**The Effect of Prebiotics and Oral Anti-Diabetic Agents on Gut Microbiome in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis of Randomised Controlled Trials**

**Omorogieva Ojo 1,\*, Xiaohua Wang 2, Osarhumwese Osaretin Ojo 3, Joanne Brooke 4, Yiqing Jiang 2, Qingqing Dong <sup>2</sup> and Trevor Thompson <sup>5</sup>**


**Abstract:** Background: Nutritional interventions such as the use of prebiotics can promote eubiosis of gut microbiome and maintain glucose homeostasis in patients with type 2 diabetes (T2D). However, it would appear that results of the effects of prebiotics on the community of microbes in the gut are not consistent. Aim: To examine the effect of prebiotics and oral antidiabetic agents on gut microbiome in patients with T2D. Methods: The PRISMA Extension Statement for Systematic Reviews and Network Meta-analyses was used to conduct this review. Searches were carried out in EMBASE, EBSCO-host databases, Google Scholar and the reference lists of articles for studies that are relevant to the research question, from database inception to 15 August 2022. The search strategy was based on PICOS framework. Network Meta-analysis which allows the estimation of relative treatment effects by combing both direct trial evidence (e.g., treatment A vs. treatment B) and indirect evidence was conducted. Furthermore, pairwise meta-analysis was also carried out to estimate effect sizes based on head-to-head comparisons of treatments and/or control conditions. Results: Findings of the Network meta-analysis revealed that prebiotics significantly reduced HbA1c compared with control and the SMD was −0.43 [95% CI, −0.77, −0.08; *p* = 0.02], whereas there was no significant difference (*p* > 0.05) between the other treatments and control. In addition, anti-diabetic agents including glipizide and metformin also reduced HbA1C, although these were not significantly different (*p* > 0.05) from control. While prebiotics promoted *Bifidobacterium* and *Akkermansia*, the improvements were not significantly different (*p* > 0.05) from control. On the other hand, metformin decreased the relative abundance of *Bifidobacterium*, but increased *Lactobacillus* and *Akkermansia*, although the differences were not significant (*p* > 0.05) compared with control. With respect to fasting blood glucose and BMI, the effects of prebiotics and oral antidiabetic agents did not differ significantly (*p* > 0.05) from controls. Conclusions: The findings of the systematic review and Network metaanalysis demonstrated prebiotics were significantly (*p* < 0.05) more effective in reducing HbA1c than control in patients with T2D. However, the effects of prebiotics and oral antidiabetic agents did not differ significantly (*p* > 0.05) from the controls in relation to fasting blood glucose, post-prandial blood glucose, body mass index and the genera of gut bacteria examined. More studies are required to fully investigate the effects of prebiotics and oral antidiabetic agents in patients with T2D

**Keywords:** prebiotics; oral anti-diabetic agents; gut microbiome; glycated haemoglobin; type 2 diabetes; Network meta-analysis; meta-analysis

**Citation:** Ojo, O.; Wang, X.; Ojo, O.O.; Brooke, J.; Jiang, Y.; Dong, Q.; Thompson, T. The Effect of Prebiotics and Oral Anti-Diabetic Agents on Gut Microbiome in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis of Randomised Controlled Trials. *Nutrients* **2022**, *13*, 5139. https://doi.org/10.3390/nu14235139

Academic Editor: Connie Weaver

Received: 3 November 2022 Accepted: 29 November 2022 Published: 2 December 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **1. Introduction**

The prevalence of type 2 diabetes (T2D) is increasing globally. It is estimated that by 2040, approximately 642 million people will have the condition worldwide [1]. Genetic predisposition and lifestyle factors such as lack of physical activities and poor nutritional intake which can lead to overweight and obesity are reported to be involved in the etiology of T2D [2]. Furthermore, diets with low fibre and high saturated fats and sugar, such as Western diets, may also influence gut microbial diversity and cause reduction in specific bacteria taxa and imbalance in gut microbiome [3,4].

There is evidence from meta-analysis of randomised controlled trials (RCTs) that T2D is associated with disequilibrium of gut microbial community and gut microbiota dysbiosis is implicated in the pathogenesis of type 2 diabetes [5]. Therefore, nutritional interventions including prebiotics have been used to promote eubiosis of gut microbiome and maintain glucose homeostasis in patients with T2D [6,7]. In addition, the role of oral anti-diabetic agents in modulating dysbiosis of gut microbiome may be a possible pathway by which these drugs regulate glucose balance [8,9].

#### *1.1. Description of the Intervention*

The concept of prebiotics relates to the food component that is not digestible. Dietary prebiotics must be resistant to gastric acid and should not be hydrolised by the effect of mammalian enzyme, and should be resistant to intestinal absorption. It should also be beneficial to the hosts through selective promotion of the growth of bacteria in the colon, not causing negative effects to the hosts including not stimulating the growth of pathogenic microorganisms [10]. Prebiotics have also been recently defined as substrates (non-viable) which are used selectively by the host microorganisms which leads to benefits [10].

