Holistic perspective of the role of gut microbes in diabetes mellitus and its management

Kannayiram Alagiakrishnan,Tyler Halverson

Kannayiram Alagiakrishnan,Tyler Halverson,Department of Medicine,University of Alberta,Edmonton T6G 2G3,Alberta,Canada

Abstract The gut microbiota (GM) plays a role in the development and progression of type 1 and type 2 diabetes mellitus (DM) and its complications.Gut dysbiosis contributes to the pathogenesis of DM.The GM has been shown to influence the efficacy of different antidiabetic medications.Intake of gut biotics,like prebiotics,probiotics and synbiotics,can improve the glucose control as well as the metabolic profile associated with DM.There is some preliminary evidence that it might even help with the cardiovascular,ophthalmic,nervous,and renal complications of DM and even contribute to the prevention of DM.More large-scale research studies are needed before wide spread use of gut biotics in clinical practice as an adjuvant therapy to the current management of DM.

Key Words:Probiotics; Prebiotics; Synbiotics; Diabetes mellitus; Microbial dysbiosis;Antidiabetic drugs

INTRODUCTION

Globally diabetes mellitus (DM) is a common medical disorder and is seen in pandemic proportions[1] with the global prevalence in adult subjects is roughly 10%[2].The International Diabetes Federation projected by 2035,there will be 592 million cases of diabetes in the world[3].DM type 1 is secondary to auto-immune-mediated loss of beta-cell function and is seen in 5% of the diabetic population.DM type 2 is mainly due to insulin resistance and is seen in 95% of diabetic subjects[4].The 2016 US National Health Interview Survey data showed roughly 8.58% of the population had type 2 DM and 0.55% had type 1 DM[5].

Various research has been done in the last decade since the study of the human microbiome in 2012[6,7].Microbes contribute to 2% of human body weight and the bacterial genomes exceeds human genes by a factor of 150[8,9].Gut microbiota (GM)varies with age,diet,geographical location,life style,and the use of xenobiotics[10-12].In the recent years there have been more focus on the GM in the development,progression,and distant organ complications due to DM[13].Many studies have shown the role of the gut microbiome in DM[14-17].

The gut microbiome starts to develop with the mode of birth and it is influenced by environmental factors,diet,as well as certain medications,including antibiotics[18].There are differences between the gut microbes seen between non-diabetic and diabetic subjects[20] (Table 1).Gut dysbiosis plays a role in numerous diseases including DM.Both altered GM and endocrine disrupters can influence the development of DM[21].In this literature review,we analyzed the evidence for the role of GM in the development,pathogenesis,complications,management,and prevention of DM.

Table 1 Changes in the microbiome in type 1 and type 2 diabetes mellitus

LITERATURE SEARCH

A literature search was performed using the electronic databases MEDLINE(1966–February 2021),EMBASE and SCOPUS (1965–February 2021),and DARE(1966–February 2021).The main search items were gut bacteria,GM,intestinal flora,gut dysbiosis,type 1 DM,type 2 DM,diabetic retinopathy,diabetic neuropathy,diabetic nephropathy,probiotics,prebiotics,synbiotics,bariatric surgery,and faecal transplantation.Non-English articles were excluded.

GM IN TYPE 1 DM

Studies have shown that Firmicutes/Bacteroides ratio is altered in type 1 DM[22].In the study by Huanget al[23] (2018) negative association was seen with gut microbeFaecalibacteriumandRuminococcaceaand hemoglobin A1c (HbA1c),whereas in the study by Fassatouiet al[24].(2019) a negative association was seen between HbA1c andAkkermansia muciciniphia.A systematic review of studies done in Hispanic populations showed that patients with newly diagnosed type 1 DM have high levels ofBacteroideswith a reduced proportion ofPrevotella,Megamonas,andAcidaminococcus.With the initiation of insulin treatment these subjects showed an increase ofPrevotellalevels.Prior to the development of type 1 DM,inverse relationship of Firmicutes/Bacteroidetes ratio has been reported[25].

