Effects of Non-insulin Anti-hyperglycemic Agents on Gut Microbiota: A Systematic Review on Human and Animal Studies

Abstract

Background: As growing evidence links gut microbiota with the therapeutic efficacy and side effects of anti-hyperglycemic drugs, this article aims to provide a systematic review of the reciprocal interactions between anti-hyperglycemic drugs and gut microbiota taxa, which underlie the effect of the gut microbiome on diabetic control via bug-host interactions. Method: We followed the PRISMA requirements to perform a systematic review on human vs. animal gut microbiota data in PubMed, SCOPUS, and EMBASE databases, and used Cochrane, ROBIN-I, and SYRCLE tools to assess potential bias risks. The outcomes of assessment were trends on gut microbiota taxa, diversity, and associations with metabolic control (e.g., glucose, lipid) following anti-hyperglycemic treatment. Results: Of 2,804 citations, 64 studies (17/humans; 47/mice) were included. In human studies, seven were randomized trials using metformin or acarbose in obese, pre-diabetes, and type 2 diabetes (T2D) patients. Treatment of pre-diabetes and newly diagnosed T2D patients with metformin or acarbose was associated with decreases in genus of Bacteroides, accompanied by increases in both Bifidobacterium and Lactobacillus. Additionally, T2D patients receiving metformin showed increases in various taxa of the order Enterobacteriales and the species Akkermansia muciniphila. Of seven studies with significant differences in beta-diversity, the incremental specific taxa were associated with the improvement of glucose and lipid profiles. In mice, the effects of metformin on A. muciniphila were similar, but an inverse association with Bacteroides was reported. Animal studies on other anti-hyperglycemic drugs, however, showed substantial variations in results. Cao et al. Anti-hyperglycemic Drugs and Gut Microbiota Conclusions: The changes in specific taxa and β-diversity of gut microbiota were associated with metformin and acarbose in humans while pertinent information for other anti-hyperglycemic drugs could only be obtained in rodent studies. Further human studies on anti-hyperglycemic drugs other than metformin and acarbose are needed to explore gut microbiota's role in their therapeutic efficacies and side effects.

The Influence of Probiotic Supplementation on Depressive Symptoms, Inflammation, and Oxidative Stress Parameters and Fecal Microbiota in Patients with Depression Depending on Metabolic Syndrome Comorbidity—PRO-DEMET Randomized Study Protocol

“…Another strength of our study is to use self-reported measures that are validated for Polish conditions, such as the FFQ to assess dietary factors, and then to use those measures in statistical analysis. Apart from diet, there are many other factors influencing our microbiome, such as the mode of delivery (vaginal or caesarean), the mode of feeding in early infancy (breastfeeding vs. formula), exposure to viral or bacterial antigens, treatment with antibiotics and several other groups of pharmacotherapeutics, genetic predispositions, age, and environmental factors such as air pollution, exercise, or stress [ 44 , 48 , 49 , 51 , 73 , 74 ]. The factors that may influence the microbiota changes in the course of our study are included in our original questionnaires: the SQ at the beginning of the protocol and in the follow-up visit and the MQ in the monitoring process included at the V2 visit.…”

“…Study Questionnaire (SQ) has been constructed to collect basic information concerning sociodemographic and health-related data. The participants will provide information on personally identifying data, as well as known factors influencing microbiota composition and function: diet, smoking cigarettes, physical activity, overall health status and specific somatic diseases connected with dysbiosis, and the use of dietary supplements and medications known to influence microbiota to a large extent, e.g., antibiotics, proton-pump inhibitors (PPIs), metformin, laxatives, systemic steroids or nonsteroidal anti-inflammatory drugs (NSAIDs) or antipsychotics additionally known to induce both metabolic and inflammation alteration [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. Both SQ and MQ applied every 2 weeks are based on exclusion criteria ( Table 1 ).…”

The Influence of Probiotic Supplementation on Depressive Symptoms, Inflammation and Oxidative Stress Parameters and Faecal Microbiota in Patients with Depression Depending on Metabolic Syndrome Comorbidity – PRO-DEMET Randomised Study Protocol

“…Another strength of our study is to use self-reported and validated for polish conditions FFQ to assess dietary factor and then use it in statistical analysis. Apart from diet, there are many other factors influencing our microbiome such as the mode of delivery (vaginal or caesarean), the mode of feeding in the early infancy (breastfeeding vs. formula), exposure to viral or bacterial antigens, treatment with antibiotics and several other groups of pharmacotherapeutics, genetic predispositions, age, environmental factors such as air pollution, exercise or stress [55][56][57][58][59][60]. The factors that may influence the microbiota changes in the course of our study are included in our original questionnaires: SQ at the beginning of the protocol and in the follow-up visit and MQ in the monitoring process including V2 visit.…”

Probiotics as a Treatment for “Metabolic Depression”? A Rationale for Future Studies

“…Additionally, it is worth remembering that there are many factors impacting microbiota function and composition, e.g., the diet, [ 39 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 ] and they should be assessed along the study process.…”