November/December 2023

Probiotics: Probiotics and Diabetes
By Carrie Dennett, MPH, RDN
Today’s Geriatric Medicine
Vol. 16 No. 6 P. 30

Can gut health management help prevent or manage type 2 diabetes?

As consumers become more aware of the role gut health has in overall health and chronic disease, many are considering probiotic supplements to support their gut microbiota. Unfortunately, the hype around the potential health benefits of probiotics currently is overstated once claims are evaluated in the context of research-based evidence. So what does this mean for the claims that probiotics can help prevent or manage type 2 diabetes?

Certainly, the gut microbiota is a contributing factor in the development and progression of type 2 diabetes. Gut microbes and their metabolites strongly influence host metabolism, gut permeability, immune function, satiety, digestion, and nutrient absorption, among other important functions.1 Dysbiosis, the alteration of a healthy microbiota, is associated with low-grade inflammation, insulin resistance, and type 2 diabetes.2

Differences in Microbiota Composition
Numerous research studies have observed relative increases in some bacterial species and decreases in others in the stool of participants with type 2 diabetes. Examples include the following:

• Decreases in bacterial species that produce short-chain fatty acids (SCFAs) via fermentation of dietary fiber. SCFAs have several functions, including modulating the secretion of hormones that can increase insulin sensitivity and satiety and decrease inflammation.1

• Differences in microbial populations also have been observed when comparing patients with diabetic nephropathy, type 2 diabetes patients without renal disease, and healthy individuals.3

• Some microbes metabolize trimethylamine from dietary choline and carnitine, which is converted in the liver to trimethylamine-N-oxide (TMAO). Patients with type 2 diabetes have elevated TMAO levels, although it’s unclear whether high TMAO levels cause diabetes.2

• Some stool studies also have observed increased expression of microbial stress genes—adaptations that help microbes adapt to adverse changes in nutrient supply or other aspects of their environment—which has been linked to insulin resistance, pancreatic beta-cell dysfunction, impaired glucose tolerance, and type 2 diabetes.1

The health and composition of the gut microbiota are influenced by diet and lifestyle factors, including alcohol intake and the use of antibiotics, other medications, and probiotics and prebiotics.1 The official definition of probiotics, as agreed on by the International Scientific Association for Probiotics and Prebiotics, is that they’re live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. While certain fermented foods may contain strains of probiotic bacteria, most of these foods wouldn’t be considered probiotics themselves because bacterial strains may vary from batch to batch and because they may not be present in sufficient numbers to produce a health benefit.

Preliminary studies suggest that altering the composition of the gut microbiota with probiotic supplementation may improve type 2 diabetes by reducing proinflammatory cytokines, intestinal permeability, and oxidative stress via multiple pathways, including SCFA formation.4 While results from animal studies on the benefits of probiotics for improving glucose metabolism and insulin sensitivity have been promising, research on humans has produced inconsistent results.5,6 Still, a 2020 meta-analysis of 15 randomized controlled trials involving 902 patients found that the groups randomized to take probiotics saw statistically significant reductions in hemoglobin A1c, fasting blood glucose, and insulin resistance, compared with patients taking a placebo, despite differences in the dosage and duration of probiotic treatment among the studies.5

Studies and Their Findings
In a 2023 review article, Akkermansia muciniphila—a bacterium first “discovered” and isolated in 2004, and which represents approximately 1% to 3% of the total gut microbiota in healthy people7—was called the “‘next generation probiotic’ for alleviating metabolic disorders and the inflammatory response.” For example, propionate, an SCFA produced by A. muciniphila metabolism, has been shown to stimulate glucagonlike peptide-1, a hormone with functions including stimulating insulin secretion.8 Another 2023 review had a similar assessment, emphasizing that A. muciniphila has a well-documented role in improving several metabolic pathways, which makes it a key element in the pathogenesis of several human diseases. The authors note that, in addition to stimulating glucagonlike peptide-1, this bacterium can reduce the expression of glucose and fructose receptors in the small intestine, reducing absorption of carbohydrates.7