GM IN TYPE 2 DM

The type of gut microbes and the changes seen with them influence the development of DM.The prominent GM seen in the intestine are the gram-positive Firmicutes and gram-negative Bacteroidetes and it is influenced by dietary changes[26].A change in the ratio of Bacteroidetes to Firmicutes is associated with DM[27].A case-control study done by Chenet al[28] (2019) in newly diagnosed type 2 DM subjects,Lactobacillusfaecal count was significantly higher whereasClostridium coccoidesandClostridium leptumwas lower,and these changes in the microbes was positively correlated with glycated hemoglobin with higherLactobacilluscount subjects,and negatively correlated with decreasedClostridiumcount subjects when compared with healthy controls.Another study found that patients with DM showed an affiliation with the following phyla of bacteria:Firmicutes,Bacteroidetes,Proteobacteria and Actinobacteria[29].Alterations in the gut microbe population may be related to DM,and gut microbesRuminococcusandFusobacteriumhas been shown with the development of type 2 DM,when compared to healthy adults[30].A study by Sedighiet al[31] (2017) found that patients with type 2 DM has increased levels ofLactobacillus,while healthy controls showed increasedBifidobacterium.With respect to theLactobacillusgenus,there are various mixed results suggesting its association with type 2 DM.Certain strain such asL.acidophilus,L.gasseri,and L.salivariushave been increased where asL.amyloyorushas been decreased[30].However,many species from this genus,such asL.plantarum,L.casei,andL.rhamnosusare often involved in probiotic preparation and have shown to be beneficial in diabetic mice models[30].Overall,it looks that there may be a strain-specific association with DM.

Further changes in the microbiome in patients with DM are listed in Table 1.Nutrient imbalance by affecting the GM can influence the development of type 2 DM.With newly diagnosed type 2 DM different measurement parameters like age,blood lipids,body-mass index,blood pressure,and dietary nutrient intake was related to the gut microbiome composition[32].

RELATIONSHIP BETWEEN GUT AND BLOOD MICROBIOME AND ITS ASSOCIATION WITH TYPE 2 DM

Caniet al[33] (2008) in their animal study showed lipopolysaccharide produced by gram negative intestinal bacteria can translocate into systemic circulation through a leaky gut and can result in endotoxemia causing metabolic dysfunction and obesity.Recent evidence points out in addition to gut microbiome,the blood microbiome plays a role in DM.Blood is usually considered to be sterile,but the research suggests the presence of a microbe or microbial component in healthy humans is known as a blood microbiome.The evidence for blood human microbiome is slowly growing[34-36].

In a study by Satoet al[37] (2014) with Japanese type 2 DM subjects,blood microbiome translocation from gut microbiome was detected at a higher rate (28%) in type 2 diabetic subjects when compared with healthy controls (4%) (P< 0.01).A recent nested case control study by Qiuet al[38] (2019) showed the blood microbeSediminibacteriumis associated with increased risk of type 2 DM [Odd ratio (OR) = 14.098,95%CI:1.358-146.330] where as the microbeBacteroidesin blood have a reduced risk for type 2 DM(OR = 0.367,95%CI:0.151-0.894).

GM AS A COMPLEX ENDOCRINE ORGAN

The regulation of the GI system is done by short-chain fatty acids (SCFA) derived from the metabolism of carbohydrates,and GM plays a role in this function.In addition,the gut microbes produce hormone like chemicals that can act at distant targets.Neuroactive compounds like tryptophan and neurotransmitters like serotonin,dopamine,noradrenaline,GABA,and hormones like leptin,ghrelin and glucagon-like peptide 1 (GLP-1) are indirectly regulated by SCFAsviaenteroendocrine cells.Overall,the gut microbes produce several substances of a hormonal nature into the circulation which act as distant sites.Because of the GM’s ability to influence distant organs and systems as mentioned above it is considered as an endocrine organ.Overall GM functions as an autonomous endocrine organ and plays a role in bodily endocrine actions including neuroendocrine and immunoendocrine regulations[39-42].

