Food Fortified with Carbohydrate-Fermenting Gut Microbes Producing Butyrate May Reverse Type 2 Diabetes Mellitus: A Silver Lining for Diabetes Research

Type 2 Diabetes Mellitus (T2DM) is one of the most common metabolic diseases in the world. Due to the rise in morbidity and mortality, it has become a global health problem. To date, T2DM still cannot be cured, and its intervention measures mainly focus on glucose control, as well as the prevention and treatment of related complications [1]. In type 2 diabetes, which affects approximately 463 million people worldwide, a person’s body gradually loses its ability to regulate blood sugar [2] effectively. Although prior research has connected changes in the gut microbiome to type 2 diabetes [3,4], a diverse large-scale study at a global level has been lacking. Mai et al. [5] analyzed data from the newly established microbiome, and cardiometabolic disease consortium (Micro-Cardio), wherein the dataset included genomic information from the gut microbiomes of 8117 people who had type 2 diabetes, pre-diabetes, or normal blood glucose levels, and were ethnically and geographically diverse, hailing from the United States, Israel, Sweden, Finland, Denmark, Germany, France, and China. They found a consistent set of microbial species that were linked to type 2 diabetes across their study population, including many that had never been reported before. To understand the role of these microbes in the gut, the researchers analyzed the species functional abilities. They found that certain strains of microbes had functions that may be linked to varied type 2 diabetes risk. For example, a strain of Prevotella copri- a common gut microbe that has the capacity to produce large quantities of branches-chain amino acids was more commonly seen in the gut microbiomes of people with type 2 diabetes. Previous studies have shown that people with chronically high levels of branched-chain amino acids in their blood have a higher risk of obesity and type 2 diabetes [6]. The researcher believed that changes in the gut microbiome cause type 2 diabetes.

Zhou et.al [1] reported that gut microbiota plays an important role in the development of metabolic diseases, especially T2DM [7] also opinioned that changes in gut microbiome may increase type 2 diabetes risk. It was found that specific species and strains of gut microbes were more common in people with type 2 diabetes. Bacteroides and Bifidobacterium are beneficial genera that are frequently reported in studies of type 2 diabetes. Roseburia and Faecalibacterium are found in lower frequencies in Type 2 Diabetes groups than in healthy control suggesting that their lower frequencies may be responsible for uncontrol metabolism associated with glucose regulation. According to a study by Candela et.al [8] type 2 diabetes patients had more Short-Chain-Fatty- Acid producers like Faecalibacterium, Roseburia, Lachnospira, Bacteroides, and Akkermansia in their gut microbiomes than the healthy individual who followed two different diet patterns (high fiber diet vs control diet). Zheng Li et al. [9] concluded that there is clear and growing evidence of a close relationship between the microbiota and diabetes, and this is worthy of future investments and research efforts. Dysbiosis in gut microbial composition and function is linked to immune responses and the development of metabolic diseases, including diabetes mellitus [9].

The composition of the gut microbiome may affect the likelihood of developing type 2 diabetes, according to the systematic review of Slouha et.al [10]. The changes to the microbiome may happen first, and diabetes develops later, not the other way around [5], and that prospective or interventional studies are needed to confirm this relationship. Research over the past decade has linked changes in the gut microbiome to the development of type 2 diabetes but has not been able to draw significant conclusions because of those studies’ small size and varied design. The gut microbiome’s relationship to complex, chronic, heterogeneous diseases like type 2 diabetes is quite subtle. The microbiome is highly variable across different geographic locations, and racial and ethnic groups. The study of a small, homogeneous population will probably give inconclusive results. Therefore, large and diverse populations are necessary for detailed microbiome variation studies. If further research confirms that these changes indeed contribute to the development of type 2 diabetes, researchers could use that knowledge to try to manipulate the microbiome to reduce type 2 diabetes risk.

Gut microbiome studies (of diabetes and non-diabetes) of all the ethnic groups around the world

There are 26 Ethnic groups reported around the world [11]. People who have a common language, race, religion, or cultural background are considered to be an ethnic group. These are the area-specific people’s groups, whose culinary and dietary practices differ from each other. It is apparent from Table 1 that irrespective of the variation in culinary and diet, the people from all these 26 Ethnic groups have diabetes. It means that it is not the diet that causes diabetes, but a change in diet and subsequent shift in the gut microbiome may be the reason for causing diabetes mellitus. Previous report from the metagenomics of the Human Intestinal Tract (MetaHIT) project indicated 32 core bacterial species in more than 80% of the European population that belonged to the genera Faecalibacterium, Roseburia, Bacteroides, Dorea, Clostridium, Eubacterium, Coprococcus, Ruminococcus, Alistipes, Collincella, Parabacteroides and Bifidobacterium [40]. In this study, Faecalibacterium, Eubacterium, Clostridium, Blautia, Ruminococcus and Roseburia were found to be core gut bacterial genera across the representative population of the world [41] (both rural and urban).

