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Clinical Trial: Probiotics in Metformin Intolerant Patients with Type 2 Diabetes (ProGasMet).
Nabrdalik, K, Drożdż, K, Kwiendacz, H, Skonieczna-Żydecka, K, Łoniewski, I, Kaczmarczyk, M, Wijata, AM, Nalepa, J, Holleman, F, Nieuwdorp, M, et al
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2023;168:115650
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Metformin has been the number one drug of choice for the management of type 2 diabetes, however there is a proportion of individuals who suffer from stomach issues and discontinue therapy. This may be due to the possibility that metformin impacts gut microbiota composition. This randomised control trial of 82 individuals with metformin intolerance aimed to determine the effect of a multi-strain probiotic in conjunction with metformin administration. The results showed that whilst on probiotics, there was a significant improvement in symptoms, with reduced incidence and severity of nausea, reduced frequency and severity of stomach pain and bloating and self-assessed improvement of tolerability of metformin. Nausea was also decreased, but only when the probiotic was allowed time to act. It was concluded that probiotic supplementation improves gastrointestinal side effects associated with metformin intolerance. This study could be used by healthcare professionals to understand that individuals who are on metformin may experience gastrointestinal side effects, which may be relieved with a multi-strain probiotic.
Abstract
BACKGROUND For decades, metformin has been the drug of first choice in the management of type 2 diabetes. However, approximately 2-13% of patients do not tolerate metformin due to gastrointestinal (GI) side effects. Since metformin influences the gut microbiota, we hypothesized that a multi-strain probiotics supplementation would mitigate the gastrointestinal symptoms associated with metformin usage. METHODS AND ANALYSIS This randomized, double-blind, placebo-controlled, single-center, cross-over trial (ProGasMet study) assessed the efficacy of a multi-strain probiotic in 37 patients with metformin intolerance. Patients were randomly allocated (1:1) to receive probiotic (PRO-PLA) or placebo (PLA-PRO) at baseline and, after 12 weeks (period 1), they crossed-over to the other treatment arm (period 2). The primary outcome was the reduction of GI adverse events of metformin. RESULTS 37 out of 82 eligible patients were enrolled in the final analysis of whom 35 completed the 32 weeks study period and 2 patients resigned at visit 5. Regardless of the treatment arm allocation, while on probiotic supplementation, there was a significant reduction of incidence (for the probiotic period in PRO-PLA/PLA-PRO: P = 0.017/P = 0.054), quantity and severity of nausea (P = 0.016/P = 0.024), frequency (P = 0.009/P = 0.015) and severity (P = 0.019/P = 0.005) of abdominal bloating/pain as well as significant improvement in self-assessed tolerability of metformin (P < 0.01/P = 0.005). Moreover, there was significant reduction of incidence of diarrhea while on probiotic supplementation in PRO-PLA treatment arm (P = 0.036). CONCLUSION A multi-strain probiotic diminishes the incidence of gastrointestinal adverse effects in patients with type 2 diabetes and metformin intolerance.
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Dynamics of gut microbiota during pregnancy in women with TPOAb-positive subclinical hypothyroidism: a prospective cohort study.
Wu, M, Chi, C, Yang, Y, Guo, S, Li, T, Gu, M, Zhang, T, Gao, H, Liu, R, Yin, C
BMC pregnancy and childbirth. 2022;22(1):592
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Subclinical hypothyroidism (SCH) in pregnancy refers to the elevation of thyroid stimulating hormone level with normal free T4 level. One third of women with SCH have been reported to test positive for anti-thyroid peroxidase antibody (TPOAb+). The aim of this study was to evaluate whether gut microbiota can be potential therapeutic targets for managing TPOAb+ SCH. This study was a nested, prospective observational cohort study. A total of 64 and 68 pregnant women with TPOAb+ and TPOAb negative SCH, respectively, were included in this study. Results showed that women who were diagnosed with TPOAb+ SCH in trimester (T)1 show distinct dynamics of gut microbiota from T2 to T3. Furthermore, changes in the abundances of three types of bacterial species were abnormal in the presence of levothyroxine treatment. Authors conclude that gut microbiota can serve as potential therapeutic targets for TPOAb+ SCH during pregnancy.