DM AND GUT DYSBIOSIS

Gut dysbiosis,is a state of increased or altered prevalence of gut bacteria which might in turn result in many disorders such as gastrointestinal,obesity,DM,immunological,and neurobehavioral diseases[43].Shifts in the GM’s composition with more pathogenic species and phyla can contribute to the above-mentioned diseases.Hyperglycemia was associated with changes of microbiota composition,preferring the non-commensal ones,on the detriment of beneficial phyla such as Bacteroidetes,Proteobacteria,and Actinobacteria.The ratio of Firmicutes/Bacteroidetes has been found to be correlated with plasma glucose concentration.Microbiota are capable to ferment undigested carbohydrates,fiber,and other dietary and xenobiotic compounds to produce SCFAs,which through their ubiquitous receptor play an important role in host glucose metabolism[37,44,45].The Human Microbiome plays a role in gut permeability,modification of bile acids,glucose breakdown and in the absorption of nutrients[46,47].

Normal commensal bacteria are helpful in maintaining the gut wall integrity,innate immunity,insulin sensitivity,metabolism,and in communication with the brain functions,as well as help to prevent the penetration of harmful microorganisms in the bowel.Bidirectional relationship exists between the GM and the brain.This chain of communication depends on the interaction of gut microbe through immune and neuroendocrine system with the central nervous system.Short-chain fatty acids,such as butyrates,acetates and propionates,produced by the GM are beneficial to different metabolic processes.The imbalance between the microbiome and host organism lead to dysbiosis.Gut microbiome dysbiosis through inflammation and metabolic dysregulation increases insulin resistance and influence the development of type 2 DM[48](Figure 1).

Figure 1 The role of gut dysbiosis in diabetes mellitus.

Microbial dysbiosis can also be the result of nutritional imbalance which can lead to a low-grade inflammatory state,obesity,and other metabolic disorders[49].Gut microbes affect gut permeability,glucose and lipid metabolism,energy homeostasis,and insulin sensitivity.Like any other medical conditions,gut microbes play a role in inflammation and immunity[50].A diet rich in fat and sugar may lead to an abundance of lipopolysaccharide (LPS) release from GM and this LPS,by entering into systemic circulation,can affect β-cells,leading to decreased insulin release,and thereby altering systemic insulin sensitivity,resulting in insulin resistance,and potentially leading to DM[51].

Diets rich in carbohydrates and fat as well as xenobiotics (medications affecting the gut microbes) can cause gut dysbiosis.Normally GM produces metabolic products like SCFA,acetate,butyrate and propionate which acts locally leading to beneficial effects on different metabolic process.When there is gut dysbiosis,it can affect the enteroendocrine L-type cells in the intestinal epithelium and increase the gut permeability(leaky gut) causing these metabolic products to enter into the systemic circulation,as well as translocation of the gut microbiome into the circulation leading to the formation of the blood microbiome.This blood microbiome can cause endotoxemia and affect both metabolic dysfunction and insulin resistance.Gut dysbiosis results in excessive production of SCFA and LPS,as well as additional GM metabolites like imidazole propionate (IMP),derived from histidine,and bacteria derived amino acids.Excessive SCFA and LPS by acting on hepatic,adipose,skeletal and pancreatic cells causes metabolic dysfunction,inflammation and altered immune response.When there is a metabolic dysfunction due to gut dysbiosis combined with inflammatory and altered immune response it can cause type 1 DM,and when combined with insulin resistance due to gut dysbiosis as well as the effect of blood microbiome it can lead to the development of type 2 DM (Figure 1).

GUT MICROBES AND METABOLIC NETWORKS

The human gut contains a wide variety of microbial communities that carry out a wide range of biochemical functions that can influence the human body through metabolite production,physiological regulation,and interacting with the host’s cellular response and immunity[52].It has also been found that the host’s own genetics can influence the composition of their gut microbiome,making each host a unique ecosystem[53].Dynamic changes in the gut microbiome have been seen within individuals often in various disease states,such as obesity,and DM[19,54-56].The GM has been found to cause enhanced transcriptional changes in the intestinal cells and protein biosynthesis in the crypts within the intestine[57].

