IJMS | Free Full-Text | Fecal Microbiota Composition, Their Interactions, and Metagenome Function in US Adults with Type 2 Diabetes According to Enterotypes

1. Introduction

Type 2 diabetes (T2DM) is a metabolic disease characterized by elevated serum glucose concentrations due to insulin resistance and impaired insulin secretion. The prevalence of T2DM has markedly increased among Asians [1] and is related to different etiology of T2DM among Asians and Caucasians [2]. In Asians, T2DM occurs in lean individuals with lower insulin-secreting capacity and pancreatic β-cell mass, which eventually causes hyperglycemia and T2DM [3]. It occurs without hyperinsulinemia in Asians [3]. However, in Western countries, increased insulin resistance due to obesity, aging, and inflammation is overcome by hyperinsulinemia, which delays the progression to T2DM. Over time, the increased insulin secretion in a person with high insulin resistance causes β-cell exhaustion, leading to T2DM. Therefore, T2DM is progressed slowly through an increase in insulin secretion in adults in Western countries, unlike Asians [4].
The difference in T2DM etiology between Asians and Western individuals is linked to lifestyle factors across generations. Traditionally, Asians have consumed a high-carbohydrate diet rich in dietary fiber, resulting in greater insulin sensitivity but lower insulin-secreting capacity and pancreatic β-cell mass compared to Caucasians [5]. On the contrary, Western individuals living in the USA have traditionally adopted a diet high in meat consumption, leading to a higher prevalence of obesity and elevated fasting serum glucose and insulin concentrations [6,7]. These differences in dietary patterns and metabolic characteristics influence the composition of the gut microbiota, contributing to the etiology of T2DM [8,9]. Butyrate and propionate among SCFA, products of fecal bacteria, are beneficial for insulin sensitivity, and T2DM patients exhibit reduced production, potentially contributing to impaired glucose homeostasis [10]. Akkermansia is positive, but certain species of Escherichia and Clostridium are inversely associated with metabolic function, contributing to T2DM risk [11,12]. Therefore, they have been shown to exert beneficial effects on glucose metabolism and insulin sensitivity.
In recent years, the crucial role of gut microbiota in the disease pathophysiology of T2DM has emerged [8,9]. The metabolites and bacterial components of gut microbiota affect the initiation and progression of T2DM [13]. Genetic differences, lifestyles, and interactions influence gut microbiota linked to T2DM [14]. The emerging evidence on the interconnectedness between the gut microbiome and host metabolism indicates that gut microbiota is associated with intestinal permeability, secretion of digestive juices, and the autonomous nervous system, all linked to the host’s genetic predisposition [15]. In a hyperglycemic state, the acute stimulation of the vagus nerve, a principal component of the parasympathetic nervous system, decreases glucose release from the liver and potentiates insulin secretion from the pancreatic β-cells [16]. The vagus nerve activation suppresses peripheral inflammation, decreases intestinal permeability, and modulates the microbiota composition [11]. The fecal bacteria community of Asians with T2DM exhibits the potential association with vagus nerve suppression, suggesting that insufficient insulin secretion in Asian T2DM may be related to the inhibition of the vagus nerve. However, T2DM, mainly with insulin resistance in Western countries, may have different gut microbiota communities.
Limited evidence exists regarding the link between fecal bacteria composition and T2DM, specifically in Western countries. Furthermore, the composition of fecal bacteria and metagenome function in adults with T2DM in the USA, which predominantly represents a Caucasian population, may exhibit differences compared to populations in Asia due to distinct T2DM etiologies between Asians and non-Asians [3]. In the present study, we aimed to identify and analyze the specific variations in gut microbiota associated with T2DM in the USA, categorized according to enterotypes by pooling the fecal bacteria data since the sample size of previous studies was too small to reveal consistent results in the association between fecal bacteria and T2DM in the USA. The present study can provide insight into T2DM etiology in the aspect of fecal bacteria in the USA.

3. Discussion

Gut microbiota related to T2DM have been studied, but the results are inconsistent. In this study, we investigated the association between fecal bacterial composition, enterotypes, and T2DM in US adults, focusing on enterotypes. Our objective was to provide valuable insights into the role of gut microbiota in T2DM pathogenesis, specifically within different enterotypes, and to shed light on the link between gut microbiota and T2DM in the US population. Using a large dataset pooling fecal bacterial files of 1039 individuals with T2DM and 872 healthy adults from HMP data, we employed machine learning and network analysis to identify key bacteria and their interactions influencing T2DM incidence. Additionally, we conducted a metagenomic analysis to explore the functional implications of the microbial composition. Our findings revealed distinct enterotypes (Bacteroidaceae, Lachnospiraceae, and Prevotellaceae) associated with T2DM incidence, along with lower α-diversity in T2DM within specific enterotypes, indicating microbial diversity differences. The XGBoost model demonstrated high accuracy and sensitivity in predicting T2DM based on fecal bacterial composition. Furthermore, we observed specific bacterial taxa in the T2DM group compared to the healthy group, and metagenomic analysis unveiled associations between bacterial abundance and metabolic pathways relevant to T2DM. These novel findings enhance our understanding of the intricate interplay between gut microbiota and T2DM in the US population.