Two randomized, double-blinded, placebo-controlled trials have demonstrated that supplementation with A. muciniphila has benefits for blood glucose control. A 2019 exploratory study published in Nature Medicine found that A. muciniphila improved insulin sensitivity compared with placebo.9 A small 2020 company-funded-and-run proof-of-concept study that used a novel probiotic formulation containing A. muciniphila along with Clostridium beijerinckii, Clostridium butyricum, Bifidobacterium infantis, Anaerobutyricum hallii, and inulin—a type of prebiotic fiber—found that among participants with type 2 diabetes currently using metformin, the group taking the formulation experienced statistically significant decreases in postprandial glucose levels (36.1 mg/dL) and HbA1c levels (0.6%) at week 12, when compared with placebo. No change in fasting glucose levels was observed.10 Currently, this formulation is the only one established by the Alliance for Education on Probiotics to reduce postprandial blood glucose in people with type 2 diabetes, giving it a level 2 recommendation11; however, several bacterial species used in commercial probiotic supplement products, including some Lactobacillus and Bifidobacterium species, have reduced fasting blood glucose levels in human and animal studies.2,4

Some studies also have looked at the combined effects of probiotics and berberine, a bioactive plant compound that has a long history in traditional Chinese medicine. Independently, berberine has been shown in studies to lower blood glucose in patients with type 2 diabetes, although the mechanism to achieve this is unknown.12

The Probiotics and BBR on the Efficacy and Change of Gut Microbiota in Patients with Newly Diagnosed Type 2 Diabetes randomized controlled trial compared the effects of probiotics plus berberine, berberine plus placebo, or probiotics plus placebo with that of placebo alone in 466 patients. After 12 weeks of treatment, the probiotic-berberine group and the berberine-placebo group had similar statistically significant reductions in HbA1c compared with the probiotic-placebo and placebo alone groups. The researchers found that berberine enhanced populations of several bacterial species that also are enhanced by treatment with metformin.13 A separate 18-week randomized, double-blinded, parallel-controlled study of 300 patients newly diagnosed with hyperglycemia compared the effects of berberine, Bifidobacterium, berberine plus Bifidobacterium, and placebo. Compared with the placebo group, the berberine plus Bifidobacterium group saw a significant reduction in fasting blood glucose, two-hour postprandial glucose, and HbA1c. The berberine-only group also saw a small reduction in two-hour postprandial glucose.14

Safety Considerations
Because healthy consumers and certain patient populations use probiotics, the International Scientific Association for Probiotics and Prebiotics published a perspective piece on emerging issues in probiotic safety earlier this year in the journal Gut Microbes. The authors explain probiotics targeted for patient populations should undergo stringent testing to meet quality standards appropriate for that population, preferably verified by an independent third party.15 For example, despite excitement about A. muciniphila, because it’s a mucin-degrading bacteria—mucin is the main glycoprotein in the mucus layer that protects the intestinal barrier—there’s concern that excessive enrichment of that species in certain intestinal environments may be harmful. For instance, it may not be safe to use in patients with endocrine or gynecological disorders that increase risk of inflammatory bowel disease, such as polycystic ovary syndrome or endometriosis. Moreover, patients with Parkinson’s disease or multiple sclerosis already may have an overabundance of A. muciniphila.16

A 2021 Cochrane Review concluded that low-quality evidence from six placebo-controlled studies involving 1,440 patients hasn’t clearly identified the effect of probiotics on the risk of gestational diabetes, which is a long-term risk factor for type 2 diabetes.17 Importantly, the authors note that while they found no solid evidence of the benefit of using probiotics to prevent gestational diabetes, they found that high-quality evidence suggests that probiotics may increase the risk of preeclampsia.

