European Review for Medical and Pharmacological Sciences 2021; 25: 4570-4578 Could the use of have a positive effect on microbiota and treatment of type 2 diabetes?

1 2 3 3 E. STACHOWSKA , M. WIŚNIEWSKA , A. DZIEŻYC , A. BOHATYREWICZ

1Department of and Metabolomics, Pomeranian Medical University, Pomeranian Medical University, Szczecin, Poland 2Clinical Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, Szczecin, Poland 3Clinic of Orthopaedics and Traumatology, Pomeranian Medical University, Szczecin, Poland

Abstract. – OBJECTIVE: This review focus- verse ecosystems on our planet. Suffice it to say es on the role of butyrate as one of the key me- that the Amazon rainforest, synonymous with tabolites of . Butyrate along with species richness, is like an empty steppe in com- other short-chain fatty acids, acetate and propi- parison with our intestinal ecosystem. onate, is one of the most important regulators The huge number of inhabit- of human metabolism. In this review, we dis- cuss how changes in gut microbiota triggered ing the human intestine (more than 100 trillion by type 2 diabetes mellitus and its treatment microorganisms, representing three domains: (e.g., metformin) affect butyrate synthesis, how , Archaea and Eukarya) is compounded to increase butyrate production and whether by the extraordinarily complicated structure of there is robust evidence for the positive effects this superorganism1,2. To raise the general aware- of sodium butyrate in the treatment of diabetes ness of this complex relationship, researchers mellitus. investigating microbiota jokingly proposed that MATERIALS AND METHODS: Literature re- view was conducted by all authors. Studies pub- Homo Sapiens should be renamed Homo Bacte- lished until 27/03/2020 were included. Search riensis. words were: (“butyric acid” OR “butyrate”) AND (“type 2 diabetes “OR ”T2DM”). The articles se- What Is Known About Our Intestinal lected for the study were not chosen in a sys- Superorganism? tematic manner, so the evidence may not be It is recognised that there are six dominant comprehensive. RESULTS: Butyrate was found to effectively microbial phyla - , Bacteroidetes, reduce inflammation and plays a prominent role Actinobacteria, Proteobacteria, in the function of the intestinal barrier. To date and Verrucomicrobia, of which the first two: the use of sodium butyrate in the treatment of Firmicutes and Bacteroidetes make up 90% of patients with T2DM is not very popular. Mean- all gut microorganisms. Firmicutes comprise while, butyric acid can beneficially modulate in- more than 200 different bacterial genera, such testinal functions, counteracting the negative ef- as , Bacillus, , En- fects of the disease as well as the drugs used to treat diabetes. terococcus and Ruminococcus. Bacteroidetes CONCLUSIONS: T2DM is a widespread chron- include predominant genera such as Bacteroi- ic disease. Understanding role of microbiota in des and Prevotella, while the less abundant type 2 diabetes and the mechanisms connecting Actinobacteria are represented mainly by the T2DM and alterations in gut microbiota could be genus Bifidobacterium2,3. the key to improved treatment of T2DM. Microbiota is known to be a very malleable Key Words: “organ” which evolves with us and adapts to the Butyric acid, Microbiota, Type 2 diabetes. host over their lifetime. As a matter of interest, a normally “aged” microbiota (in people at the age of 105-109 years) should be rich in health-associ- What Is Gut Microbiota and Is There A ated bacterial species, i.e., Akkermansia, Bifido- “Gold Standard” Microbiota? bacterium and Christensenellaceae. Surprisingly, The human is regarded as it is also expected to feature decreasing amounts one of the most densely populated and most di- of saccharolytic bacteria (essential for maintain-

