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Microbial Ecosystem in Diabetes Mellitus: Consideration of the Gastrointestinal System

Authors Yehualashet AS, Yikna BB

Received 9 February 2021

Accepted for publication 31 March 2021

Published 28 April 2021 Volume 2021:14 Pages 1841—1854

DOI https://doi.org/10.2147/DMSO.S304497

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Antonio Brunetti

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Awgichew Shewasinad Yehualashet, Berhan Begashaw Yikna

Pharmacology and Toxicology Unit, Department of Pharmacy, College of Health Sciences, Debre Berhan University, Debre Berhan, Ethiopia

Correspondence: Awgichew Shewasinad Yehualashet
Pharmacology and Toxicology Unit, Department of Pharmacy, College of Health Sciences, Debre Berhan University, PO Box 445, Debre Berhan, Ethiopia
Tel +251 935450290
Email [email protected]

Abstract: Intestinal microbiota is established to be a crucial element in the control of human health, and keeping the symbiotic relationship between the human body and intestinal microbes will have paramount importance. A number of investigations illustrated that many chronic diseases are associated with intestinal micro-ecological disorders implying intestinal floras as an important component among the environmental factors, and perturbations in their composition are correlated with metabolic disorders, including obesity and diabetes mellitus (DM). Increased evidence suggests that alterations in the gut microbial ecosystem have been involved in part in the pathogenesis of both type 1 and type 2 DM. Short chain fatty acids (SCFAs), derived from microbiota, have been studied for their potential action in modulating CNS, gut barrier axis, and the immune system as a promising mechanism for the observed protective effects on diabetes pathogenesis. Besides, the role of bile acid (BA) stimulated receptors to have a significant role in liver metabolism, and pathophysiology of liver-based metabolic diseases has also been investigated. In the current review, we will try to summarize the correlation between intestinal microbiota and diabetes considering the existing current evidence revealing the role of gut microbiota in onset and disease progression.

Keywords: gut microbiota, intestinal flora, microbial ecosystem, diabetes mellitus

Introduction

Diabetes mellitus (DM) is a chronic hyperglycemic condition as a result of pancreatic β cell dysfunction or insulin resistance, known to cause macrovascular and microvascular complications.1,2 The cause of defect in carbohydrate, fat, and protein metabolism in DM is the compromised action of insulin on its targets.3,4

Genetic predisposition and environmental factors are among the crucial elements in the pathogenesis of DM. Out of the environmental factors accounting for the disease; gut microbiota has been regarded as a potential contributory factor associated with the disease. Gastrointestinal microbiome is established to be a key element in controlling human health, and maintenance of the symbiotic relationship between the human body and gut microbes will have paramount importance. Numerous investigations have revealed that many chronic diseases are related to intestinal microecological disorders implying intestinal flora as an important component among the environmental factors, and its modifications could lead to some sort of metabolic problems like diabetes and obesity.5,6

Gut Microbiota and Diabetes

Homeostasis can be maintained as a result of a mutual interaction between the human host and gut microbes, therefore, any dysregulation to the normal composition of commensal communities, the so-called ‘dysbiosis’ could weaken the homeostasis and contribute in the emergence of many autoimmune disorders. With the help of high-throughput sequencing technologies, aggregate evidence has illustrated that there are visible variations in the profile of intestinal microbial between type 1 diabetic patient and the controls, implying a close interaction between gut microbiota and diabetes. Consequently, a number of studies have suggested that changes in gut microbiota composition have got a place in the pathogenesis of the disease. However, whether these microbial changes are causal, responsive, or both are becoming an active area of investigations requiring scrutiny in the scientific community. In this review, we will discuss the association between intestinal microbiota and diabetes considering the existing animal and human evidence revealing the influence of the gut microbial ecosystem in onset and disease progression.5–7

The microbiota is regarded as microbial ecosystems living together in a symbiotic interaction with their host, sheltered on skin, respiratory, and urogenital systems and the intestinal tract. Among the variety of microorganisms found in the gut, bacteria are relatively best studied.7,8 There are around a hundred trillion cells of microbes in the human gut, which is 10-times higher compared to the number of human cells. The majority of microbiota of the gut are categorized into the following phyla: Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. The intestinal microbiota so-called “hidden organ“ is involved invarious physiological functions such as fighting against pathogens, energy production, intestinal epithelial integrity maintenance, and immune regulation.9