SCFAs produced by GM can serve as signaling molecules that can influence the host’s lipid and glucose levels,liver,skeletal muscle,and even immunity[52].When there is a disruption of the gut microbiome,the altered mixture of SCFA may influence obesity,insulin sensitivity,weight gain and other comorbidities[58,59].Obese individuals with type 2 DM have shown changes in the GM that are distinct,from non-diabetic subjects.It was found that individuals with type 2 DM showed an increase level ofProteobacteriaandBacteroideswith a decreased level ofFirmicutes[19].

The GM has been found to influence the host’s metabolism and show great adaptability to the changing environment within the intestines based on diet,genetics,and various physiological cues from the host[52].The human gut microbiome can modulate absorption as well as nutrient availability within the host.This can be achieved through gene expression changes,alteration of hormones and immunity[52].

ASSOCIATION BETWEEN MICROBIOME,OBESITY AND DM

Microbial diversity and the production of SCFA as well as products such as butyrate,propionate,and acetate have been found to have a protective role against obesity and insulin resistance[60,61].SCFAs are able to act as signaling molecule that can activate a variety of pathways that are involved in cholesterol,lipid,and glucose metabolism[58].Modifications of the microbiome can influence metabolic parameters,in particular when there is a higher abundance of Firmicutes leading to a higher Firmicutes/Bacteroidetes ratio that may be linked to obesity[62].This may in part be due to the fact that Firmicutes are more efficient at promoting the nutrient absorption leading to subsequent weight gain compared to Bacteroidetes[63].

A study showed the GM composition is different in obese subjects with and without type 2 DM[20].A recent study also showed for the first time in subjects with type 2 DM the relationship between body composition and GM[64].Faecal microbiota of obese subjects without DM had increased numbers of SCFA producing microbes,whereas obese subjects with type 2 DM had less beneficial SCFA butyrate producing microbes[65].

ROLE OF GUT MICROBES IN THE PROGRESSION OF DM

The progression of DM is seen as macrovascular[66] and microvascular complications like retinopathy,nephropathy,and neuropathy[67].Gut microbes seem to play a role in the progression of DM and also shown to play a role in these complications.Diet induced diabetic animal models helps to study these complications[68].Studies have shown that subjects with DM and eye complications have higher bacterial conjunctival flora when compared to subjects without DM[69-72].Beliet al[73] (2018) in their animal study showed the association between the GM and diabetic retinopathy(Table 2).More research is needed to understand the mechanism how GM causes diabetic retinopathy[74].

Table 2 Selected animal studies showing the effect of various interventions on the gut microbiome and the role of gut microbiota in diabetes mellitus management

Diabetic neuropathy is seen as autonomic neuropathy as well as distal sensory and motor neuropathy and correlate with diabetic control,and GM also seems to play a role[75].In a human study with early diabetic nephropathy,Barrioset al[76] (2015)showed an increase in colonic GM,whereas with end-stage renal disease patients microbes producing urease,uricase,p-cresol and indole-forming enzymes were seen[77].The proposed mechanisms for progression of kidney disease could be due to GM imbalance,metabolic shifts,immunosuppression,inflammation,as well as accumulation of uremic toxins[78].

MANAGEMENT

In DM,normal GM can be restored using diet,gut biotics,faecal transplantation,and bariatric surgery,which may help with the proper management of DM.

Faecal transplant,bariatric surgery

There is some evidence from human studies,that both faecal transplant and bariatric surgery improved the glucose and metabolic parameters by altering the GM[48].A meta-analysis done by Magouliotiset al[79] (2017) showed some discrepancy between the human studies and the benefits witnessed from bariatric surgery.Another study looking at obese insulin resistant subjects who received allogenic faecal transplants from a lean insulin sensitive donor show improved insulin sensitivity for a short period of 6 weeks,however the benefit was not seen past 12 weeks[80] (Table 3).