4570 Corresponding Author: Ewa Stachowska, MD; e-mail: [email protected] Butiric acids and diabetes ing intestinal health in younger people), that is by the shortage of needed for the Faecalibacterium, Coprococcus and Roseburia4. growth of (SCFA-producing) commensal micro- A healthy microbiota - in a state known as eu- biota. Absence of dietary fibre (in enteral formu- biosis - is made up of a wide variety of species las) leads to the rapid depletion of bacteria synthe- and is characterised by: sising SCFAs (e.g., Clostridium clusters IV/XIVa) a) relative stability over the long term5,6; and reduced levels of butyrate in the gut. This in b) variability correlated with geographical dif- turn results in increased ferences7; and an increased risk of infection by pathogenic c) responsiveness to dietary variations8; bacteria (e.g., C. difficile)17. d) variability induced by direct use of antibi- otics9,10, other medication, illness, injury and Microbiota in Type 2 Diabetes and hormonal changes5. Metabolic Consequences of Diabetes The rich diversity of microbial species was Type 2 diabetes mellitus (T2DM) is accompa- found to be reduced in people with certain condi- nied by adverse quantitative, qualitative and func- tions5, e.g., diabetes. tional alterations in gut microbiota. The condition is referred to as dysbiosis and is known to be im- What Is the Role of Our Intestinal plicated in the development and progression of Superorganism? type 2 diabetes18. It appears that altered gut bac- The microorganisms in our gut perform myr- terial composition may be directly responsible for iad tasks, supporting the function of the whole the low-grade inflammation observed in T2DM18. body. Gut bacteria are key regulators of digestion A study of a group of 18 men with T2DM in the gastrointestinal tract. It is not very well rec- showed that the disease is associated with com- ognised that complete digestion of carbohydrates positional changes in intestinal microbiota19. Dia- is enabled by -fermenting (saccha- betes patients presented significantly lower levels rolytic) intestinal bacteria. They provide more of bacteria representing phylum Firmicutes. What than 80 enzymes necessary for this process (by is more, the proportions of the two main phyla, comparison, there are only 17 human enzymes to Bacteroidetes and Firmicutes, were altered (in fa- break down carbohydrates). vour of Bacteroidetes and Proteobacteria). High- Without them, we would not have access to er abundance of Prevotella, Betaproteobacteria resistant , fibre, as well as animal-derived (from the phylum Proteobacteria) may be cor- glycosaminoglycans (known as microbiota-ac- related with changes in plasma glucose levels19. A cessible carbohydrates, MACs)11. When breaking metagenomic analysis of T2DM patients showed down MACs, the bacteria produce short-chain that their microbiota produces significantly less fatty acids (SCFAs), including butyric acid, a sub- butyric acid (compared to healthy individuals). stance with extraordinary health benefits. This is due to the depletion of precious butyr- Commensal bacteria also play an important ate-producing bacteria, such as spp., role in the synthesis and absorption of replaced by opportunistic microorganisms, such and metabolites. These include bile acids, lipids, as various species of Clostridium clostridioforme, amino acids, (B12, B9, H, B1, B2, PP, Bacteroides caccae, Clostridium hathewayi, and B6, B5 and K) and neurotransmitters others20,21. (e.g. gamma-aminobutyric acid (GABA), sero- In conclusion, the key characteristics of micro- tonin)5,12,13. biota alterations in type 2 diabetes include: Gut microbiota serves a crucial function in a) reduced abundance of butyrate-producing maturation and enhances its bacteria (notably Roseburia intestinalis, Fae- function, e.g. by stimulating the synthesis of bac- calibacterium prausnitzii); teriocins, regulating signalling and affecting mu- b) transition to a moderate dysbiotic state of gut cin production14,15. The latter is also important in microbiota; terms of intestinal barrier integrity16. By preserv- c) development of a proinflammatory environ- ing the integrity of the intestinal epithelial barrier, ment; microbiota also prevents pathogen invasion. In in- d) reduced expression of genes involved in vi- tensive care units, loss of microbial diversity was tamin synthesis; observed already at 72 hours following admis- e) increased intestinal barrier permeability, sion to the unit. Interestingly, impairment of the leading to higher levels of lipopolysaccha- epithelial barrier function seems to be provoked rides (LPS) in circulation22.

4571 E. Stachowska, M. Wiśniewska, A. Dzieżyc, A. Bohatyrewicz

Figure 1. Microbiota and intestinal barrier in healthy individuals and in type 2 diabetes.

