fetal number, likely due to stable glucose homeostasis and a favorable maternal environment that minimized embryonic resorption. Uncontrolled increases in blood glucose levels can lead to Large for Gestational Age (LGA) driven by excess transplacental glucose that triggers fetal hyperinsulinemia and promotes excessive fetal growth (Fitria et al., 2024; Mousa et al., 2019). The use of metformin and LD4 probiotics can reduce maternal glucose, thereby reducing glucose transfer from the mother to the fetus and preventing fetal hyperinsulinemia and excessive growth, resulting in babies with more normal birth weight (Salomäki  et al., 2013).
       
Significant differences in glucose levels across treatment groups are supported by the probiotic’s ability to regulate glucose homeostasis by inhibiting intestinal glucose absorption, preventing the production of anti-inflammatory cytokines and reducing pancreatic β-cell damage caused by oxidative stress. LD4 reduces glucose levels by modulating the gut microbiota and lactic acid production, thereby inhibiting carbohydrate absorption and reducing insulin resistance (Yuniritha et al., 2019).
 
Strengths and limitation
 
This study has several strengths, including a controlled experimental design with a clearly defined comparison group, which allows for a systematic evaluation of the effects of Lactococcus lactis D4 (LD4) on maternal and fetal parameters. The key finding, a significant reduction in blood glucose levels in the LD4 group, suggests the potential of this probiotic as a candidate for adjunctive therapy in hyperglycemic pregnancy. However, this study has limitations, including the use of a single LD4 dose, a relatively small sample size and limited exploration of the molecular mechanisms underlying LD4’s hypoglycemic effects. Furthermore, the study’s limited observation period and preclinical nature limit the generalizability of the findings to the human population. Therefore, further research with varying doses, larger sample sizes, mechanistic approaches and clinical trials is needed to confirm the safety, effectiveness and clinical relevance of LD4.

CONCLUSION

This study demonstrates that Lactococcus lactis effectively manages the adverse effects of hyperglycemia in a pregnant mouse model. LD4 may improve metabolic conditions by modulating the gut microbiota, which in turn could lead to better glucose homeostasis. This is particularly relevant in the context of hyperglycemia in pregnancy, where maternal hyperglycemia poses a direct threat to both the mother’s health and fetal development. The data support the potential of LD4 as a therapeutic agent, either alone or in combination with standard treatments like Metformin, to mitigate the complications of hyperglycemia in pregnancy and promote healthier pregnancy outcomes. Further research is warranted to directly measure blood glucose levels and other metabolic markers to confirm these findings.

ACKNOWLEDGEMENT

The authors would like to thank the Animal Product Technology Laboratory, Animal House Laboratory and the Pharmacology Laboratory at Andalas University, Padang, Indonesia, for the support provided in facilities, resources and technical expertise during the implementation of this research. All research activities were carried out in accordance with the ethical standards for animal research applicable at Andalas University.
 
Author contribution
 
AS contributed to the conceptualization, methodology, analysis and preparation of the original draft manuscript. N. Yulianti did animal handling and data curation. AA was involved in the validation process. NF contributed to the conceptualization, project administration and review and editing of the final version of the manuscript. All authors have read and approved the final manuscript.
 
Disclaimers
 
The views and conclusions expressed in this article are solely those of the authors and do not necessarily represent the views of their affiliated institutions. The authors are responsible for the accuracy and completeness of the information provided, but do not accept any liability for any direct or indirect losses resulting from the use of this content.
 
Informed consent
 
All animal procedures for experiments were approved by This manuscript complies with ethical approval from the Faculty of Pharmacy Universitas Andalas, Number 75/UN16.10.D.KEPK-FF/2025
 
Funding
 
No Funding for this study.
 
Registration and ethical approval
 
This manuscript complies with ethical approval from the Faculty of Pharmacy Universitas Andalas, Number 75/UN16.10.D.KEPK-FF/2025.

CONFLICT OF INTEREST

All authors declare no conflict of interest.

