The surprising role of gut health in improving diabetes outcomes and the potential of probiotics

Introduction
Diabetes is arguably the greatest health threat society faces in modern times since it features as a top 10 leading cause of death worldwide (1) but also increases the risk of cardiovascular disease (2), kidney disease (2) and even Alzheimer's (3,4).

So far, evidence-based approaches to diabetes include significant weight loss achieved by liquid diets (5), dietary modification (6), and/or combined pharmaceutical intervention (7).

Despite this, the number of diabetic foot amputations has increased in recent years (8). Almost a third of people with type 2 diabetes experience neuropathy, and nearly half of those with type 1 diabetes experience neuropathy (9).

Clearly, new and novel ways of improving glycaemic control are urgently needed & gut health modulation may offer exciting new possibilities.

This article aims to summarize the role of gut health in managing diabetes and the evidence in this area.

Gut Health Basics
The human microbiome includes microbes found in various parts of the body: oral cavity, skin, stomach, duodenum, jejunum, ileum, and colon. The "gut microbiome" refers to the microbes (e.g. bacteria, fungi, viruses) primarily located in the large intestine. This is the most abundant collection of microbes. Bacteria have been the most extensively studied (10).

Altered gut microbiome composition has been associated with several diseases, including IBD, IBS, celiac disease, colorectal cancer, pancreatic disorders, and even diabetes (10).

Generally, these bacteria directly influence the host's health by producing various metabolites, which can either activate or inhibit signalling pathways throughout the body (10).

The Link With Diabetes
The short-chain fatty acids (e.g. acetate, butyrate, propionate) are the main metabolites produced via fermentation of non-digestible nutrients in the large intestine. They are known to regulate metabolic pathways in the liver, adipose tissue, muscle and brain tissues. Consequently, they help regulate energy balance, glucose/lipid metabolism, inflammation, and even immunity (10).

As a result, the gut microbiome has been shown to play a significant role in the pathophysiology of diabetes. Human studies have revealed that the composition of gut bacteria differs between those with diabetes and non-diabetic individuals. For example, people with diabetes have fewer butyrate-producing gut bacteria (11,12). This imbalance, often referred to as dysbiosis is significant because butyrate decreases lipid synthesis, increases lipid oxidation, reduces triglycerides, reduces systemic inflammation, and increases mitochondrial function (13).

Specifically relevant to people living with diabetes, butyrate promotes survival of the pancreatic beta-cells, regulates insulin secretion, promotes GLP-1 secretion and inhibits histone deacetylases (HDAC) all of which conspires to reduce blood sugar and preserve insulin sensitivity.

Probiotics
Studies have shown that modulation of the gut microbiome through probiotic supplementation results in significant reductions in blood sugar, insulin resistance and reduced CRP (14).

Several meta-analyses have also been done and found a consistent modest benefit to probiotic supplementation in diabetes. The table below summarizes these studies and their findings.

Taken together these results suggest a modest but consistent benefit to modulating the gut microbiome with the intention to improve diabetes outcomes. Longer term studies are needed and specifically around which strains of probiotics may be best but for now there is sufficient evidence to suggest a net positive benefit.

Further studies have shown blood sugar reducing effects in those either supplemented with oral butyrate or inulin powder which would lead to endogenous production of butyrate (15,16).

Click to enlarge the table

Practical Applications for Clinicians
Probiotic supplementation is a potentially easy to administer and moderately effective way to modulate the gut microbiome to reduce glucose excursions as well as inflammation. So long as the bacteria survive digestion and facilitate the production of butyrate it will benefit those living with diabetes.

The combined administration of probiotics and prebiotics (fibre) will likely have the greatest positive impact.

Practically, the easiest and cheapest way to do this may be to encourage a higher fibre intake via a diverse intake of plant-based foods (e.g. wholegrains, fruit, veg, nuts, seeds, legumes, herbs, spices) (22, 23) . There have also been some promising studies using flaxseed (24-27).

Conclusion
Diabetes is a rapidly growing pandemic. The most evidence-based options to treat this disease include weight loss, pharmaceutical intervention, or a combination of both. We urgently need more options to help patients avoid the burdens of this lifestyle disease. The microbiome of people with diabetes produces significantly less butyrate, which negatively affects lipid/glucose metabolism and inflammation.

A series of systematic reviews spanning 114 controlled trials with over 7154 participants show that modulating the microbiome using probiotics has a significant positive effect. Encouraging patients to supplement their diet with prebiotic fibres (like flaxseed) also has a significant positive impact (23). Doing both simultaneously is likely to have the fastest and most potent positive impact for patients.

It's not clear if diabetes leads to gut health abnormalities or if gut health abnormalities lead to diabetes. However, what is clear is that there are simple and effective actions you can encourage patients to take to improve their gut health, which will positively impact their diabetes. This provides you, the clinician, with more tools to help them achieve remission.

References

1. World Health Organization (WHO) Factsheet – The Top 10 Causes of Death. Available at: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death#:~:text=One. Date accessed: August 2024.
2. Swamy S, et al. J Clin Med 2023;12(22):6984.
3. Barbiellini Amidei C, et al. JAMA 2021;325(16):1640-9.
4. Michailidis M, et al. Int J Mol Sci 2022;23(5):2687.
5. Lean MEJ, et al. Lancet Diabetes Endocrinol 2024;12:233-46.
6. Unwin D, et al. BMJ Nutrition, Prevention & Health 2023;e000544.
7. Tsapas A, et al. Ann Intern Med 2020;173(4):278-86.
8. Public Health England Press Release: Preventing amputations major concern as diabetes numbers rise. Available at: https://www.gov.uk/government/news/preventing-amputations-major-concern-as-diabetes-numbers-rise. Date accessed: August 2024.
9. Mathur R, et al. BMJ Open 2017;7:e014444.
10. De Vos WM, et al. Gut 2022;71(5):1020-32.
11. Karlsson FH, et al. Nature 2013;498(7452):99-103.
12. Qin J, et al. Nature 2012;490(7418):55-60.
13. Mayorga-Ramos A, et al. Front Nutr 2022;9:1067647.
14. Asemi Z, et al. Ann Nutr Metab 2013;63(1-2):1-9.
15. Roshanravan N, et al. Horm Metab Res 2017;49(11):886-91.
16. Khosravi Z, et al. Clin Nutr ESPEN 2022l49:79-85.
17. Ruan Y, et al. PLOS One 2015;10(7):e0132121.
18. Nikbakht E, et al. Eur J Nutr 2018;57:95-106.
19. Ardeshirlarijani E, et al. DARU Journal of Pharmaceutical Science 2019;27:827-37.
20. Chen Y, et al. Medicina Clínica (English Edition) 2020;154(6):199-206.
21. Ayesha IE, et al. Cureus 2023;15(10):e46741.
22. Fu J, et al. Microorganisms 2022;10(12):2507.
23. Reynolds AN, et al. PLoS Med 2020;17(3):e1003053.
24. Mueed A, et al. Foods 2022;11(20):3307.
25. Mani UV, et al. J Diet Suppl 2011;8(3):257-65.
26. Thakur G, et al. Int J Food Sci Nutr 2009;60(6):126-36.
27. Hutchins AM, et al. Nutr Res 2013l33(5):367-75.