Prediabetes and Microbiota Bacteroidetes, while acetate - by the majority of Alterations in gut microbiota are observed anaerobic bacteria26. already in prediabetes. Patients present reduced The following metabolic functions of SCFAs counts of Clostridiales, and more abundant Dor- have been shown27: ea, Sutterella and Streptococcus. Depletion of a) anti-inflammatory effects (mainly acetic and great butyrate producers in the gut (e.g., Clostrid- butyric acid), iales and Akkermansia muciniphila) appears to b) alteration of gut pH, suggest that depletion of this type of bacteria may c) trophic functions for colonocytes and other precede diabetes (in predisposed individuals)23 species of gut bacteria (mainly butyric acid), (Figure 1). d) regulating the immune response, participa- tion in inhibiting allergic and autoimmune Short-Chain Fatty Acids and Their diseases (mainly acetic acid, promoting in- Correlations with Glucose Metabolism testinal IgA secretion), Numerous studies have provided evidence for e) preventing carcinogenesis by inducing apop- the wide-ranging influence of short-chain fatty tosis (especially butyric acid), acids (acetic, butyric, propionic) on human metab- f) epigenetic regulation of gene expression as olism. SCFAs are generated and used primarily in histone deacetylase (HDAC) inhibitors, the gut, where their concentrations reach 50-150 g) modulating adipose tissue function and pre- mM. Consequently, their levels in peripheral cir- venting (via GPR43 receptor); appe- culation are much lower (~100 μM)24. Acetate is tite control (via GPR41 receptor) and glucose the most abundant fatty acid produced by bacteria homeostasis (GPR43 receptor), in the colon, while the others - propionate and bu- h) regulating the gut-brain axis function. In tyrate - are produced in smaller amounts (with a women with depression, blood levels of ace- ratio of 1:1:3 for butyrate, propionate and acetate tic acid are significantly decreased (with a respectively)25. SCFAs are rapidly absorbed by in- similar trend observed for propionic acid). testinal epithelial cells and only 5% are secreted Acetate and butyrate also share structural in faeces24. Butyric acid is produced primarily by similarities with ketone bodies, acetoacetate and phylum Firmicutes, propionic acid by the phylum D-β-hydroxybutyrate respectively. This may be

4572 Butiric acids and diabetes relevant in the treatment of neurological disor- butyric acid creates a favourable environment ders. for gut bacteria, enhancing the intestinal barrier and reducing inflammation in situ36. In an animal Butyric Acid – the Key Player In study, administration of butyrate suppressed sys- “Healthy Microbiota” temic inflammation by reducing the impairment Butyrate is the most “versatile” SCFA - a major of barrier integrity. Enhanced intestinal barrier source of energy for epithelial cells28, involved in function decreased the translocation of lipopoly- the gut-brain axis function. Butyrate presents an- saccharide S (LPS - a cell wall component charac- ticarcinogenic and anti-inflammatory effects29,30 teristic of Gram-negative bacteria) and attenuated and prevention inflammation38. Interestingly, the composition of may represent a tractable model system. Fiber is SCFA-producing gut microbiota in T2DM pa- fermented by colonic bacteria into short-chain tients may be modulated by metformin. fatty acids such as butyrate. One molecular path- way that has emerged involves butyrate having Metformin, Gut Microbiota and Butyrate differential effects depending on its concentration Metformin is the most commonly prescribed and the metabolic state of the cell. Low-moderate medication for type 2 diabetes and a first-line concentrations, which are present near the base of treatment option recommended by many inter- colonic crypts, are readily metabolized in the mi- national guidelines39. Metformin therapy appears tochondria to stimulate cell proliferation via ener- to have a beneficial effect on gut microbiota40. A getics. Higher concentrations, which are present metagenomic meta-analysis revealed that met- near the lumen, exceed the metabolic capacity of formin reduced the counts of some species of in- the colonocyte. Unmetabolized butyrate enters testinal bacteria (Intestinibacter), increasing the the nucleus and functions as a histone deacetylase abundance of others, like Escherichia producing (HDAC and plays a prominent role in the function butyrate and propionate41. Wu et al42 in Nature in of the intestinal barrier31. 2017 suggested that some of the antidiabetic ef- Interestingly, butyric acid is credited as a reg- fects of metformin may be due to the alterations it ulator of energy intake32. Butyrate binds to GPR induces in gut microbiota. Individuals with newly 41/43 receptors (found on gut epithelial cells) and diagnosed diabetes (treatment-naïve) were divid- stimulates the production of appetite-suppressing ed into two groups - the experimental group which hormones - peptide YY (PYYY), glucagon-like was put on metformin (1700 mg/d over 4 months) peptide-1 (GLP-1) and GLP-233. Butyrate also in- and the placebo group. They showed significant hibits the expression of fasting-induced adipose changes in the relative microbial abundance in factor (FIAF), which promotes lipoprotein degra- the metformin group-reduction of more than 80 dation and deposition of free fatty acids in adi- bacterial strains, mostly representing Proteobac- pose tissue34,35. teria and Firmicutes. Subsequently, fecal samples Low-grade inflammation is one of the most im- obtained from donors before and 4 months after portant pathophysiological factors contributing to metformin treatment were transferred to germ- T2DM progression with hyperglycaemia and in- free mice. A significant improvement in glucose sulin resistance. Loss of gut microbiota diversity tolerance in the mice that received metformin-al- observed in diabetes leads to an increase in patho- tered stool samples was noted42. Can this have any genic bacteria, inflammation and progression of implications for therapy? Yes-metformin enriched diabetes36. Butyrate was found to effectively re- the patients’ microbiota, probably by introducing duce inflammation and consequently improve in- additional bacterial genes responsible for efficient sulin sensitivity in the hypothalamus33. metabolism of carbohydrates and amino acids. The total concentration of SCFAs in the intesti- The metabolome analysis of metformin-treated nal lumen ranges from 60 mmol/kg to 150 mmol/ patients showed that metformin significantly in- kg and the proportions of individual acids remain creased the levels of butyrate and propionate in relatively constant. The daily production of SC- men (but not in all of the women)42. FAs in a healthy colon amounts to 300-400 mmol. Unfortunately, metformin is not a perfect drug. Physiological concentrations of butyric acid in the A large percentage of patients cannot tolerate it intestinal content fall in the range of 1-10 mmol/l37. due to adverse gastrointestinal side effects. Typ- Butyrate protects the integrity of the intestinal ical gastrointestinal symptoms resemble those of barrier, stimulating mucus production and forma- irritable bowel syndrome (IBS) and include diar- tion of a healthy mucoprotein layer. In this way, rhea, nausea, , indigestion, vomiting and