REFERENCES


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    Full Research Article

    Innovative Potential of Lactococcus lactis D4 From Fermented Buffalo Milk (Dadiah) in Improving Fetal-maternal Outcomes in Hyperglycemic Animal Model

    A
    Ade Sukma1,*
    0000-0001-9940-6518
    N
    Nadia Yulianti2
    0009-0007-1493-6810
    A
    Almahdy Almahdy3
    0000-0003-4311-6233
    N
    Najmiatul Fitria3
    0000-0002-3255-1961
    1Department of Livestock Product Technology, Faculty of Animal Sciences, Universitas Andalas, Kampus Unand Limau Manis, Padang, 25163, West Sumatera, Indonesia.
    2Bachelor Program, Faculty of Pharmacy, Universitas Andalas, Kampus Unand Limau Manis, Padang, 25163, West Sumatera, Indonesia.
    3Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Andalas, Kampus Unand Limau Manis, Padang, 25163, West Sumatera, Indonesia.

    ABSTRACT

    Background: Hyperglycemia in pregnancy, which can adversely affect both maternal and fetal outcomes. Sustainable strategies for its management are urgently needed. This study explores the therapeutic efficacy of Lactococcus lactis D4 (LD4), a probiotic strain isolated from traditional fermented buffalo milk (dadiah), as an innovative biofunctional approach to controlling hyperglycemia.

    Methods: This experimental study involved 20 pregnant mice divided into four groups: K1 (control), K2 (10% glucose induction), K3 (10% glucose induction plus metformin) and K4 (10% glucose induction plus LD4). Blood glucose levels were measured at baseline. Laparotomy was performed on day 16 to assess maternal body weight, fetal number and fetal body weight. Data were analyzed using repeated-measures ANOVA followed by Duncan’s Multiple Range Test, with statistical significance set at p<0.05.

    Results LD4 administration during pregnancy did not affect maternal body weight, fetal count, or fetal body weight (p>0.05). However, LD4 significantly influenced blood glucose levels in mice (p<0.05). LD4 demonstrates significant effects, indicating its potential as a probiotic-based strategy for managing hyperglycemia during pregnancy. Further studies are needed to confirm its long-term safety and efficacy in clinical settings.in improving glycemic control during pregnancy and shows strong potential to become an effective probiotic.

    INTRODUCTION

    Maternal hyperglycemia during pregnancy remains a major health concern affects both maternal and fetal outcomes (Murphy, 2020). Uncontrolled blood glucose levels can lead to adverse pregnancy complications such as fetal overgrowth, preterm birth and increased risk of metabolic disorders later in life for the offspring (Nicholas et al., 2013). Despite advances in clinical management, the search for effective and safe adjunct therapies to improve maternal-fetal health in hyperglycemic conditions is ongoing (Fitria et al., 2025).
           
    Probiotics have emerged as a promising intervention for modulating metabolic and inflammatory pathways associated with hyperglycemia (Susmiati et al., 2023; Thorakkattu et al., 2022). Among the diverse probiotics, Lactococcus lactis, a member of lactic acid bacteria (LAB), has garnered interest due to its historical use in fermented dairy products and its potential therapeutic properties (Dahou et al., 2021; Hammadeche  et al., 2025; Kumari et al., 2021; Sukma et al., 2021).
           
    Dadiah, a traditional fermented buffalo milk product from West Sumatra, Indonesia, is a rich source of indigenous LAB, including unique strains of Lactococcus lactis (Milfiadi et al., 2023; Syahriandra et al., 2022). It has been proved that the treatment with probiotic derived from fermented milk, such as dadiah, exerted beneficial effects on glucose metabolism and inflammation (Fitria et al., 2021; Sukma  et al., 2024). However, the specific efficacy of Lactococcus lactis strains isolated from dadiah in improving fetal-maternal outcomes under hyperglycemic conditions remains underexplored (Arnold et al., 2021; Sukma et al., 2018; Yadav et al., 2022).. To preserve dadiah as a traditional Minangkabau food with significant health benefits, this research tested the potential of Lactococcus lactis D4, an isolate from dadiah, as a candidate therapy for gestational diabetes in a pregnant animal model.

