Journal of Mahatma Gandhi Institute of Medical Sciences

REVIEW ARTICLE
Year
: 2020  |  Volume : 25  |  Issue : 2  |  Page : 66--71

Dysbiosis of gut microbiota and human diseases


Sangeeta Huidrom, Mirza Atif Beg 
 Department of Pharmacology, Shri Guru Ram Rai Institute of Medical and Health Sciences, Dehradun, Uttarakhand, India

Correspondence Address:
Dr. Sangeeta Huidrom
Department of Pharmacology, Shri Guru Ram Rai Institute of Medical and Health Sciences, Dehradun - 248 001, Uttarakhand
India

Abstract

Gut microbiota of humans harbour a complex and dynamic community of more than 100 trillion beneficial microbes. Recent advances in tools and techniques of microbial analysis have made it possible to understand better the important role played by gut microbiota in the human body. The composition of gut microbiota depends on many factors, such as the mode of delivery of the baby, environmental conditions, antibiotic usage, age, and diet. Homeostasis of gut microbiota is important for maintaining good health as it influences human nutrition, metabolism, and immune function, while dysbiosis of the gut microbiota is associated with various gastrointestinal and metabolic disorders, such as inflammatory bowel disease, obesity, type 2 diabetes, colon cancer, and dysregulation of the immune system. Clinical evidences have shown that diseases caused by imbalance gut microbiota can be treated by probiotics. However, more research work is required to get insightful knowledge of what kind of particular microbes and underlying molecular mechanisms are responsible for a particular disease.



How to cite this article:
Huidrom S, Beg MA. Dysbiosis of gut microbiota and human diseases.J Mahatma Gandhi Inst Med Sci 2020;25:66-71


How to cite this URL:
Huidrom S, Beg MA. Dysbiosis of gut microbiota and human diseases. J Mahatma Gandhi Inst Med Sci [serial online] 2020 [cited 2021 Jan 25 ];25:66-71
Available from: https://www.jmgims.co.in/text.asp?2020/25/2/66/303422


Full Text



 Introduction



Microbes residing in the human gut play a very significant role in combating disease causing bacteria, and thereby maintaining good health. The human body is inhibited by various types of microbes. Microbes flourish on our skin and in the genitourinary tract, gastrointestinal tract (GIT), and respiratory tract.[1],[2],[3],[4] The collection of microorganisms that live in peaceful coexistence with their hosts has been referred to as the microbiota, microflora, or normal flora.[3],[5],[6] Due to recent development in high-throughput sequencing technologies, the composition and function of the gut microbiota in the host have been studied well. It is estimated that the human microbiota contains as many as 1014 bacterial cells, a number that is 10 times greater than the number of human cells present in our bodies.[7],[8],[9] The presence of a huge number of microbiota in the human body shows their importance in the normal functioning of the body. In the GIT, the colon is the most heavily populated region which is estimated to contain over 70% of all the microbes in the human body.[7],[9] The combination of multiple factors such as genotype, mode of delivery, early antibiotic therapy, diet composition, lifestyle, social interactions, and environmental exposure to various xenobiotics shape the gut microbiota to make every individual microbially unique.[10],[11] In the healthy state, gut microbiota plays an essential role in the human body such as protection against pathogens, immune system modulation, fermentation of nondigestible dietary fibers, anaerobic metabolism of peptides and proteins, interaction with the host's circadian clock, and biotransformation of xenobiotics.[12],[13],[14] However, in the case of dysbiosis, the gut microbiota of the host leads to susceptibility to various kinds of diseases. Chronic diseases such as obesity, inflammatory bowel disease (IBD), diabetes mellitus, metabolic syndrome, atherosclerosis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), cirrhosis, and hepatocellular carcinoma have been associated with the human microbiota.[7],[15] This review gives an overview of the composition of the gut microbiota and its importance to the host. Then, this review discusses the diseases caused by the dysbiosis of the gut microbiota and the biotherapeutic intervention of microbiota using probiotics.

