Association of obesity , diabetes and linked complications with gut microbiota

Gut microbiota is the microorganism community comprising of bacteria, eukaryotes and archaea as well as different viruses that live in the small intestinal tract and gut. Human have clusters of bacteria in the intestine. Gut microbiota encompasses tens of trillions microorganisms, including different types of bacteria with more than 3 million genes. In normal humans, microbiota usually weighs up to 2 kg. In simple words, microbiota in our intestine is like a person’s identity card. Microbiota may corresponds to many inter-related diseases such as obesity, diabetes and complications linked to them e.g. renal toxicity, kidney stones, diabetes retinopathy, hypertension, atherosclerosis, diabetic foot ulcer, Alzheimer’s disease and cystic fibrosis. Germ free animals protected against obesity when transferred with gut microbes from conventionally raised animals resulted in dramatic increase in their body fat content and resistance to insulin. Moreover, composition of the gut microbiota has shown to differ in lean and obese humans changed rapidly in response to dietary factors. There are some factors that affect the composition of gut microbiota such as food, disease state, medications, genetics of host etc. This review highlights the fact that modification of gut microbiota may be a beneficial way in the treatment of obesity, diabetes and other metabolic disorders.


Association of obesity, diabetes and linked complications with gut microbiota
Amina Arif 1* , Zobaria Khan 1 , Seemab Khalid 1 , Muhammad Azam Gujjar 1 , Rafique Ahmed 2 and Mushtaq Ahmad Saleem 1 Introduction Disorders like obesity have extended to dangerous level worldwide.During last few decades' over-weight and its related problems like type 2 diabetes (T2D) has increased to exponential level [1].Inactive life style and extra food utilization has been considered as main reason for this obesity scourge [2].Term gut microbiota covers all micro-organisms living in gastrointestinal (GI) tract.Most of gut microbiota that exist in large intestine play an important role in the vitamin synthesis, digestion and metabolism.Although the correct mechanism is far from being well recognized, it is accepted that gut microbes can upsurge energy creation from food, they also can donate to regulate fatty acids tissue composition and low grade inflammation [3].These activities besides other have initiated linkage between gut microbiota and over-weight.Genetic factors and some environmental factors induce changes in gut microbiota leading to the metabolic diseases [4].Although the accurate contribution of gut microbiota is not very clear in the development of diabetes and obesity because of so many reasons including complicated changes in gut microbes' composition, inherited changes and large differences between individuals of the population in study [5].In spite of regulations made by gut microbes having massive therapeutic prospective, they can also help to recover the growing obesity and related complications mostly when combined with exercise and diet [6].All over the world, the major health problem is diabetes, according to an estimation 9% of the population is suffering from this disease.This can affect standard of life and often has led to major issues including risk of kidney failure, heart attack and overall mortality.Due to the inheritance based complicated changes in gut microbes' composition and large differences between individuals of population in the study, the human body pool anchorages trillions of bacteria that were genetic contents of our micro flora and 150 times extra in number as other body parts [7].There are three domains of gut microbiota including (Bacteria, Eukaryote and Archaea) along with their viruses, that dominated anaerobic bacteria.Each individual harbors 160 species and has been given new idea that cored gut microbiota at functional level and necessary for gut functioning in the ecosystem [8].Almost 90% of prevalent bacterial species are grouped into two phyla Bacteroidetes (Gram negative) and Firmicutes (Gram positive) [9].The gut microbiota helps in maturing and regulating the immune system and also protects from pathogens.They regulate the intestinal hormone secretion for gastrointestinal movement, they synthesize vitamin K and Bvitamin (Folate, Vitamin B12) and they create short-chain fatty acids (SCFAs) by fermentation of carbohydrates which are nondigestible, conventionally bacteria are being studied by culture methods.Yet it's not easy to culture bacterial strain so the cultureindependent method has been established [10].Culture-independent methods are easier because they take more advantages and approach of next-generation sequencing expertise to know DNA microbes from fecal trials; they are generally well-thought-out illustrative of distal gut microbiota.Complicated relationship between diabetes, over-weight and gut microbiota was uncovered with emerging evidences.Obesity and its related problems have reached to a disturbing stage globally.During the last few years' exponential rise in the number of people suffering from fatness and its related syndromes such as T2D has been experienced [11].All of us have our own unique microbiota and gut microbiota (microorganism genes).Microbiota genes are hundredfold higher than the numbers of genes of human [12].A study investigated that the effects of nutrients (such as fats, roughage) and dietary habits (weather vegetarians or omnivores) in diverse population have permitted that the classification of human population will be based on their microfilm's genetic abundance [13].Gut  Staphylococcus species being coagulasenegative are the main planter of foot normal flora; these are identified as a strong participants for the infection related to S. aureus.During last few years, it has been examined that there is an increase in the percentage of conversion of non-pathogenic staphylococcus to pathogen S. aurues.Although present in the small concentration on the feet of diabetic men as contrast to standard the small concentration is present on men of diabetic feet [47].After the analysis of the microbes in foot ulcers of diabetic patient it was found that depth of ulcer and period of the microbial growth are negatively related with profusion of Staphylococcus whereas the time duration of the ulcers was positively related to the bacterial protein and all this work was done by pyro-sequencing of 16S rRNA gene of bacteria [48].