    MATERIALS AND METHODS

    Materials
     
    All materials used in this study included female and male white mice (Mus musculus L.) provided with standard laboratory feed and water; Lactococcus lactis D4 isolated from dadiah;  10% glucose solution; metformin tablets (OGB Dexa®); sodium carboxymethyl cellulose (Na-CMC); distilled water and agar media for bacterial culture. Experimental procedures utilized plastic cages, oral gavage needles, analytical balances, an Easy Touch® glucometer.
     
    Study design and setting
     
    This experimental study was conducted from July - October 2025 at the Laboratory of Animal Product Technology, Faculty of Animal Sciences. Animal House Laboratory, Faculty of Pharmacy and the Laboratory of Pharmacology, Universitas Andalas, Padang, Indonesia. All experimental procedures complied with institutional ethical standards for animal research (Institutional Ethic Committee Faculty of Pharmacy Universitas Andalas No. 75/UN16.10.D.KEPK-FF/2025, date 2 September 2025).
     
    Experimental Animals, acclimatization and mating procedure
     
    A total of 25 female white mice and 5 male white mice (Mus musculus L.), weighing 20-25 g, were used in this study. Before experimentation, mice were acclimatized for 10 days in the Animal House Laboratory. Animals were housed in plastic cages with a wire cover under controlled environmental conditions with ad libitum access to standard laboratory feed and drinking water (Sukma  et al., 2024). Animals were eligible for the study if they exhibited normal behavior and body weight fluctuations of ≤10%. Mating was performed during the estrus phase using a female-to-male ratio of 4:1. Pregnancy was confirmed by the presence of a vaginal plug, indicating gestational day 0 (GD 0) (Gonzalez, 2016).
     
    Probiotic LD4 isolation and preparation
     
    Lactococcus lactis D4 was obtained from the fermentation of dadiah (traditional fermented buffalo milk). The selected dose of 109 CFU/mL, administered in 0.5 mL, was based on scientific evidence indicating that this concentration supports adequate bacterial viability (Anami et al., 2023).
     
    Preparation of metformin suspension
     
    A 0.5% Na-CMC solution was prepared by dispersing 0.5 g Na-CMC in 20 mL of hot distilled water until fully swollen, then diluting to 100 mL. Metformin (OGB Dexa®) 500 mg was then suspended in the Na-CMC solution to obtain a homogeneous suspension for oral administration. Metformin was used as a positive control and administered at 1.3 mg per 20 g of body weight, according to standard dosing guidelines (Wang et al., 2020).

    Experimental grouping
     
    Pregnant mice were randomly assigned to four experimental groups (n = 5 per group). The pregnant mice were randomly allocated into four experimental groups: a control group consisting of pregnant mice without any treatment (K1); 10% glucose group (K2); a positive control (10% glucose+metformin) (K3) and an intervention group (10% glucose+ Lactococcus lactis D4) (K4).
     
    Surgical procedures and outcome measurement
     
    Pregnant mice (45-47 g) underwent laparotomy under anesthesia to expose the uterus (Day 16). Primary outcomes comprised maternal blood glucose levels, maternal weight gain, fetal number and fetal weight. Secondary outcomes included comparative effects of LD4 administration under normoglycemic and hyperglycemic conditions, reflecting potential probiotic-mediated fetal-maternal benefits.
     
    Data analysis
     
    All data were analyzed using Statistical Product and Service Solutions (SPSS) software. Differences among groups were evaluated using one-way Analysis of Variance (ANOVA). When significant differences were observed, Duncan’s multiple range test (DMRT) was applied as a post-hoc analysis. Statistical significance was defined as p≤0.05.

    RESULTS AND DISCUSSION

    Observations of maternal weight gain during pregnancy were conducted to assess the nutritional status, health and the effect of LD4 on blood sugar levels in mice. Table 1 shows maternal weight data from day 0 to day 16 of pregnancy. Maternal body weight increased progressively throughout pregnancy in all experimental groups, reflecting normal gestational weight gain. Although the control group consistently exhibited slightly higher body weights than the hyperglycemic groups, no statistically significant differences were observed among the four groups at any observation point from gestational day 0 to day 16 (all p>0.05).