 The Human Gut Microbiota



The vast microbial species residing in our gut differ in composition and function, becoming richer and diverse, from 101 to 103 bacteria per ml of content in the stomach reaches up to 1011–1012 bacteria per ml of colonic content.[12] The structure and composition of the gut flora reflect natural selection at both the microbial and host levels, which promote mutual cooperation within and functional stability of this complex ecosystem.[12] It has been estimated that the collective human gut microbiota is composed of over 35,000 bacterial species.[16] The human GIT microbiome is dominated by four main bacterial phyla, including Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria.[17] The Firmicutes are primarily associated with energy harvested from food,[18] and the Bacteroidetes are associated with several health benefits due to their capacity to degrade complex sugars and proteins into metabolizable short-chain fatty acids (SCFAs).[7] The heavily colonized region by the microflora in the colon in which about 400–500 microorganisms species are inhabited and 99.9% are anaerobic bacteria. Such diversity is probably due to the decreased intestinal motility and the very low potential for oxy-reduction in this region.[19],[20],[21],[22] The microbial floras which dominate in the colon are strict anaerobes such as Bacteroides, Eubacteria, Bifidobacteria, and Peptostreptococcus. The infant gut is presumed to be sterile in utero and acquires microbes during the process of birth or immediately thereafter.[23],[24],[25],[26] After the initial establishment of the intestinal microbiota and during the 1st year of life, the microbial composition of the mammalian intestine is relatively simple and varies widely between different individuals and also with time.[27],[28] Gut microbiota provides a wide range of protective effects to the host. Colonic bacteria express carbohydrate-active enzymes, which endow them with the ability to ferment complex carbohydrates generating metabolites such as short-chain fatty acids short-chain fatty acids (SCFAs),[29] and they are involved in the regulation of cellular processes such as gene expression, chemotaxis, differentiation, proliferation, and apoptosis.[30] The gut bacteria are able to produce a variety of vitamins, synthesize all essential and non-essential amino acids, and carry out biotransformation of bile.[31] Commensals make their immediate environment inhospitable to many pathogens by producing biosurfactants, by competing for sites of attachment and nutrients, and by excreting metabolites with antimicrobial effects.[32] Bacteria are integral to the early development of the gut–mucosal immune system, both in terms of its physical components and its function, and continue to play a role later in life in its operation.[33] The cells of the intestinal epithelium avert threats from pathogens by signaling to the innate immune system through specific receptors.[31]

 The Gut Microbiota and Human Diseases



Recent studies on gut microbiota suggest that dysbiosis of gut microbiota contributes to the development of diseases. When dysbiosis of gut microbiota takes place, the symbiotic relationship of host-microbe tends to progress to various gastrointestinal tract (GI) and metabolic diseases. Recent advances in culture-independent tools and techniques such as denaturing gradient gel electrophoresis (DGGE) and temperature gradient gel electrophoresis, terminal restriction fragment length polymorphism (T-RFLP), 16sRNA, fluorescence in situ hybridization (FISH), and DNA microarray have revolutionized our understanding of the human microbiome. Here, we highlight the link between gut microbiota and human diseases.

Irritable bowel syndrome

The symptoms of irritable bowel syndrome (IBS) are characterized by recurrent abdominal pain or discomfort, accompanied by abnormal bowel habits, in the absence of any discernible organic abnormality.[34] Although the etiology is multifactorial, a recent understanding of the pathophysiology of IBS has revealed that variations in the normal gut microbiota may have a role to play in the low-grade intestinal inflammation associated with the syndrome.[35],[36] In a patient with IBS, gut microbiota was characterized by an increase in Firmicutes and more specifically, in the numbers of Ruminococcus, Clostridium, and Dorea, in addition to a marked reduction in Bifidobacterium and Faecalibacterium spp.[37]

Inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic and relapsing inflammation of the GIT which is caused by a dysregulated immune response to host intestinal microflora. The two common types of IBD are ulcerative colitis (UC) and Crohn's disease (CD). CD can cause inflammation in any part of the digestive tract, whereas UC is associated with the inflammation of the large intestine. Although the etiopathogenesis of IBD is currently unknown, recent studies have highlighted the pivotal role of intestinal microbiota for disease manifestation[38] In UC, DGGE analysis suggested that Lactobacillus salivarius, Lactobacillus manihotivorans, and Pediococcus acidilactici were present in remission, but not during active inflammation.[39] Bacteria of the Clostridiales group were more prominent in samples from the inflamed colon, indicating that these bacteria might accumulate during colitis.[40] Recent evidence found that there is an interaction between the human commensal microbiota and the host as an important factor in the development of the diseases. The most prevalent observation is a reduction in the diversity of Firmicutes in CD patients, with reduced numbers of specific members of the microbiota, mostly within the Clostridium leptum(Clostridium cluster IV) group.[41],[42] There have also been reports of an imbalance (dysbiosis) between beneficial and detrimental bacteria in the intestinal microbiota that is correlated to the CD.[41],[43] In UC, mucosal permeability increases and the inflammatory reaction is caused by the excessive reaction below the lymphoid tissue.[44] Patients with UC demonstrated reduced bacterial diversity with an increase in Proteobacteria, Bacteroides, and Clostridiales species along with a decrease in Firmicutes to Bacteroides ratio.[45]

 Allergy and Asthma



Allergy is more prevalent in a developed country or in an urban area where there is more hygiene. The hygiene hypothesis emphasizes the importance of the microbial composition that establishes in newborn infants[46] The microbial diversity has been found to be significantly lower in infants with atopic disease compared to non-atopic disease[47] The “microflora hypothesis,” initially put forth by Noverr and Huffnagle, suggests that perturbations in the GI microbiota as a result of reduced microbial exposure due to changes in diet and antibiotic use result in an underdeveloped microbiota which delays proper maturation of the immune system, disrupting the normal sequence of events that promote the development of immunological tolerance, increasing the incidence of allergic hypersensitivity.[48] Studies have revealed that there is a correlation between the reduction of certain groups of microbes in the gut and allergy. Children with eczema were found to harbour a more diverse total microbiota. A higher abundance of the Clostridium cluster XIVa bacteria was observed in infants with eczema than in healthy controls.[49] The Koala Birth Cohort Study in the Netherlands found that the differences in the gut microbiota composition precede the manifestation of atopic symptoms and atopic sensitization in which Clostridium difficile was associated with all atopic symptoms and sensitization, whereas Escherichia coli appeared to be only associated with (non-atopic) eczema.[50]

Colorectal cancer

Cancer which develops in the colon or rectum is called colorectal cancer (CRC). CRC is the third most common cancer and the fourth leading cause of cancer deaths worldwide, accounting for approximately 1.2 million new cases and 600,000 deaths per year.[51] The role of gut microbiota in the development of CRC is not clear properly; however, many studies have reported that gut microbiota may play a critical role in the development of colon cancer. Gut microbiota can promote the development and progression of CRC by different processes, including the induction of a chronic inflammatory state or immune response, altering stem cell dynamics, the biosynthesis of toxic and genotoxic metabolites, and affecting the host metabolism.[52],[53] Emerging evidence has indicated that these microbes may induce inflammation, facilitate cell proliferation, and provide a microenvironment for host cells to alter stem cell dynamics and produce metabolites that affect glycolysis or immune response.[52] A pathological imbalance in the microbial community has been observed in subjects with adenomas compared with normal controls.[54],[55] Zackular et al., 2013 observed that gut flora from tumor-bearing mice promotes inflammation and tumorigenesis in recipient animals, thus directly contributing to CRC.[56] Mucosa-associated E. coli belonging to the B2 phylogroup is found to be more prevalent in CRC tissues and is identified to encode cyclomodulin which is vital for colon epithelial cells mutation.[57] It was found that Bacteroides fragilis, Enterococcus, Escherichia, Shigella, Klebsiella, Streptococcus, and Peptostreptococcus display a higher relative abundance in CRC patients, while Roseburia- and Lachnospiraceae-related operational taxonomic units (OTUs) dominate with a high load in the healthy controls.[58] A significant increase in Bacteroides massiliensis, Bacteroides ovatus, Bacteroides vulgatus, and E. coli has also been observed from advanced adenoma to carcinoma.[59]