Notably, Asians exhibit lower insulin-secreting capacity than non-Asians, contributing to the etiological differences in T2DM development between these populations [3]. The different etiology may be closely linked to distinct gut microbiota communities in Asians and non-Asians. The present study explored the differences in gut microbiota composition between individuals with T2DM and healthy individuals in the USA, predominantly Caucasians. It showed that the enriched bacteria in the T2DM patients in the USA were Bacteroides, Blautia, and Germmiger. However, in Asians, the T2DM-enriched genera are Enterobacter, Coprococcus, Negativibacillus, Rothia, Desulfovibrio, Megasphaera, Eubacterium Prevotella, Clostridium sensu stricto 1, Olsenella, Lactobacillus, and Neisseria. Coprobacter, Butyrivibrio, Paraprevotella, Tyzzerella 3, and Barnesella belong to T2DM-depleted genera [11]. Furthermore, Asians with T2DM displayed a higher proportion of Escherichia fergusonii and lower Faecalibacterium prausnitzii compared to the healthy group within both ET-L and ET-P enterotypes [11]. These differences in gut bacteria between the healthy and T2DM groups in the Asian population highlight the potential association of gut dysbiosis with intestinal permeability and the enteric vagus nervous system [11]. Activation of the enteric vagus nervous system in the intestines can generate aberrant signals to the hypothalamus, leading to a distorted efferent message that induces insulin resistance [17]. Unlike the findings in the Asian population containing ET-L and ET-P, the fecal bacteria in the US population were clustered into ET-B, ET-L, and ET-P, and T2DM-related fecal bacteria did not appear to be associated with intestinal permeability and the enteric vagus nervous system. In the metagenomic analysis, unlike healthy adults, the high fecal bacteria in T2DM patients were implicated in reduced energy utilization, butanoate and propanoate metabolism, and insulin signaling pathways. These findings suggest that the gut bacteria associated with T2DM in the US population primarily relate to energy metabolism and insulin resistance.
Several studies have reported a significant difference in the gut microbiota profiles across ethnicities in the US population [18]. The α-diversity plays a critical role in disease prevalence, and the α-diversity (Choa1 and Shannon indexes) is reported to be lower in the order of ET-L, ET-P, and ET-B in healthy persons [19]. It suggests that ET-B may be more susceptible to metabolic diseases, including T2DM. However, the decrement in α-diversity in T2DM remains controversial [11,20]. A systematic review and meta-analysis of stool microbial profiles, including seven studies, involving 600 T2DM patients and 543 controls from China, Pakistan, Mexico, Columbia, and Nigeria, showed significant β-diversity but not α-diversity between the T2DM and control groups as shown in a random effect model [20]. In the other Asian study separated into ET-P and ET-L clusters, α-diversity is lower in the T2DM group than the healthy group in ET-L, but not ET-P [11]. The present study demonstrated that α-diversity was lower in the T2DM group than the healthy group in the total participants. A similar trend was seen in ET-L and ET-P, but not ET-B. These results suggest that the population with no difference between the healthy and T2DM groups may be susceptible to T2DM. Therefore, Asians with ET-P and US adults with ET-B may be at a high risk of T2DM. ET-B may benefit by switching to a different enterotype.
Enterotypes are linked to not only the host’s genetic factors, but also diets [11,14,21,22]. Asians have consumed a low-fat diet with grains and vegetables and have ET-L or ET-P, but not ET-B. Prevotella and Bacteroides belong to Bacteroidetes in the phylum level, and a high-fat diet partly changes ET-P to ET-B [23]. Although enterotypes are challenging to alter [24,25], dietary patterns are the primary drivers of enterotypes, regardless of other factors. Overall, ET-B is mainly related to a high-fat and protein diet from animal foods, ET-P is linked to insufficient energy intake, simple sugars, fruits, and vegetables, and ET-L is involved with a mixed diet, possibly a balanced diet [19]. Bile acid acts as a molecular cross-talk between gut microbiota and the host, and the bile acid pool in the colon modulates gut microbial metabolism and diversity [26]. A high-fat diet, especially with gallbladder removal, has been shown to elevate Bacteroides and decrease α-diversity in mice [21]. In contrast, irritable bowel disease is linked to high bile acid content and a lower proportion of Bacteroides [27]. It suggests that elevated bile acid may promote a gut condition to increase Bacteroides. In recent years, the sudden increase of T2DM in Asians may be related to increasing Bacteroides, although enterotypes cannot be easily altered. US adults have a high-fat diet with high meats and low vegetables and more ET-B than Asians. Since US adults with ET-B showed no difference in α-diversity between the T2DM and healthy groups, they may be susceptible to T2DM. Therefore, US adults may need to make dietary modifications to decrease Bacteroides.
T2DM is involved in increased insulin resistance and insufficient insulin secretion, which are linked to gut microbiota [ref]. In the Rotterdam study, patients with T2DM and high insulin resistance (high HOMA-IR) exhibited a lower Shannon index and richness than those without T2DM. A higher abundance of Christensenellaceae, Marvinbryantia, and Ruminococcaceae was inversely associated with insulin resistance [28]. A higher abundance of Clostridiaceae, Intestinibacter, and Peptostreptococcaceae was inversely associated with the incidence of T2DM. These bacteria were involved in butyrate production [28]. The present study showed that Enterocloster bolteae, Facalicatena fissicatena, Clostridium symbiosum, and Facalibacterium prausnitizii were present in higher abundance, and Bacteroides koreensis, Oscillibacter ruminantium, Bacteroides uniformis, and Blautia wexlerae were present in lower numbers in the T2DM group compared to the healthy group in the USA, regardless of enterotypes. Akkermentia muciniphila was higher in the healthy group than the T2DM group only in ET-L. In a metagenomic analysis of fecal bacteria, the predominant bacteria in T2DM from the USA were related to reduced energy utilization, decreased butanoate and propanoate metabolism, and disturbed insulin signaling pathways compared to healthy adults, somewhat different from those associated with Asian T2DM.
Each bacterium may or may not be related to T2DM in a cause-and-effect relationship. It is not individual bacteria, but their group influencing glucose metabolism and progression to T2DM. Facalibacterium prausnitizii and Bacteroides uniformis act as probiotics to promote health benefits [29,30]. However, the present study demonstrated that these bacteria were present in higher numbers in participants with T2DM than in healthy adults. For example, Facalibacterium prausnitizii and Bacteroides uniformis could be involved in the development and progression of T2DM since the results of the present study came from case-control studies and not randomized clinical trials. Gut microbial networking has been studied mainly in the context of infections since co-existent bacteria significantly prevent infections and are not detrimental to the host [31]. However, few studies have been conducted to investigate gut microbial interactions to prevent metabolic diseases, and these studies have not been conducted according to enterotypes [32]. A stable bacterial network can prevent gut dysbiosis, which in turn can prevent disease progression. Probiotics and prebiotics should regulate the gut bacterial network to prevent disease development and progression. Gut bacteria are better at promoting butyrate-producing bacteria, such as Akkermansia muciniphila, to prevent the development of T2DM [8,9].
This study has some merits. First, the study included a large sample size by pooling all studies conducted with US adults (1039 T2DM and 872 healthy adults). Second, the gut microbiota in US adults showed a distinct gut microbiota community different from Asians. Dysfunction of the parasympathetic nervous system can develop and exacerbate T2DM, especially in Asians, contributing to gut dysbiosis [33]. The present study provides evidence that T2DM patients in the USA were not related to suppressing the parasympathetic nervous system, but linked to insulin signaling pathways and energy metabolism, reiterating the etiological differences in T2DM between Asians and Caucasians [34]. This contributes to understanding T2DM etiology and highlights potential implications for personalized interventions or treatments. However, the present study also has some limitations. First, the data were collected in case-control studies, and the results could not be applied to evaluate cause and effect. Second, the fecal FASTA/Q data from the adults in the USA were collected from the GMrepo database. However, the demographic characteristics of the participants, such as age, gender, ethnicity, food intake, and lifestyle, were not provided and hence could not be used for adjustments in the statistical analysis. Information on the drugs used to treat T2DM and antibiotic intake was also not provided. Third, the direct effect of insulin secretion, insulin resistance, and the parasympathetic nervous system on gut microbiota could not be evaluated due to the non-availability of biochemical data.