    Table 1: Maternal body weight progression (Days 0-16) in pregnant mice receiving glucose, metformin, or Lactococcus lactis D4.


           
    Table 2 shows the number of fetuses in pregnant rats for each treatment group. The control group showed the highest average fetal number, no statistically significant differences were observed among the groups (p = 0.209). These findings suggest that glucose induction, metformin treatment and LD4 administration did not significantly influence fetal number under the experimental conditions. The effects of Metformin and Lactococcus lactis D4 on Blood Glucose Levels were presented in Table 3. Blood glucose levels differed significantly among the treatment groups throughout the observation period. Both metformin and LD4 treatments progressively reduced glucose levels. By gestational day 16, the LD4-treated group had blood glucose levels comparable to those of the metformin-treated group and markedly lower than those of the untreated hyperglycemic group, indicating that LD4 effectively improved glycemic control during pregnancy (p<0.05).

    Table 2: Number of fetuses and fetal growth parameters in maternal mice from each group.



    ​

    Table 3: Effects of metformin and Lactococcus lactis D4 on blood glucose levels in hyperglycemic pregnant mice.


           
    Table 4 shows that the four groups can be divided into two similar groups based on their blood glucose levels. Pregnant mice given 10% glucose and those given 10% glucose plus metformin had similar, relatively low blood glucose levels. Post-hoc analysis using Duncan’s multiple range test further confirmed significant differences in blood glucose levels among the treatment groups. The untreated hyperglycemic group consistently showed the highest glucose concentrations, whereas both the metformin and LD4 groups formed homogeneous subsets with significantly lower glucose levels. These findings indicate that LD4 produced a glucose-lowering effect comparable to that of metformin in hyperglycemic pregnant mice.

    ​

    Table 4: Comparison of mean blood glucose levels across treatment groups using duncan’s multiple rank test.


           
    Maternal weight gain tended to increase from day 11 to day 16 of pregnancy due to fetal development and increased volumes of amniotic fluid, placenta and amniotic membranes. The research findings reveal a significant difference in maternal weight gain from the beginning of the treatment until the end of the study period (p=0.0279). This is consistent with data on maternal weight gain from day 0 to day 4 after induction and from day 16 before laparotomy (p=0.036). The effect of metformin on lower maternal weight is to inhibit intestinal glucose absorption, reduce hepatic glucose production (gluconeogenesis) and increase insulin sensitivity in peripheral tissues. This suppresses the accumulation of excess fat and calories during pregnancy so that maternal weight does not increase as much as in other test groups and prevents maternal obesity (Salomäki  et al., 2013). The LD4 test group experienced slight weight gain because probiotics can reduce insulin resistance and stabilize weight gain without causing absolute weight loss by modulating the gut microbiota to increase insulin sensitivity and reduce inflammation. This increase is consistent with the physiology of mouse pregnancy. Maternal hyperglycemia is transferred to the fetus, reducing maternal fat deposition, resulting in absolute weight loss in the mother (Mahdizade Ari  et al., 2022).
           
    Probiotics, including Lactococcus lactis, can modulate the gut microbiota, increasing the production of short-chain fatty acids (SCFAs). These SCFAs play a crucial role in regulating energy metabolism, improving insulin sensitivity and reducing systemic inflammation (Diana and Fitria, 2022). Other studies in mice have shown that maternal weight gain is closely correlated with fetal and conceptus weight gain (Putri et al., 2020). Maternal obesity affects fetal growth and pregnancy outcomes and weight loss before conception may improve fetal growth, but some effects of prior obesity persist on the offspring phenotype (Panchenko et al., 2016).
           