 Type 2 Diabetes Mellitus



Recent decades have witnessed an increase in the prevalence of type 2 diabetes (T2D) in the world. According to recent estimates by the International Diabetes Federation, there are 382 million people living with diabetes worldwide, and the number is expected to rise to 592 million by 2035.[60] Diabetes is a chronic metabolic disorder characterized by the insensitivity of insulin to glucose, thereby causing high blood sugar. Heredity, dietary factors and sedentary lifestyle are some of the main risk factors of T2D mellitus (T2DM). However, recent evidence has indicated that diabetes is caused by the imbalanced gut microbiota in the human body. Ley et al., 2005 analyzed 5088 bacterial 16SrRNA gene sequences from the gut microbiota of obese ob/ob mice and their lean control group and found that ob/ob mice had a 50% decrease in the abundance of Bacteroidetes and a proportional increase in Firmicutes.[61] Sato et al., 2014 showed that stool samples of diabetic patients had significantly reduced levels of the Clostridium coccoides group, Atopobium cluster, and Prevotella and a significantly increased level of total lactobacilli compared with control subjects.[62] Pedersen et al., 2016 recently demonstrated that the human gut microbiome may affect the serum metabolome and induce insulin resistance through species such as Prevotella copri and Bacteroides vulgates.[63] The microbiome of patients with T2DM is characterized by reduced levels of Firmicutes and Clostridia and an increased ratio of Bacteroidetes: Firmicutes; this ratio correlates with plasma glucose concentration.[64]

 Nonalcoholic Fatty Liver Disease



Altered gut microbiota is associated with the pathogenesis of various types of liver diseases. Nonalcoholic fatty liver disease (NAFLD) is a common clinical syndrome of liver disease. NAFLD is the most common chronic liver disease due to the prevalence of obesity worldwide.[65] The liver and the gut communicate bidirectionally through the bile, hormones, digestive metabolite, etc. Hence, the quantity, quality, and composition of the intestinal microbiota can be expected to have both direct and indirect effects on liver function and physiology.[66] Nonalcoholic fatty liver is mostly observed in obese patients rather than in lean patients. Small intestinal bacterial overgrowth (SIBO) is observed in ~17% of obese individuals, compared to only 2.5% of healthy subjects.[67] SIBO has been shown to be a strong predictor of severe hepatic steatosis. Data from animal studies also support the hypothesis that gut bacteria contribute to the pathogenesis of NAFLD by increasing gut luminal ethanol production, metabolizing dietary choline (which is required for very-low-density lipoprotein synthesis and hepatic lipid export), and/or through production of lipopolysaccharide (LPS), which may activate proinflammatory cytokines in luminal epithelial cells, liver macrophages, or both.[68],[69] The gut microbiota is also involved in choline metabolism by converting it into toxic dimethylamine and trimethylamine, which are transported to the liver and converted into trimethylamine oxide that causes liver inflammation and damage.[70]