Functionally, the vital role of the gut is enhancing digestion of food, absorption of nutrients, helps in the removal of waste products, and protecting against invasion by pathogenic bacteria. The protective mechanism is by acting as an impermeable barrier on intestinal epithelial cells along with other cells.7,10 In addition, the gut gives protection against pathogen overgrowth, impeding their aggregation by inhibiting adherence, bacteriocin generation and nutrient competition. It participates in the metabolism of drugs, detoxification of exogenous toxins, synthesis of essential vitamins like B1, B2, B5, B6, B12, K, folic acid, and deconjugation of bile acids (BA). Moreover, the ability to ferment indigestible carbohydrates helps them to provide 5–10% of daily energy need. Besides, in the intact colon, it aids intestinal repair through enhancing cellular proliferation and differentiation which have a substantial role in the maintenance of gut integrity.7,10

Their role in maturation and continued education of the host’s immunity has been pointed out with recent investigations. As a result of continued education, the immune system learned to identify the commensal from pathogenic bacteria where commensal bacteria can trigger an anti-inflammatory response, while pathogenic bacteria provoke a pro-inflammatory condition. Hence, gut microbiota regulates migration and function of neutrophils and affects T-cell differentiation, favoring differentiation and expansion of regulatory T-cells (Tregs), which are crucial components in mediating immune tolerance. The ability of controlling the immune system is via generation of short-chain fatty acids (SCFAs), like butyrate, acetate, and propionate that are produced by bacterial fermentation of non-digestible carbohydrates. In T lymphocytes, SCFAs are employed in stimulating G protein-coupled receptors (GPR41/GPR43) signaling cascades, inhibiting histone deacetylases, and eliciting metabolic changes via promoting the action of a mammalian target of rapamycin (mTOR) complex. Consequently, inflammatory cascades will be inhibited; triggering the expansion of mucosal Tregs, and generation of inflammatory cytokines like interleukin-10 (IL-10) and interferon- (IFN-) will be reduced. Provided that they have a key role in regulating health of the host, it is not amazing that dysbiosis could be implicated in the pathogenesis of various extra intestinal diseases including diabetes.7

Changes of Intestinal Flora in Diabetic Populations

Family history and environmental factors are key elements in the pathogenesis of diabetes. Among environmental factors, gut microbiota has been regarded as a potential contributory factor associated with type 1 diabetes.11,12 Studies showed that the microbiota has a linkage with weight gain and adiposity through many other related processes including energy harvest and formation of microbial metabolites, although their effect on inflammatory reactions and the gut–brain axis. One major metabolic function of gut microbiota is generating non-gaseous and absorbable SCFAs which are vital in modulating gut health and the immune system, promoting intestinal hormone production and lipogenesis.12

The anti-inflammatory effects of SCFAs is as a result of produced immunoglobulin A and immunosuppressive cytokines. Therefore, loss of early-life exposure because of continued use of antibiotics and a reduced fiber intake could end up with dysbiosis, which in turn allows the incidences of inflammatory problems, including diabetes. Several investigations have reported that the number of bacteria employed in generation of SCFA was significantly lowered in people with type 2 diabetes. SCFAs bind to GPCRs and result in enhancing the release of glucagon-like peptide-1 (GLP-1); which has an incretin effect and hinders glucagon release, prevents gluconeogenesis in the liver, ameliorates insulin sensitivity, and builds up central satiety, thereby resulting in bodyweight loss. Moreover, SCFAs can directly hamper the low-grade inflammatory response produced because of the migration of bacteria from the intestines into the mesenteric adipose tissue and the blood.13

Dietary fats promote absorption and removal from lipopolysaccharides (LPS) through intestinal/epithelial cells by inducing chylomicrons. LPS has an affinity for chylomicrons and is co-transported along with other dietary fats. Insulin insensitivity is associated with obesity and low-grade inflammation which is distinguished in part to alterations in gut microbiota.14 Different animal and human studies were conducted to evaluate whether changes are causal or merely a consequence of obesity or metabolic syndrome. To date, different animal and human investigations have been undertaken to evaluate the role of gut microbiota in the pathogenesis of both types of DM. In the table below, we have been tried to summarize the existing evidence showing the causal relationship between the disease and the gut microbiota.