Table 3 Selected human studies showing the effect of diet,gut biotics,faecal transplantation and bariatric surgery on gut microbiome and the role of gut microbiota in diabetes mellitus management

Nutritional therapy

Diet can modulate the GM and play a role in the management of DM by preventing gut dysbiosis[81] (Table 2).Fruits and vegetables contain polyphenols which can increase beneficial GM likeA.muciniphila,LactobacilliandBifidobacteria[82].Unbalanced dietary intake can affect the structure and abundance of GM which can play a role in the development of DM[83].

Artificial sweeteners

Artificial sweeteners are no-calorie sugar substitutes,may induce glucose intolerance by affecting the gut microbes.In an animal study with saccharin-fed mice showed an increase in Bacteroides and a reduction inLactobacillus reuterileading to GM dysbiosis and glucose intolerance[84].Similar effects were seen in another study by Chiet al[85](2018) using the artificial sweetener,Neotame.In a cross-sectional human study by Frankenfeldet al[86] (2015),showed sweeteners like aspartame or acesulfame-K found no effect on gut bacterial abundance.A recent randomized-blinded crossover study in healthy participants did not demonstrate measurable changes in the GM or in SCFAs after 14 d daily intake of aspartame and sucralose[87].These preliminary observationsneeded to be established in future human research studies.

ALTERATION OF GM BY ANTIDIABETIC DRUGS AND ITS ROLE IN DM MANAGEMENT

Antidiabetic drugs can influence the gut microbiome by affecting the drug microbiome interface,whereas the gut microbiome also influences the metabolism and play a role in the efficacy of antidiabetic drugs.The interactions of antidiabetic drugs and microbiota is getting more attention as it may play a role in the management of DM[88].Antidiabetic agents cause alteration of the specific gut microbes.Metformin increases the population ofAkkermansia muciniphilaby 18-fold,enhancing the digestion of mucin and increasing SCFA[89].Metformin,in addition toAkkermasia,causes increase inLactobacillusandBifidobacterium,whereas insulin increaseFusobacterium[90].This first line antidiabetic agent in type 2 DM modifies the GM,alter the bile acid circulation and thereby a possibility that primary site of action may be gut and the GM[91].

Understanding the pharmacokinetics,pharmacodynamics and pharmacomicrobiomics of antidiabetic medications and gut microbes can help to understand druggut microbiome and its potential benefit with antidiabetic drugs.Overall,it may help to better manage the DM management[92].

Antidiabetic drugs have been shown to affect the different gut microbes and their metabolic effects through the medication-microbiome-metabolism axis.GM can influence the pharmacokinetics of various antidiabetic drugs such as drug absorption,drug metabolism which can affect the potency of these medications.Overall,there is a bidirectional relationship exist between antidiabetic drugs and gut microbes[88].

Different combinations of antidiabetic drugs are used to better control DM.The commonly used combination is metformin with sulphonylureas,thiazolidinediones,DPP-4 inhibitors and insulin.One animal study showed some delay in the progression of DM when sitagliptin/metformin combination given with a prebiotic fibre[93].Currently,there is a need for more research of different combination therapies on GM.

GUT BIOTICS AND DM

Animal studies

Several animal studies have showed that gut biotics,like prebiotics and probiotics,can improve the efficacy of antidiabetic drugs.Treatment with individual or a cocktail of antibiotics reduced dysbiosis and decrease fasting glucose but did not affect body weight,as well as antibiotic treatment also changed gene expression in the ileum and liver,and shifted the alpha (α) and beta (β) diversities of GM[94].In an animal study with mice,combining probiotics and/or prebiotics with antidiabetic medications showed an improvement in glycemic control and insulin sensitivity[95].A study by Reimeret al[93] (2014) found that using a combination of sitagliptin and metformin with a functional fiber can delay DM progression.In an animal study usage of mannan-oligosaccharides by altering the GM increased the hypoglycemic effects of metformin[96].Yanget al[97] (2020) found that Genistein found in soybeans and soy derived foods (prebiotic) helped to improve glucose and lipid metabolism by altering GM composition[97].In another animal study,certain GM likeBacteroides fragilis,A.muciniphila,L.plantarum,L.caseican induce interleukin 10 (IL-10),which has been shown to improve both insulin resistance and glucose metabolism[98] (Table 2).