Alzheimer's disease (AD)
The risk of Alzheimer's disease (AD) can also be increased by diabetes type 2 and have a common pathogenic mechanism [49].The potential mechanism that link two medical conditions, include insulin resistance or role of insulin deficiency that facilitates cerebel βamyloidogenesis, which increases the danger of dementia in diabetic patients [50].Diabetes type 3 could be considered as Alzheimer's disease [51].A very minute data exists to understand the residential flora of Alzheimer's disease patients but how they are related to each other is badly perceived.There is a study that openly relates to the gut physiology and structure of microbiota in which alteration in gut was categorized by an increase of gram-negative bacteria that was escorted by mucosal disturbance in AD transgenic mice [52].The testing area of gut microbiota in AD is under studies, might be in future there will be a possibility to treat AD through enteric bacteria considerable.Usually putative drugs like indole propionic acids (IPAs) are used to treat AD and type 2 diabetes [53].The plasma amino acid by products include bioactive indole comprising metabolites moreover conversion of indole 3 propionic acid was known reliant on gut microflora by colonization with the bacterium Clostridium sporogenes [54].Thus extraction of microbiota seems to be an essential way to overhaul the plasma IPA level.Metabolic characteristics of the AD was the disappearance of GABA (A) receptors in the hippocampus of the brain [55].There are some direct evidences that show interaction between host metabolisms of residence flora, which deals with new potential or treatment goals for AD.

Cystic fibrosis
Cystic fibrosis (CF) patients are also linked with T2DM [56].Microbiota in CF respiratory tract also have an imperative position in its pathogenesis; evidences show that most common bacteria that are collected from airways of cystic fibrosis victims were Pseudomonas aeruginosa, Haemophilus influenza, S. aureus, Burkholderia cepacia complex species [57].From highthroughput sequencing method, like 16S rRNA amplicon pyro-sequencing was done to figure out the genetic bases of the airway microbiota.But through a direct sampling of explanted lungs only one or three species were found dominated in CF lungs [58].Micro flora in the throat and sputum could not resemble to the normal micro flora that had been observed previously.

Factors affecting on gut microbiota composition
Numerous factors like food, level of disease condition, medication moreover host genetics, effect the configuration of gut microbiota (Figure 1).The constitutions of gut microbiota are persistently changed and influence the health and welfare of host especially in the disease condition as well as during treatment through diverse medicine like antibiotics.The most dietary strategies are prebiotics and probiotics that are established to regulate the configurational activity of gut microbiota.Nonpathogenic microorganism e.g.prebiotic, are used as food ingredient for the benefits of the host health.The existence of bile salt hydrolase (BSH) in probiotics makes them more permissive to bile salts, which is also helpful in reducing the blood cholesterol level of the host

Conclusion
The accumulative evidences sturdily suggest that the gut microbiota play an important role in the regulation of metabolism and weight maintenance in humans as well as put impact on the development and progression of obesity plus other metabolic disorders, including type 2 diabetes.Constitution of the gut microbiota has been shown to diverge in lean and obese humans and change quickly in response to dietary factors.There are some factors that affect the composition of gut microbiota such as food, disease state, medications, genetics of host etc. Manipulation of the gut microbiome represents a novel approach in treating obesity, diabetes and complications linked to them such as renal toxicity, kidney stones, diabetes retinopathy, hypertension, atherosclerosis, diabetic foot ulcer, Alzheimer's disease and cystic fibroses.