4573 E. Stachowska, M. Wiśniewska, A. Dzieżyc, A. Bohatyrewicz abdominal discomfort. One potential solution is Likewise, sitagliptin may also be recognised to start therapy with a low dose and increase it as a drug with a positive effect on gut microbi- gradually, but some patients are unable to toler- ota and the intestinal barrier49. Promising results ate metformin at all39. Could butyrate provide a were also obtained for vildagliptin, with normal- solution for such individuals to alleviate bowel isation of butyrate-producing bacteria, including symptoms? Such an approach to the treatment of Bacteroides and Erysipelotrichaeae, in the gut. diabetic patients is not yet gained traction in the Moreover, the drug reduced the abundance of medical community. Meanwhile, findings from Lachnospira which are negatively correlated with studies carried out mainly among patients with fasting blood glucose levels 50. abdominal pain are very promising. In IBS patients, sodium butyrate supplementa- How To Raise Butyrate Levels tion reduced abdominal problems (bloating, num- in Practice? ber of bowel movements, pain) after just a few There are three possible approaches (Figure 2): weeks of use37. a)use butyrate (a postbiotic) Sodium butyrate therapy produced a measur- b)use , that is live bacterial cultures able reduction in the number of stools in people c)use prebiotics, that is fibre, which will stimulate suffering from travellers’ diarrhea (1.9 stools in growth of butyrate-producing bacteria, the butyrate group vs. 4.2 in the placebo group, The use of prebiotics is not always possible. In p=0.04)43 administration of vaccines and antibiot- patients with dysbiosis, products rich in dietary ic agents.\nAIM: To assess the efficacy of sodium fibre must be eliminated, as they aggravate bloat- butyrate (SB. Similarly encouraging results were ing and digestive distress. obtained in a study of patients with ulcerative In such a case, the best approach may well be to colitis. The latter study demonstrated that sodium administer a postbiotic (sodium butyrate), which is butyrate (at an oral dose of 4 g/day) was safe and well tolerated by patients51there has been a growing well tolerated for improving the efficacy of mesal- interest in (Fermentable Oligo-, Di-, azine in the therapy of ulcerative colitis44. Similar Mono-saccharides, And Polyols (Figure 2). findings were obtained for 5-aminosalicylic acid (5-ASA), where combined treatment with butyr- Probiotics ate was more effective than 5-ASA alone45. The use of probiotics has been shown to hold A study involving a large group of patients promise for the treatment of T2DM. Probiotics (n=166) undergoing prostate cancer radiation improve intestinal barrier integrity, reduce sys- therapy46 showed that sodium butyrate enema at temic inflammation in intestinal lamina propria, 1 g, 2 g or 4 g daily had no protective effects on reduce endoplasmic reticulum stress and increase rectal mucosa. On the other hand, quite contradic- peripheral insulin sensitivity18. In clinical appli- tory results were obtained in another study where cations, the effects of a depend on the the use of butyrate at 80 mmol/L accelerated re- strain (of a given bacterial species). Thus, a for- mission of symptoms and led to a faster recov- mulation comprising 14 strains of Bifidobacteri- ery44. Similar results were obtained in a group of patients with a temporary stoma who were given enemas of 600 mmol/L sodium butyrate-colorec- tal mucosal atrophy was significantly reduced in the butyrate group47.