    Statistical analysis revealed a highly significant difference in the number and/or weight of fetuses among the treatment groups (p=0.000), indicating a strong effect of LD4 on fetal development. The control group had the highest fetal number, likely due to stable glucose homeostasis and a favorable maternal environment that minimized embryonic resorption. Uncontrolled increases in blood glucose levels can lead to Large for Gestational Age (LGA) driven by excess transplacental glucose that triggers fetal hyperinsulinemia and promotes excessive fetal growth (Fitria et al., 2024; Mousa et al., 2019). The use of metformin and LD4 probiotics can reduce maternal glucose, thereby reducing glucose transfer from the mother to the fetus and preventing fetal hyperinsulinemia and excessive growth, resulting in babies with more normal birth weight (Salomäki  et al., 2013).
           
    Significant differences in glucose levels across treatment groups are supported by the probiotic’s ability to regulate glucose homeostasis by inhibiting intestinal glucose absorption, preventing the production of anti-inflammatory cytokines and reducing pancreatic β-cell damage caused by oxidative stress. LD4 reduces glucose levels by modulating the gut microbiota and lactic acid production, thereby inhibiting carbohydrate absorption and reducing insulin resistance (Yuniritha et al., 2019).
     
    Strengths and limitation
     
    This study has several strengths, including a controlled experimental design with a clearly defined comparison group, which allows for a systematic evaluation of the effects of Lactococcus lactis D4 (LD4) on maternal and fetal parameters. The key finding, a significant reduction in blood glucose levels in the LD4 group, suggests the potential of this probiotic as a candidate for adjunctive therapy in hyperglycemic pregnancy. However, this study has limitations, including the use of a single LD4 dose, a relatively small sample size and limited exploration of the molecular mechanisms underlying LD4’s hypoglycemic effects. Furthermore, the study’s limited observation period and preclinical nature limit the generalizability of the findings to the human population. Therefore, further research with varying doses, larger sample sizes, mechanistic approaches and clinical trials is needed to confirm the safety, effectiveness and clinical relevance of LD4.

    CONCLUSION

    This study demonstrates that Lactococcus lactis effectively manages the adverse effects of hyperglycemia in a pregnant mouse model. LD4 may improve metabolic conditions by modulating the gut microbiota, which in turn could lead to better glucose homeostasis. This is particularly relevant in the context of hyperglycemia in pregnancy, where maternal hyperglycemia poses a direct threat to both the mother’s health and fetal development. The data support the potential of LD4 as a therapeutic agent, either alone or in combination with standard treatments like Metformin, to mitigate the complications of hyperglycemia in pregnancy and promote healthier pregnancy outcomes. Further research is warranted to directly measure blood glucose levels and other metabolic markers to confirm these findings.

    ACKNOWLEDGEMENT

    The authors would like to thank the Animal Product Technology Laboratory, Animal House Laboratory and the Pharmacology Laboratory at Andalas University, Padang, Indonesia, for the support provided in facilities, resources and technical expertise during the implementation of this research. All research activities were carried out in accordance with the ethical standards for animal research applicable at Andalas University.
     
    Author contribution
     
    AS contributed to the conceptualization, methodology, analysis and preparation of the original draft manuscript. N. Yulianti did animal handling and data curation. AA was involved in the validation process. NF contributed to the conceptualization, project administration and review and editing of the final version of the manuscript. All authors have read and approved the final manuscript.
     
    Disclaimers
     
    The views and conclusions expressed in this article are solely those of the authors and do not necessarily represent the views of their affiliated institutions. The authors are responsible for the accuracy and completeness of the information provided, but do not accept any liability for any direct or indirect losses resulting from the use of this content.
     
    Informed consent
     
    All animal procedures for experiments were approved by This manuscript complies with ethical approval from the Faculty of Pharmacy Universitas Andalas, Number 75/UN16.10.D.KEPK-FF/2025
     
    Funding
     
    No Funding for this study.
     
    Registration and ethical approval
     
    This manuscript complies with ethical approval from the Faculty of Pharmacy Universitas Andalas, Number 75/UN16.10.D.KEPK-FF/2025.

    CONFLICT OF INTEREST

    All authors declare no conflict of interest.

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