Alteration of the gut microbiome by anti-diabetic drugs 

By Shiyi Liang

Diabetes is a disease that affects millions of people around the world. In the UK, there are more than 3.5 million diagnosed diabetic patients. The capital expenditure on antidiabetic drugs in the UK have increased to a figure of up to £686 million in recent years.1 Type 2 diabetes comprises 90% of diagnosed diabetes cases. Type 2 diabetes mellitus (T2DM) is mainly characterized by insulin resistance and a lack of insulin – and treatment for T2DM often impacts the microbiome of the gut.

The human gut microbiota is mainly dominated by Firmicutes and Bacteroidetes. However, in type 2 diabetic patients, the relative abundance of Firmicutes is lower and the abundance of Bacteroidetes and Proteobacteria is comparatively higher.2 At the genus level, a greater abundance of Lactobacillus, Fusobacteria, and Prevotella was found in T2DM patients compared to healthy subjects.3 The pattern of changes in Firmicutes and Bacteroidetes were similarly found in type 1 diabetic children, alongside a significant decrease in the number of Actinobacteria.4 P.D Cani et al hypothesized and found that there were more Gram-negative bacteria than Gram-positive bacteria in High-Fat diet-fed mice.3 They also suggested that Gram-positive bacteria and plasma endotoxin (lipopolysaccharide [LPS]) concentrations were negatively correlated.5 LPS was found to contribute to oxidative stress, endotoxaemia and upregulated several inflammatory cytokines which lead to insulin resistance – suggesting a mechanistic role in diabetes symptom presentation.3

Common types of anti-diabetic drugs include alpha-glucosidase inhibitors (α-GIs), incretin-based drugs, and biguanides. α-GI functions by delaying carbohydrate digestion and reducing postprandial hyperglycemia. Acarbose, one of the α-GI drugs, increases the number of starch-fermenting and butyrate-producing bacteria, and it prevents starch processing and starch use by other short-chain fatty acid-producing bacteria.6 The effect of Acarbose in Zucker fatty diabetic rats has undergone investigation. A clinical dosage of Acarbose was distributed to the rats daily for 4 weeks – with results showing that the phylum Actinobacteria became more abundant after receiving the acarbose treatment.7 At the genus level, Ruminococcus 2 was the dominant enterotype in the acarbose group. In general, there was an overall decrease in microbial diversity and richness after the treatment

Metformin is one of the most frequently used anti-diabetic drugs and it belongs to biguanides. It blocks the action of glucagon and interacts with insulin receptors to stimulate glycolysis and suppress gluconeogenesis. The interaction with insulin receptors includes increasing the tyrosine kinase activity, which promotes insulin-mediated glucose uptake in skeletal muscle.2 Similarly, metformin was provided to rats daily for 4 weeks – and unlike the acarbose group, Lactobacillus was the main bacterium in the enterotype of metformin given rats.7 As such , it was seen that metformin has an effect of rising Lactobacillus abundance in the subject rats. In both humans and rodents, metformin upregulates the level of short-chain fatty acid-producing bacteria (e.g. Blautia, Bacteroides, Butyricoccus or Phascolarctobacterium).7 In T2DM patients, Lactobacillus was also enriched after receiving metformin – with side effects of metformin including vomiting, bloating, diarrhoea and nausea.7 Forslund et al. built a T2DM metagenomic dataset of patients from 3 countries. They analysed gut microbial functional potential and suggested that metformin could reduce LPS- triggered local inflammation and provide a suitable condition for Escherichia living. The side effects of metformin were thought to be related to the increasing abundance of Escherichia which cause hydrogen production to rise and could lead to bloating.8

Incretin based drugs involve GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Wang et al observed that GLP-1 receptor agonists like liraglutide did not directly influence the gut microbial composition, but do alter the gut environment and therefore affect the microbial component.9 They focused on modulation of gut microbiota after incretin-based treatment and identification of bacterial phylotypes with key roles – and identified 13 phylotypes thrived and 20 were suppressed. Lactobacillus was again found to increase in number, whilst at the order level, Clostridiales and Bacteroidales were phylotypes that decreased in number.9

Sitagliptin is a commonly used DPP-4 inhibitor that inhibits the degradation of GLP-1 and GLP-2. Yan et al. treated High-fat/High-glucose fed rats with sitagliptin daily for 12 weeks and analyzed their stool samples to get an overview of the changes in gut microbiota composition.10 Compared with diabetic rats, the relative abundance of Firmicutes again lowered and that of Bacteroidetes enriched in drug-received rats – with the relative abundance of Tenericutes fluctuating throughout the whole experiment.10

In this review, it has been illustrated that Lactobacillus, and some other short-chain fatty-acid producing bacteria, are commonly affected by the distribution of anti-diabetic drugs. The discovery of such patterns impacts future strategies for preventing and treating T2DM – which may consider gut microbiota modification or targeting specific microbiota. Advancing our understanding and knowledge in how gut microbiota affects the pharmacological efficacy of anti-diabetic drugs, alongside the potential side effects of drugs on the microbiota could enable  more advanced design and strategies for treating T2DM.

References:

  1. Prescribing for Diabetes – England 2015/16 to 2020/21 [Internet]. NHS choices. NHS; [cited 2022Jan26]. Available from: https://www.nhsbsa.nhs.uk/statistical-collections/prescribing-diabetes-england/prescribing-diabetes-england-201516-202021
  2. Larsen N, Vogensen FK, van den Berg FW, Nielsen DS, Andreasen AS, Pedersen BK, et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS ONE. 2010;5(2). DOI: 10.1371/journal.pone.0009085
  3. Sedighi M, Razavi S, Navab-Moghadam F, Khamseh ME, Alaei-Shahmiri F, Mehrtash A, et al. Comparison of gut microbiota in adult patients with type 2 diabetes and healthy individuals. Mic Pat. 2017;111:362–9. https://doi.org/10.1016/j.micpath.2017.08.038
  4. Murri M, Leiva I, Gomez-Zumaquero JM, Tinahones FJ, Cardona F, Soriguer F, et al. Gut microbiota in children with type 1 diabetes differs from that in healthy children: A case-control study. BMC Med. 2013;11(1). DOI: 10.1186/1741-7015-11-46
  5. Cani PD, Neyrinck AM, Fava F, Knauf C, Burcelin RG, Tuohy KM, et al. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia. 2007;50(11):2374–83. DOI: 10.1007/s00125-007-0791-0
  6. Weaver GA, Tangel CT, Krause JA, Parfitt MM, Jenkins PL, Rader JM, et al. Acarbose enhances human colonic butyrate production. The Jou of Nut. 1997;127(5):717–23. DOI: 10.1093/jn/127.5.717
  7. Zhang M, Feng R, Yang M, Qian C, Wang Z, Liu W, et al. Effects of metformin, acarbose, and sitagliptin monotherapy on gut microbiota in Zucker Diabetic Fatty Rats. BMJ Ope Dia Res & Care. 2019;7(1). DOI: 10.1136/bmjdrc-2019-000717
  8. Forslund, K., Hildebrand, F., Nielsen, T. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015). https://doi.org/10.1038/nature15766
  9. Wang L, Li P, Tang Z, Yan X, Feng B. Structural modulation of the gut microbiota and the relationship with body weight: Compared evaluation of Liraglutide and saxagliptin treatment. Sci Rep. 2016;6(1).  DOI: 10.1038/srep33251
  10. Yan X, Feng B, Li P, Tang Z, Wang L. Microflora disturbance during progression of glucose intolerance and effect of sitagliptin: An animal study. Journal of Diabetes Research. 2016;2016:1–DOI: 10.1155/2016/2093171

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