The definition of prebiotics has been revised to include ingredients that are selectively fermented and allows changes that are specific to the community and actions of microbes inhabiting the gastrointestinal tract which confers effect on the host which are beneficial physiologically [11]. Prebiotics are different from most dietary fibres including pectins, cellulose and xylans which promote the development of a broad variety of gut microbes [12].

Although prebiotics are not the only substrates that can affect the gut microbial community, a primary criterion that distinguishes prebiotics from other substrates is their selective utilisation by host microorganisms [12]. While a selective effect does not mean utilisation by just one microbial group, it may include several microbial groups, but not all the microbial groups [12].

Metformin is one of the oral anti-diabetic agents and it is a biguanide [13]. It is a first line medication for treating T2D and is effective in lowering body weight and cardiovascular risks [13]. Other oral anti-diabetic agents that are associated with modulation of gut microbiota include sulfonylurea and acarbose [9,14].

#### *1.2. How This Intervention Might Work*

Dysbiosis of intestinal microflora has been shown to have significant effect in the pathogenesis of metabolic disorders such as T2D [15]. Therefore, sustaining an ecosystem that is healthy and having good lifestyle and feeding habits are useful approaches in managing T2D [15]. The consumption of prebiotics may regulate gut microbiota dysbiosis and enable the growth of beneficial microbes [11]. There is evidence to suggest that prebiotic dietary fibre is a selective substrate that is utilised by bacteria which are beneficial to the host including *Bifidobacterium* and *Lactobacillus* that promote the health of the host [10]. For example, prebiotics may promote the growth of bacteria that are beneficial including *Lactobacillus*, *Bifidobacterium*, *Akkermansia*, *Eubacterium* and *Roseburia* [10].

Prebiotics are usually metabolised by the gut microbes through a process of fermentation to produce metabolites which are useful to the host [10]. The end product of metabolism of prebiotics is short chain fatty acids (SCFAs), which are primarily propionic, butyric and acetic acid [10]. SCFAs influence the integrity of the gut epithelium, immunity, glucose homeostasis, lipid profile and body weight [11]. In addition, SCFAs have effects on insulin

resistance, suppress appetite and lipolysis, increase expenditure of energy and promote insulin sensitivity and production [9,15].

While butyrate is a good source of energy for colonocytes and enterocytes, propionate is a substrate for intestinal and hepatic gluconeogenesis, and the most abundant SCFA found in circulation is acetate [11]. The phenomenon of cross-feeding by other bacteria has also been discussed as possible mechanism employed in the production of SCFAs which are crucial for the intestinal health and other health benefits in areas distant to the gut [12,16]. Cross feeding is a process where a substrate stimulates the growth of members of the gut microbiota which produces metabolites which are utilised by other microbes to produce butyrate and other SCFAs [12].

Antidiabetic agents have also been shown to restore the richness and diversity of the gut microbial community to some level and have demonstrated ability to promote the growth of some useful bacteria [15]. In particular, anti-diabetic agents not only influence gut microbiota, in turn, microbiota affects how the individual responds to those drugs which explains the bidirectional relationship between microbes in the gut and anti-diabetic medications [17]. Metformin has been shown to reduce blood glucose in patients with T2D by interacting with microbes in the gut including altering the composition and diversity of gut microbiome [8,18].

#### *1.3. Why It Is Important to Do This Review*

The definition of prebiotics has been evolving over the years, therefore, a good knowledge of their effect on gut microbiome in patients with T2D will help in enriching our understanding of this concept, broaden their application and health related outcomes [10–12,16]. Furthermore, an understanding of gut microbial ecology in patients with T2D is useful in developing effective approaches to regulate gut microbiota dysbiosis for purposes that are preventive and therapeutic [15]. It has been suggested that the effectiveness of prebiotics in patients with T2D is based on the modulation of gut microbiome although the results are not consistent [19]. In addition, it seems the systematic reviews and/or meta-analysis conducted previously [20–22] have not focused on the effect of prebiotics on gut microbiome in patients with T2D. In other systematic reviews, studies involving probiotics [23] and prebiotics or symbiotics supplementations [24,25] were included. In addition, the review by Merkevicius et al. [24] included one animal study, but did not involve meta-analysis. The Bock et al. [25] review included patients with type 1 diabetes. In our previous systematic review [26], we examined the effect of dietary fibre in regulating the imbalance in the gut microbial community, but did not compare this with oral antidiabetic agents. In contrast, the current review is a systematic review and Network Meta-analysis (NMA) of RCTs which seeks to evaluate the impact of prebiotics and oral anti-diabetic agents on gut microbiota and metabolic parameters in patients with T2D.