 Bacteriotherapeutic Intervention for Manipulation of Microbiota



Since time immemForial, the beneficial health effects of fermented food are known to humanity. Cheese and fermented milk were well known to the Greeks and Romans, who recommended their consumption, especially for children and convalescents.[71] The existence of the concept of probiotics took place around 1900 when Nobel Prize-winning Eli Metchnikoff in 1908 at the Pasteur Institute suggested that “the dependence of the intestinal microbes on food makes it possible to adopt measures to modify the flora in our bodies and to replace the harmful microbes by useful microbes.”[72] Probiotics may be defined as good live bacteria which when given in certain adequate amounts exert beneficial health effects to the host by manipulating the microflora of the host. The common probiotic microorganisms belong to the genera of Lactobacillus such as Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus delbrueckii subsp . bulgaricus, Lactobacillus reuteri, Lactobacillus brevis, Lactobacillus fermentum, and Lactobacillus plantarum and genera of Bifidobacteria such as Bifidobacterium infantis, Bifidobacterium longum, Bifidobacterium bifidum, Bifidobacterium adolescentis, and Bifidobacterium animalis. Some species of Saccharomyces and bacillus such as Saccharomyces boulardii and Bacillus coagulans are also used as probiotics. Many studies have showed that prevention or treatment of various diseases is possible by the consumption of probiotics. Probiotics affect the immune system in different ways which include producing cytokines, stimulating macrophages, and increasing secretory IgA concentrations.[73],[74] Probiotics are important in downregulating the inflammation associated with hypersensitivity reactions in patients with atopic eczema.[75],[76] Probiotics have been implicated to be protective against several clinical complications, such as allergy development,[77] IBD,[78] and irritable bowel syndrome.[79] In a clinical trial probiotic preparation (VSL#3) was given to patients with mild-to-moderately active UC (ulcerative colitis) for 8 weeks and found to be effective in inducing remission in patients.[80] In an experimental study, IBS patients (n = 60) were treated with L. plantarum for 4 weeks and decreased pain and flatulence in patients with IBS were recorded and these effects continued for 1 year in which the test group maintained a better overall GI function than control patients.[81] In a study, a probiotic preparation L. plantarum DSM 15313 was fed to high-fat diet (HFD) fed C57BL/6J mice, a model of human obesity and early diabetes for 20 weeks and observe that the group fed probiotics had a significantly lower insulin release compared to the control group which showed the antidiabetic properties of L. plantarum DSM 15313.[82] In another study, NAFLD patients were treated with a probiotic preparation containing a mixture of different species of bacteria with fructooligosaccharides, vitamins, and minerals supplementation for 2 months followed by 1-month washout period; serum levels of the aminotransferases, markers of oxidative stress malondialdehyde and 4-hydroxynonenal (MDA and 4-HNE), and tumor necrosis factor (TNF)-α in the NAFLD patients were found to be reduced.[83] Three years later, the same group published another study in which VSL#3 which is a multispecies probiotic consisting of a combination of eight strains of bacteria had been shown to improve liver function tests and its significant improvement in the serum levels of the lipid peroxidation markers, plasma levels of MDA and 4-HNE, whereas cytokines (TNF-alpha, interleukin-6 [IL-6], and IL-10) improved only in alcoholic liver cirrhosis (AC) patients.[84] In a randomized double-blind clinical trial, L. bulgaricus and Streptococcus thermophilus(500 million CFU/day) given to 28 patients NAFLD (biopsy-proven) for 3 months found that the serum levels of alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase were decreased, and there were no changes in anthropometric parameters and cardiovascular risk factors.[85]

 Conclusion



This review article discusses the delicate symbiotic relationship between gut microbiota and human beings, and then, the therapeutic manipulation of the dysbiosed microbiota using probiotics. It is clear that gut microbes play a crucial role in maintaining human well-being. Recent research in the human microbiome has proved that dysbiosis of gut microbiota leads to various kinds of chronic diseases. Probiotics have been found to be helpful in various chronic diseases caused by the imbalance of microbiota of the human gut. However, more research is necessary to get insightful knowledge of what kind of specific microbes and underlying molecular mechanisms are responsible for a particular disease.

Financial support and sponsorship

Department of Science and Technology, Govt. of India, for providing financial support in the form of a research project (No. SR/WOS-A/LS-196/2018) under the Woman Scientist (WOS-A) scheme.

Conflicts of interest

There are no conflicts of interest.

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