Evidence on the Role of Gut Microbiota in the Pathogenesis of Type 1 and Type 2 DM

Current Evidence on the Role of Gut Microbiota in the Pathogenesis of Type 1 DM

Until recently, the correlation between gut microbiota and pathogenesis of type 1 DM has been investigated in animal models, the condition may better be elaborated with various cohort studies to recognize the alteration of intestinal microbiota abundance prior to occurrence of the disease.

Prospective studies can give information regarding progression of the disease in time, whereas etiological association could be obtained from interventional studies. Investigations in huge lines of children will be crucial to prove the involvement of microbiome disturbance prior to the development of type 1 DM.7,9 The aggregate evidence summarizing preclinical and clinical trials conducted to explore the correlation of microbiota and type 1DM have been presented in Table 1 .

Table 1 Evidence from Animal and Human Studies Revealing the Causal Relation between Gut Microbiota and Type 1 Diabetes

Current Evidence on the Role of Gut Microbiota in the Pathogenesis of Type 2 DM

Alterations in the composition of intestinal microbiota is correlated with metabolic disease including type 2 DM. Different studies in animals showed various mechanisms contributing to the pathogenesis of the disease.12 Basically (as presented in Table 2), many of the investigations revealing the role of microbiota in glucose homeostasis are derived from studies in mice. But a change in the composition of microbiota has also been illustrated in a series of human cohort type 2 DM.

Table 2 Evidences from Animal and Human Studies Revealing the Causal Relation between Gut Microbiota and Type 2 Diabetes

Possible Mechanisms of Gut Microbiota in Diabetes Pathogenesis

Mechanisms Involving SCFAs

According to a hypothesis by Trowell, dietary changes are blamed for diabetes, and increased use of processed carbohydrates with a low level of dietary fiber (DF) has been regarded as one potential risk factor for diabetes. Major DFs include soluble fibers, like pectin, inulin, arabinoxylan, and hemicellulose, and insoluble fibers such as cellulose. The soluble fibers can be fermented by microbiota to produce SCFAs acetate, propionate, and butyrate. The generation of SCFAs in distal gut is via bacterial fermentation of macrofibrous material that might get out of digestion by upper gastrointestinal tract and reach the colon (Figure 1). Current findings showed the role of SCFAs in modulating CNS, gut barrier axis, and the immune system which are assumed to be promising mechanisms for the observed protective effects of DF on diabetes pathogenesis. Recent findings indicated that microbiota is modulated by SCFAs for their protective activity on type 1 diabetes pathogenesis.15,16 Moreover, evidence suggested that protective potentials of SCFAs on β-cells and endogenous FFA2 expression probably accounted for this effect. Based on prior reports, it was concluded that sodium acetate and propionate reduced islet cell death elicited by cytokine or palmitate; FFA2 deficiency induced β-cell death and decreased β-cell mass, whereas SCFAs protected islet β-cells.17

Figure 1 Acetate and effects in metabolic health. The solid lines show well studied effects of acetate, while broken lines imply more inconsistent findings. Reproduced from Hernández MAG, Canfora EE, Jocken JWE, Blaak EE. The Short Chain Fatty Acid Acetate in Body Weight Control and Insulin Sensitivity. Nutrients. 2019;11(1943).18 Copyright © 2019 by the authors. Licensee MDPI, Basel, Switzerland. Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). 

Low grade inflammation and high level of cytokines like IL-6, IL-1, or TNF-α are characteristic features of Type 2 diabetes. These inflammatory markers are expressed in insulin target tissues, such as liver, adipose tissue, and muscles, hence leading to insulin insensitivity. It was investigated that changes in the gut microbial ecosystem provokes a pro-inflammatory condition in the adipose tissue that is related to obesity and resultant insulin resistance. The diversity of the gut microbiota, and its subsequent metabolic products is highly modified by diet changes; proper use of dietary fibers is usually correlated with a level of SCFA that could promote an anti-inflammatory effect, while a higher fat consumption was linked to reduced profile of SCFAs and raised LPS, implying aggregation of G−ve bacteria. LPS was found to elicit the generation of pro-inflammatory molecules that are taking part in enhancing permeability and inflammation in the gut epithelium, the so-called “metabolic endotoxemia“.16