Human studies

Many gut microbes have been shown to have antidiabetic effect in humans by different mechanisms including effect on insulin sensitivity[99].Roseburia intestinaliscan improve insulin sensitivity by increasing IL-22 production[100].Some strains ofLactobacilliact like acarbose and have been shown to inhibit alpha glucosidase[101].Prebiotics can feed the gut microbiome and increase the population of L-cells in the intestine and thereby increase the amount of GLP-1[102] and prevent high fat diet induced insulin resistance[103].In the recent PREMOTE randomized control trial(RTC) study,probiotics showed antidiabetic effect by altering metabolic homeostasis[104].Thus,GM may be useful in the management of DM[105].Jafarnejadet al[106](2015) and Asemiet al[107] (2014),in their two studies showed multi-probiotic supplement as well as synbiotic(L.sporogenesplus inulin) product helps to reduce glucose and other metabolic parameters.Tonucciet al[108] (2015) in their double-blind RCT study comparing fermented milk containingL.acidophilus (LA-5)plusB.animalis(Lactis BB-12)with plain fermented milk in 45 type 2 DM subjects showed decreased in HbA1c as well as low-density lipoproteins cholesterol and inflammatory cytokines.Multiple RTCs and the meta-analysis of these RCT’s with different gut microbes demonstrated antidiabetic effect as well as effect on different metabolic parameters[109-111] (Table 3).

A recent meta-analysis of 14 RCTs showed significant decrease in HbA1c in the probiotic group compared to placebo controls,weighted mean difference (WMD) is-0.33%,95%CI-0.53 to –0.13,P= 0.001.In this meta-analysis,probiotics significantly reduced fasting blood glucose,insulin,lipid profile and inflammatory marker in addition to blood pressure levels[112].Another meta-analysis showed similar result with reduction in HbA1c% (WMD =-0.24,95%CI:-0.44 to-0.04,P= 0.02),fasting blood glucose (WMD =-0.44 mmol/L,95%CI:-0.74 to-0.15,P= 0.003)[113,114].A meta-analysis study done in 2021 with probiotics,prebiotics or synbiotics on type 2 DM also showed significant improvement in glucose and other metabolic parameters[115].Prebiotic inulin improves glycemic control in young adults with type 1 DM[116].Certain specific species of probiotic microbes as well as certain prebiotics by altering the GM was shown to improve the auto-immune condition,which plays a major role in the pathogenesis of type 1 DM[117].

A study by Didariet al[118] (2014) looked at the safety of probiotics and synbiotics and found that certain populations,such as patients who are immunocompromised,with cardiac valvular disease,having a central venous catheter,or those with shortbowel syndrome may have an increased risk for systemic infections.Thus,caution may be warranted when using these products in diabetic patients and a risk-benefit analysis should be considered.

GUT MICROBES AND THE PREVENTION OF DM

Some preliminary evidence in animal studies indicates altering GM may help to prevent DM[119,120].A recent study by Gurunget al[30] (2020) showed with certain gut microbes likeBifidobacterium,Bacteroides,Faecalibacterium,AkkermansiaandRoseburiahave a negative association with DM and appears to be protective.In 42 healthy adults,GMLactobacillus johnsoniiseems to reduce the risk of type 1 DM[121].

CONCLUSION

Gut dysbiosis plays a role in the development and progression of DM.The current evidence also points out that the GM can play a role in DM related complications.Modulation of the gut bacteria or dysbiosis can be corrected by fibre,diet,antidiabetic medications,and by using gut biotics like prebiotics,probiotics,and synbiotics as well as by bariatric surgery and faecal transplantation.The interaction between gut microbes and antidiabetic agents is a promising field that may change the landscape of DM management in the future.There is some preliminary evidence to show that GM may play a role in the prevention of DM.More research is needed on a large scale to confirm these findings.