Acarbose and Other Antidiabetic Drugs Acarbose, a classic alpha-glucosidase inhibitor, inhibits enzymes needed to digest oligosaccha- rides in the gastrointestinal tract. It affects gut microbiota composition. A study with a group of 95 patients treated with acarbose showed an in- crease in and Enterococcus fae- calis in the gut. Acarbose regulates bile acid me- tabolism and has a positive effect on the patients’ microbiome48. Figure 2. Possible supply routes for butyrate.

4574 Butiric acids and diabetes

Table I. Examples of prebiotics and their dietary sources and effect on gut microbiota.

Prebiotic Dietary sources Effect on microbiota

Gum Arabic carob powder, acacia powder, carrageenan, Stimulates growth of Bifidobacteria, Lactobacilli, guar gum, xanthan gum Bacteroides

Fructooligosaccharides Jerusalem artichoke, , leek, cereals Stimulates growth of Bifidobacteria and honey

Galactooligosaccharides lentils, chickpeas/hummus, green peas, Stimulates growth of Bifidobacteria lima bean, common bean

Inulin chicory, onion, leak, , , Stimulates growth of Bifidobacteria , artichoke

Isomalto- isomaltose, other branched Stimulates growth of Bifidobacteria and Lactobacilli. oligosaccharides Inhibits proliferation of pathogenic Clostridium perfringens

Soybean oligosaccharides soybean and peas Stimulates growth of Bifidobacteria. Inhibits proliferation of pathogenic

um, Lactobacillus, Lactococcus, Propionibacteri- Sodium Butyrate um (Symbiter), administered over 8 weeks, reduced The use of sodium butyrate in the treatment the levels of TNF-α, IL-1β, IL-6, and improved of patients with T2DM is still not very popular. HOMA-IR, HbA1c in 52 patients with T2DM- Findings from studies involving patients with di- 52randomized placebo-controlled trials (RCT. Lac- agnosed irritable bowel syndrome suggest that tobacillus reuteri DSM 17938 administered to 46 supplementation with sodium butyrate reduces patients with T2DM over 12 weeks improved in- abdominal problems (bloating, number of bowel sulin sensitivity index (ISI) - though with no ef- movements, pain) after just a few weeks of use37. fect on HbA1c - in individuals whose microbiota was in a relatively good condition (i.e. with high microbial diversity) at baseline53. In another study, Conclusions 60 patients with T2DM were given a multi-strain probiotic containing Lactobacillus (L. acidophilus, T2DM is a widespread chronic disease. Under- L. casei, L. rhamnosus, L. bulgaricus), Bifidobac- standing the mechanisms connecting T2DM and terium (B. breve, B. longum) and Streptococcus alterations in gut microbiota could be the key to thermophilus over a six-week period, showing im- improved treatment of T2DM. The main novelty proved lipid profiles (higher levels of HDL-C) and of this study is that it draws attention to the pos- a decline in fasting glucose54. sible function of butyric acid in the treatment of patients with type 2 diabetes. Prebiotics Dietary fibre is a necessary for healthy gut bacteria. Fibres such as and guar gum produce a rapid increase of beneficial bacteria and Funding Acknowledgments SCFAs. Similar results can be obtained with long- The project is financed from the Program of the Minister of term consumption (ranging from days to weeks) of Science and Higher Education under the name “Regional Initiative of Excellence” in 2019-2022 project number 002 / 20-30 g of . Arabinoxylan oligosac- RID / 2018/19 amount of financing 12 000 000 PLN. charides (AXOS) can provide an excellent nutrient source for bacteria, and their content in bread may be increased by adding xylanase into the dough prior to baking27,54. Examples of prebiotics and Conflict of Interest their dietary sources are given in Table I. The Authors declare that they have no conflict of interests.

4575 E. Stachowska, M. Wiśniewska, A. Dzieżyc, A. Bohatyrewicz

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