In summary, the fecal bacterial composition of US adults with T2DM was clearly separated from those of healthy participants. Regardless of enterotypes, Enterocloster bolteae, Facalicatena fissicatena, Clostridium symbiosum, and Facalibacterium prausnitizii were present in higher abundance, and Bacteroides koreensis, Oscillibacter ruminantium, Bacteroides uniformis, and Blautia wexlerae were present in lower numbers in the T2DM group compared to the healthy group in the XGBoost model. The gut microbiota in adults with T2DM in the USA was somewhat different from those in Asians with T2DM, which may be linked to different β-cell functions and mass in Asians and non-Asians. The interaction between the fecal bacteria was also different in different enterotypes. ET-L had a more stable gut microbiota population than ET-B, and adults with ET-P and ET-L had a lower T2DM incidence than those with ET-B. In the metagenomic analysis, gut bacteria composition in T2DM patients was inversely associated with energy utilization, butanoate and propanoate metabolism, and insulin signaling pathways compared to healthy adults. In conclusion, the gut bacteria related to T2DM mainly influence the energy metabolism and insulin signaling pathways in the US population, Caucasians, and the regulation of their network is linked to T2DM risk in different enterotypes. Therefore, the present study provides valuable insights into the link between gut microbiota and T2DM in US adults. This contributes to understanding T2DM etiology and highlights potential implications for personalized interventions or treatments.

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