Figure 1 .
Figure 1.Some aspects that effect the gut microbiota configuration.Gut microbiota constitution depends on the food, diseased state, medication and host genetics These victims exhibit high stages of Lactobacillus sp. as related to non-diabetic Clostridium sp.It correlates negatively with fasting glucose, HbA1C and insulin while Lactobacillus sp.Positively correlates with fasting glucose and glycolated hemoglobin (HbA1C) levels.Plasma triglycerides or Cpeptides are positively linked with adiponectin and high-density lipoprotein (HDL) cholesterol [22].Furthermore, onset based metagenomics clusters in obese and genetically diet-induced leptin-resistant mice, 26 distinctive bunches were found when associated normal mice with diabetic [23].Microbiota has low amount of Roseburia intestinalis and Faecalibacterium prausnitzii (both butyrate producing bacteria) and high level of Lactobacillus gasseri, Streptococcus mutants as well as clostridiales members in different population levels.Administration of metformin caused and increased Akkermansia muciniphila, gram negative bacteria in mucous layer [24].A. muciniphila concentration associates inversely with the presence of diabetes and loss of weight.Induced improvement in weight loss, tolerance of glucose, and inflammation [25, 26].Management of a prebiotics such as oligofructose increases A. muciniphila level, with some beneficial effects on metabolic mechanism, neomycin given to non-obese diabetic (NOD) mice increases the concentration of A. muciniphila and increases glucose homeostasis.Some of the Firmicutes and Clostridium sp. were seriously reduced in the patients where diabetes was tried to control [27].In same way relationship between Bacteroidetes to

Table 1 . Effects of different type of foods on the diversity of gut microbiota Food type Effects on bacteria
[66].Starchand insulin are prebiotic compounds that are used by food industry to change the configuration of gut microbiota to value human health, these compounds mostly target Lactobacillus and Bifidobacterium [67].Recent research tells that prebiotics and probiotics (symbiotic) can also thicken human body making it fat and large [68].The humanized mice produce by incorporating the human genes, cells, tissues or organs could be used to examine the reaction of diet on microbiota, exchanging mice from low fat, rich diet called western diet, high fat sugar diet that changed the anatomy of microbiota within one day [69, 70].Mice fed with western diet up surged the number of Erysipelotrichia bacteria, a class in the Firmicutes phylum and lowered the Bacteroids spp.compared to the mice that were given vegetarian diet rich in nutritional fibers, later had low Bacteroids spp. as compared to control E.coli and other bacteria.Table 1 explains the change in gut microbiota on the ingestion of different types of diet that have different level of sugar, fat, starch, protein, vegetarian or calorie limited food and western diet.Bifidobacterium species replace variation in microbiota, minimize the overabundance of Formicates and LPS-producing proteobacteria, helps in improving systemic inflammation by fabrication of B cells and cytokinesis (IL-6, MCP-1, TNF-α, IL-17) [78].Triglycerides, insulin, low level of cholesterol and lowering the body weight help in increasing restoration of insulin sensitivity and oral glucose forbearance, all these factors are involved in improving the metabolic dysfunctions [80].In diabetic/obese persons, rapid diabetic cancellation and metabolic enhancement along with the weight loss can be achieved by a bariatric surgery-named as, Roux-en-Y Gastric Bypass (RYGB).E.coli and other microbes' population increase after three months that inversely correlates with leptin level and fat mass as a result of several changes in food intake.Three months later, decrease in lactic acid bacteria (LAB),