Bottom Line
These findings serve as a good reminder that much of the research on probiotics and glucose metabolism is in animal models, and mechanisms to explain observed benefits aren’t fully explained. Additional research may shine light on those mechanisms, as well as a better understanding of the relative risks and benefits for different patient populations. In the meantime, knowing the current limitations of the research can help dietitians counsel clients and patients who want to know if they should take probiotics to manage their blood sugar—especially patients who may think that probiotics are more powerful than they actually are.

— Carrie Dennett, MPH, RDN, is the nutrition columnist for The Seattle Times, owner of Nutrition By Carrie, and author of Healthy for Your Life: A Non-Diet Approach to Optimal Well-being.

References
1. Barlow GM, Mathur R. Type 2 diabetes and the microbiome. J Endocr Soc. 2022;7(2):bvac184.

2. Huda MN, Kim M, Bennett BJ. Modulating the microbiota as a therapeutic intervention for type 2 diabetes. Front Endocrinol (Lausanne). 2021;12:632335.

3. Zhou Z, Sun B, Yu D, Zhu C. Gut microbiota: an important player in type 2 diabetes mellitus. Front Cell Infect Microbiol. 2022;12:834485.

4. Kim YA, Keogh JB, Clifton PM. Probiotics, prebiotics, synbiotics and insulin sensitivity. Nutr Res Rev. 2018;31(1):35-51.

5. Tao YW, Gu YL, Mao XQ, Zhang L, Pei YF. Effects of probiotics on type II diabetes mellitus: a meta-analysis. J Transl Med. 2020;18(1):30. Erratum in: J Transl Med. 2020;18(1):105.

6. Kobyliak N, Conte C, Cammarota G, et al. Probiotics in prevention and treatment of obesity: a critical view. Nutr Metab (Lond). 2016;13:14.

7. Pellegrino A, Coppola G, Santopaolo F, Gasbarrini A, Ponziani FR. Role of Akkermansia in human diseases: from causation to therapeutic properties. Nutrients. 2023;15(8):1815.

8. Li J, Yang G, Zhang Q, Liu Z, Jiang X, Xin Y. Function of Akkermansia muciniphila in type 2 diabetes and related diseases. Front Microbiol. 2023;14:1172400.

9. Depommier C, Everard A, Druart C, et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med. 2019;25(7):1096-1103.

10. Perraudeau F, McMurdie P, Bullard J, et al. Improvements to postprandial glucose control in subjects with type 2 diabetes: a multicenter, double blind, randomized placebo-controlled trial of a novel probiotic formulation. BMJ Open Diabetes Res Care. 2020;8(1):e001319.

11. Clinical guide to probiotic products available in USA: applications, dosage forms and clinical evidence to date, 2023 Edition. Alliance for Education on Probiotics website. https://usprobioticguide.com

12. Xie W, Su F, Wang G, et al. Glucose-lowering effect of berberine on type 2 diabetes: a systematic review and meta-analysis. Front Pharmacol. 2022;13:1015045.

13. Zhang Y, Gu Y, Ren H, et al. Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study). Nat Commun. 2020;11(1):5015.

14. Ming J, Yu X, Xu X, et al. Effectiveness and safety of Bifidobacterium and berberine in human hyperglycemia and their regulatory effect on the gut microbiota: a multi-center, double-blind, randomized, parallel-controlled study. Genome Med. 2021;13(1):125.

15. Merenstein D, Pot B, Leyer G, et al. Emerging issues in probiotic safety: 2023 perspectives. Gut Microbes. 2023;15(1):2185034.

16. Chiantera V, Laganà AS, Basciani S, Nordio M, Bizzarri M. A critical perspective on the supplementation of Akkermansia muciniphila: Benefits and Harms. Life (Basel). 2023;13(6):1247.

17. Davidson SJ, Barrett HL, Price SA, Callaway LK, Dekker Nitert M. Probiotics for preventing gestational diabetes. Cochrane Database Syst Rev. 2021;4(4):CD009951.