Table 1:Ethnic groups, their geographical locations, food habits, and major non-communicable diseases for consideration of gut microbiome studies.

Further study of the gut microbiome may need to assess the presence of gram-negative bacteria [30] in these ethnic groups with diabetes and non-diabetes. Gram-negative bacteria may produce gut microbial variables such as bacterial Lipopolysaccharides (LPS) [42]. LPS is a toxin that induces insulin resistance, Type 2 diabetes, and Alzheimer’s disease. Plasma LPS may need to be measured in these ethnic groups to reduce the risk of Type 2 diabetes.

The bacterial species, particularly Faecalibacterium, Eubacterium, Clostridium, Ruminococcus, and Roseburia are important carbohydrate-fermenting bacteria that are mostly involved in starch fermentation with the production of butyrate. Butyrate is a Short-Chain Fatty Acid (SCFA) produced by gut microbiota that plays a key role in gut health with various functions. Butyrate is the primary energy source for colonocytes. It strengthens the gut barrier by targeting tight junctions, the mucus layer, and the production of antimicrobial peptides. It inhibits inflammation and oxidative stress. It can protect against epithelial injury and improve tissue repair. It promotes a healthy microbiome. It regulates metabolism and helps with the transepithelial transport of fluids. It helps to prevent non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, inflammation, cancer, and liver injuries. Butyrates help to produce gut hormones that regulate blood sugar levels, which may improve insulin resistance and obesity. Butyrate is produced from fermentative carbohydrates of plant-origin food material, such as fibers, cellulose, and complex sugar in the colon with the help of gut bacteria [43]. Therefore, the production of butyrate in the gut by the gut microbiome seems to be the most important aspect in the regulation of blood sugar levels and needs further confirmation.

It will be advisable to study the gut microbiome of all the ethnic groups (diabetes and non-diabetes) to assess the presence/absence of carbohydrate-fermenting gut bacteria with their population density variation among diabetes and non-diabetes. This will give a clear-cut picture of gut microbial variables in these people. Once it is confirmed that carbohydrate fermenting bacteria and butyrate produced by these have a role in the regulation of blood sugar and diabetes, these can be used in the form of probiotics in the management and probably reversal of diabetes mellitus all over the world.

Furthermore, the performance of probiotic bacterial strains is influenced by the carrier food and its functional components, which while buffering the probiotic through the gastrointestinal tract, contribute to an efficient implantation of bacterial cells and regulate probiotic features [44]. Plant-based matrices are eligible substrates for hosting and delivering microbial populations because of their richness in nutrients, fibers, vitamins, minerals, and dietary bioactive phytochemicals. The health-promoting properties of solid plant-based matrices (particularly artichokes, table olives, apples, and cabbage) and their association with probiotic bacteria are indicative of the role of the food matrix in sustaining probiotic cells during product processing, digestive process, gut implantation, and finally in exerting beneficial effects [2,3]. The functional attributes of plant-based matrices, their structure and their suitability to fermentation make them appropriate for carrying probiotic strains that would take advantage of the characteristics of plant-based matrices and, by exploiting prebiotic and bioactive molecules, take benefit for their survival during product processing and shelf life as well as in the digestive process and gut colonization [45]. The available research on fortified food items with probiotics suggests that carbohydrate-fermenting probiotics producing butyrate can also be used in food fortification and diabetic reversal programs [46].

Diabetes mellitus, widely prevalent around the world in people of all ethnic groups, is probably caused by a change in carbohydrate metabolism, as a result of various factors, including changes in food habits. This change in food habits alters the human gut microflora responsible for carbohydrate metabolism. The involvement of certain gut microbial species related to carbohydrate metabolism plays an important role in the disease initiation and prevalence. These bacterial species, as probiotics, can alter carbohydrate metabolism and thereby diabetes. The food fortified with these carbohydrate-fermenting, butyrate-producing bacteria can be of significant importance in reversing type 2 diabetes.

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