Abstract
BACKGROUND Anti-thyroid peroxidase antibody (TPOAb) positivity can contribute to inhibit thyroxine synthesis. Gut microbiota can interact with metabolic or immune diseases. However, dynamics of gut microbiota from the second (T2) to the third trimester (T3) in women with TPOAb-positive/negative subclinical hypothyroidism (TPOAb+/TPOAb- SCH) have not been reported. Therefore, we aimed to evaluate whether gut microbiota can be potential therapeutic targets for managing TPOAb+ SCH. METHODS In this single-center prospective cohort study, we observed gut microbiota dynamics by sequencing 16S rRNA from fecal samples collected in T2 (20-23+ 6 weeks) and T3 (28-33+ 6 weeks). TPOAb+/TPOAb- SCH were stratified depending on whether or not they used levothyroxine (LT4) during the pregnancy (LT4+/LT4-). Microbiome bioinformatics analyses were performed using QIIME2. The linear discriminant analysis effect size (LEfSe) was used for the quantitative analysis of biomarkers. Functional profiling was performed with PICRUSt2. RESULTS Distinct gut microbiota dynamics from T2 to T3 were noted in the TPOAb- (n = 68) and TPOAb+ (n = 64) SCH groups. The TPOAb+ LT4- group was characterized by enriched bacterial amplicon sequence variants (ASVs) of Prevotella in T2 and Bacteria, Lachnospirales, Lachnospiraceae, Blautia, and Agathobacter in T3 and by depleted ASVs of Gammaproteobacteria, Enterobacterales, and Enterobacteriaceae in T2 and Actinobacteriota, Coriobacteriia, Actinobacteria, Coriobacteriales, Bifidobacteriales, Bifidobacteriaceae, Bifidobacterium, Dorea formicigenerans, and Bifidobacterium longum in T3. The TPOAb+ LT4+ group was characterized by enriched bacterial ASVs of Blautia, Streptococcus salivarius, and Bifidobacterium longum in T3 and by depleted ASVs of Bacteroidota, Bacteroidia, Bacteroidales, and Prevotella in T2 and Agathobacter in T3. Moreover, we identified 53 kinds of metabolic functions that were mainly involved in sugar, lipid, and amino acid metabolism. CONCLUSIONS Our results indicated that low dynamics of gut microbiota composition and high dynamics of its metabolic function from T2 to T3 were associated with TPOAb+ SCH. We concluded that gut microbiota could be new targets for treatment of TPOAb+ SCH during pregnancy. TRIAL REGISTRATION This study was retrospectively registered at the Chinese Clinical Trial Registry (registration number ChiCTR2100047175 ) on June 10, 2021.
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Effects of Lactococcus lactis subsp. cremoris YRC3780 daily intake on the HPA axis response to acute psychological stress in healthy Japanese men.
Matsuura, N, Motoshima, H, Uchida, K, Yamanaka, Y
European journal of clinical nutrition. 2022;76(4):574-580
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The hypothalamic-pituitary-adrenal (HPA) axis is involved in the stress response and is linked to the microbiome through a number of possible mechanisms, including immune-related ones. Lactococcus lactis subsp. cremoris YRC3780 (YRC3780), a probiotic isolated from kefir, has been shown to have beneficial immune-modulatory properties. The aim of this double-blind, placebo-controlled trial, which included 27 healthy young men, was to assess sleep quality, mental health, HPA axis activity (salivary cortisol) and response to an acute stress test during/after 8 weeks of supplementation with YRC3780. At 8 weeks, salivary morning cortisol levels were significantly reduced in the probiotic compared to the placebo group. The effect on the stress test depended on whether or not participants were considered “cortisol-responders” or not. Improvements in sleep quality were seen at 6 weeks (but not at any other time points) in 1 out of 2 sleep questionnaires in the YRC3780 group, whilst no significant differences were observed in actigraphy-measured sleep efficiency. There were no differences in mood between groups, but significant improvements in general health in the probiotic group. Interestingly, no changes in the microbiome of the probiotic group were seen, suggesting that the observed effects may be mediated via the immune system.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Research indicates a bidirectional interaction between the gut microbiome and the central nervous system, affecting the functions of the brain and spinal cord.
- This clinical trial suggests that daily intake of Lactococcus lactis subsp. cremoris (YRC3780) may enhance the HPA axis response to acute psychological stress, potentially linked to a reduction in morning cortisol levels.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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X
B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
A randomized, placebo-controlled, double-blind clinical trial was conducted to investigate the influence of Lactococcus lactis subsp. cremoris (YRC3780), isolated from kefir, on stress response, sleep quality, and mental health.