Regulation of BGLs, insulin insensitivity, and GLP-1 release in improving metabolic function is as a result of expressed SCFA receptors in various tissues, hence are able to induce a protective effect provoked by them. The blood glucose lowering potential of SCFAs might be because of their beneficial effects such as: reduced inflammatory condition, hence decreases insulin insensitivity enhance decreased inflammatory state that reduces insulin resistance, simultaneously enhances the release of GLP-1 that promotes insulin release, and ameliorate β-cell function, thereby helping to maintain glucose homeostasis. Different preclinical and clinical trials showed that the acetate has a role in host energy and substrate metabolism through its positive effect on the release of GLP-1 and peptide YY, therefore affecting appetite by reducing lipolysis, pro-inflammatory mediators, and increasing utilization of energy and fat oxidation.16,18

Mechanisms Involving Bile Acids

BAs are metabolites of cholesterol catabolism in the liver and their synthesis accounts for about half of the daily cholesterol output, whereas 40% of the output is because of biliary secretion, and the remaining 10% is employed for membrane and steroid hormone synthesis. As a result, BA metabolism has a central role in regulating cholesterol homeostasis. Extensive research regarding BAs has created a ground for viewing them as signaling molecules that activate several nuclear receptors: farnesoid X receptor (FXR), vitamin D receptor (VDR), pregnane X receptor (PXR); and the membrane GPCRs: Takeda GPCR 5 (TGR5), sphingosine-1 phosphate receptor 2 (S1PR2), and muscarinic M2 receptor. These BA stimulated receptors have a significant role in liver metabolism, and the roles of FXR and TGR5 in regulating metabolism and pathophysiology of liver based metabolic diseases has been investigated.19,20 The human BA pool is determined by the enterohepatic cycle and microbial metabolism in the gut (Figure 2). BAs can undergo decongugations induced by a broad spectrum of gut bacteria. Therefore, regarding the level of BAs excreted in feces, the majority contain secondary BAs, and highly rely on gut microbiota metabolism.21

Figure 2 BA signaling controls the systemic glycemic response. Reproduced from Shapiro H, Kolodziejczyk AA, Halstuch D, Elinav E. Bile acids in glucose metabolism in health and disease. J ExpMed. 2018;215(2):383–396.20 Copyright © 2018 Shapiro et al. Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described athttps://creativecommons.org/licenses/by-nc-sa/4.0/). 

Recent data suggests that dysregulation in luminal enteral communication because of BA sequestrants could reveal the attractive effects of these drugs. Various gastrointestinal cells and hormones work together to contribute in neuroendocrine regulation of digestion and metabolic function. Detecting a way to augment endogenous GLP1 secretion, without increasing overall energy intake and deposition, is an attractive concept in the future treatment of type 2 diabetes – simultaneously improving our understanding of endocrine gut physiology.22 To date, the use of BA chelates are the only treatment modalities for diabetes involving BA, however, it was revealed that part of the advantages of bariatric surgery on controlling glucose level in diabetic patients is something associated with BA metabolism.23

In the brain, BA-TGR5 cascading regulates satiety. In skeletal muscles and brown adipose tissue, BA-TGR5 sensing enhances the conversion of T4 to T3, provoking a rise in energy expenditure. In the pancreas, both BA-TGR5 and BA-FXR signaling in β-cells stimulates insulin production. Glucose-induced insulin release is also enhanced by BA-TGR5 signaling in α-cells, that promotes proglucagon to be changed to GLP-1 and GLP-1 release. TGR5-BA in immune cells inhibits NLRP3-inflammasome and reduced inflammation.

Conclusion

The current review of aggregate evidence from animal and human investigations has shown that dysbiosis in gut microbial ecosystem and reduction of their diversity was associated with the onset and progression of both types of diabetes. The possible mechanisms include the generation of SCFAs in distal gut is via bacterial fermentation of macrofibrous material that might get out of digestion by upper gastrointestinal tract participates in modulating CNS, gut barrier axis, and immune system which are assumed to be promising mechanisms for the observed protective effects of SCFAs on diabetes pathogenesis. Furthermore, extensive research regarding BAs has created a ground for viewing them as signaling molecules that activate several nuclear receptors in regulating metabolism and pathophysiology of liver based metabolic diseases. Considering these findings, the research community should give emphasis on studies illustrating the significance of maintaining healthy microbial composition because related findings could be useful for developing strategies to control diabetes by modifying the gut microbiota. In fact, bringing these understandings into reasonable therapeutic measures is challenging. Therefore, in the future, ongoing randomized controlled trials in huge human cohorts are needed to uncover unresolved questions and prove the efficacy of microbiota-based therapeutic approaches.

Author Contributions

Both authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest for this work.

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