Method
Twenty-seven healthy young men, with an average age of 23.5 years, and mean body mass index of 21.5 kg/m2 , were randomly assigned to either the YRC3780 group or the placebo group. Participants were administered YRC3780 or a placebo daily for 8 weeks.
Throughout the study, participants completed assessments, including the Athens Insomnia Scale (AIS), the Pittsburgh Sleep Quality Index (PSQI), the General Health Questionnaire (GHQ-28), and the Profile of Mood States 2nd Edition-Adult Short, Total Mood Disturbance subscale (POMS 2 TMD), every 2 weeks. Additionally, diurnal rhythms of HPA axis activity were assessed every 2 weeks through saliva samples collected at 2-hour intervals during the day. At the end of the 8-week supplementation period, participants underwent the Trier Social Stress Test (TSST) to evaluate the effects of daily YRC3780 intake on the HPA axis stress response. In addition, three fecal samples were collected to analyse the gut microbiome (on the last day of baseline, and at 4 and 8 weeks).
A total of 27 out of 33 subjects (81%) completed the study, with six participants withdrawing without providing explanations.
Results
The primary findings of this study were as follows:
- At week 6 of YRC3780 supplementation, salivary cortisol levels at 2 hours and 6 hours after waking were significantly lower in the YRC3780 group compared to the placebo group (p=0.05).
- Salivary cortisol concentrations at 40 minutes after the TSST were significantly lower in the YRC3780 group (4.2 ± 4.4 nmol/L, mean ± SD) than in the placebo group (7.6 ± 4.7 nmol/L) (p=0.043).
- AIS scores at 6 weeks and GHQ-28 scores at 8 weeks were significantly lower in the YRC3780 group compared to the placebo group (AIS, p=0.031; GHQ-28, p=0.038) indicating better sleep quality and a better mental state.
Conclusion:
Oral supplementation with YRC3780 may have beneficial effects on the HPA axis response to acute psychological stress, potentially associated with a decrease in morning cortisol levels. Additionally, the study suggests that the lower basal activity and stress reactivity of the HPA axis may lead to improvements in subjective sleep quality and mental health.
Clinical practice applications:
- The precise mechanisms underlying the correlation between the gut microbiota and the gut-brain axis remain incompletely understood, emphasising the need for further research.
- This clinical trial demonstrated that daily intake of YRC3780 decreased morning salivary cortisol levels at 6 and 8 weeks and reduced the salivary cortisol response to acute psychological stress.
Considerations for future research:
- Larger, adequately powered clinical trials are required to provide deeper insights into the mechanisms responsible for the stress-reducing and sleep-improving effects of Lactococcus lactis subsp. cremoris.
- Furthermore, investigations into optimal dosage and duration of probiotic supplementation are warranted for a more comprehensive understanding, particularly in diverse demographic groups.
- Comparative research is needed to explore the effects of various probiotic strains on objective stress responses.
Abstract
BACKGROUND Lactococcus lactis subsp. cremoris (YRC3780), which is isolated from kefir, has been associated with anti-allergic effects in humans. However, it remains unknown whether daily intake of YRC3780 attenuates the response to psychological stress in humans in parallel with changes to the gut microbiome. We examined the fundamental role of YRC3780 in the gut microbiome, stress response, sleep, and mental health in humans. METHODS Effects of daily intake of YRC3780 on the hypothalamic-pituitary-adrenal (HPA) axis response to acute psychological stress were investigated in a double-blind, placebo-controlled clinical trial involving 27 healthy young men (mean age and body mass index: 23.5 years and 21.5 kg/m2) who were randomly assigned to placebo (n = 13) or YRC3780 (n = 14) groups. The HPA axis response to acute psychological stress, the diurnal rhythm of HPA axis activity, and gut microbiome were assessed and compared between the two groups. RESULTS The results showed that daily intake of YRC3780 significantly lowered morning salivary cortisol levels compared with placebo. In addition, salivary cortisol levels following a social stress test significantly decreased +40 min after beginning the TSST in the YRC3780-treated group compared to placebo. There were no significant differences between the two groups in terms of actigraphy-based sleep quality, but the subjective sleep quality and mental health were significantly improved in the YRC3780-treated group compared to placebo. CONCLUSIONS Our study suggests that daily intake of YRC3780 improves the HPA axis response to acute psychological stress, which might be associated with a decrease in morning cortisol levels.