Ibnosina Journal of Medicine and Biomedical Sciences

ORIGINAL ARTICLE
Year
: 2020  |  Volume : 12  |  Issue : 4  |  Page : 264--271

An analysis of gut dysbiosis in obesity, diabetes, and chronic gut conditions


Ahmed Haleem1, Sama Anvari1, Aisha Nazli2, Mohamed Sager3, Mahmood Akhtar4,  
1 BHSc Program, Michael G. DeGroote Centre for Learning and Discovery, McMaster University, Hamilton, Ontario, Canada
2 McMaster Immunology Research Centre, Michael G. DeGroote Centre for Learning and Discovery, McMaster University, Hamilton, Ontario, Canada
3 Research Centre, KKMC, King Fahad Specialist Hospital, Al Muraikbat, Dammam, Saudi Arabia
4 BHSc Program, Michael G. DeGroote Centre for Learning and Discovery, McMaster University, Hamilton, Ontario, Canada; Research Centre, KKMC, King Fahad Specialist Hospital, Al Muraikbat, Dammam, Saudi Arabia

Correspondence Address:
Dr. Mahmood Akhtar
Research Centre, KKMC, King Fahad Specialist Hospital, Ammar Bin Thabit Street, Al Muraikbat, Dammam 32253

Abstract

Introduction: Gut dysbiosis is an imbalance in the microbial communities of the intestine and has been associated with numerous chronic diseases. Objectives: We aimed to compare gut dysbiosis within and across various disease states (Crohn's disease [CD], colorectal cancer [CRC], irritable bowel syndrome [IBS], and type 2 diabetes mellitus [T2DM], and obesity). Materials and Methods: Assessing comparative studies which examined levels of bacterial phyla in cases and controls. PubMed and Web of Science were searched to identify relevant studies, in which human fecal samples were used to analyze microbial flora. Results: Twenty-one studies were included, which met inclusion and exclusion criteria. Three studies were included assessing IBS, which found a decrease in Bacteroidetes in the IBS population, but inconsistent findings for other phyla. Six studies were included assessing obesity, and no consistent patterns emerged. Five studies were included examining T2DM, which found a consistent decrease in the Firmicutes/Bacteroidetes ratio in cases as compared to controls. No patterns were found for other phyla. Three studies were included examining CD, and five examining CRC. Conclusions: No consistent patterns were found for either of these diseases. While some patterns were found in bacterial phyla distribution, there were few commonalities, even in same-system disorders. However, uncovering underlying dysbiosis patterns shows great promise in furthering the understanding of disease pathogenesis and the potential for new therapeutic and diagnostic interventions. Further systematic reviews and well-controlled studies are warranted.



How to cite this article:
Haleem A, Anvari S, Nazli A, Sager M, Akhtar M. An analysis of gut dysbiosis in obesity, diabetes, and chronic gut conditions.Ibnosina J Med Biomed Sci 2020;12:264-271


How to cite this URL:
Haleem A, Anvari S, Nazli A, Sager M, Akhtar M. An analysis of gut dysbiosis in obesity, diabetes, and chronic gut conditions. Ibnosina J Med Biomed Sci [serial online] 2020 [cited 2021 Jan 25 ];12:264-271
Available from: http://www.ijmbs.org/text.asp?2020/12/4/264/299526


Full Text



 Introduction



The gastrointestinal (GI) tract, home to a diverse ecosystem of over one hundred trillion bacteria, viruses, fungi, and archaea, is the most colonized organ of the human body.[1] The gut microbiome, consisting of all microbes inhabiting the intestines, has been well characterized in recent years. Improved sequencing methods such as 16S rRNA gene-based approaches and analytic techniques have revealed a complex and diverse array of microbial functions related to human health, as well as tremendous interindividual and intraindividual variations in the composition of the gut microbiome.[2] This makes it difficult to precisely define a “healthy” microbiome. Indeed, the richness and diversity of the microbiome, as opposed to the presence or absence of particular species, has been associated with better overall health.[3],[4],[5] Despite this variability, the gut microbiome has been consistently demonstrated to serve a variety of important developmental and physiological functions, including defense against pathogenic colonization, immune regulation, maintenance of epithelial barrier integrity, and metabolism.[1]

Given the importance of the intestinal microbiome to human health, dysbiosis – a deviation in microbial composition from a healthy state – has been associated with a variety of diseases, including Crohn's disease (CD), irritable bowel syndrome (IBS), type 2 diabetes mellitus (T2DM), obesity, colorectal cancer (CRC), and many others. However, it remains unclear whether dysbiosis plays a causal role in disease pathogenesis or results from it. As such, this relationship has been a recent focus of research attempting to better understand factors related to disease development and progression.

Context

Dysbiosis and Crohn's disease

CD is a type of inflammatory bowel disease that can cause chronic and relapsing inflammation anywhere in the GI tract. Although the etiology of CD is likely a complex and multifactorial combination of genetic and environmental factors, intestinal dysbiosis has been linked to its pathogenesis.[5] Specifically, a dysregulated response to commensal gut microbes is believed to contribute to the proinflammatory state of Crohn's GI tract.[5] Several studies have reported decreased microbial diversity in CD patients compared to healthy controls, particularly within the Firmicutes.[5],[6],[7] Frank et al. also noted decreased abundance of Firmicutes and Bacteroidetes compared to controls.[8] However, research investigating a potential causal role for dysbiosis in CD has been inconclusive, and no clear pathogenetic mechanism related to the microbiome has been elucidated.[3]

Dysbiosis and irritable bowel syndrome

IBS is a common functional intestinal disorder characterized by recurring bouts of abdominal pain or discomfort, as well as changes in stool form and frequency.[9] While the etiology of IBS remains largely unknown, the gut microbiome has recently been proposed to play a pathogenic role.[10] This has been supported by studies documenting symptomatic relief of IBS following antimicrobial treatments such as antibiotics.[9] Studies of the fecal microbiome of IBS patients have also shown it to be significantly different to that of healthy controls, with studies reporting decreases in Bacteroidetes and Actinobacteria, as well as increases in Firmicutes and Proteobacteria compared to controls.[11] However, while an association between intestinal dysbiosis and IBS has been demonstrated, associated compositional changes have not been consistently characterized.

Dysbiosis and type 2 diabetes mellitus

T2DM is a metabolic disorder characterized by insulin resistance and associated with obesity. Recent advances concerning the role of the gut microbiome in metabolism and control of body weight, particularly related to obesity, have implicated intestinal microbial dysregulation as a potential etiological factor for T2DM. Dysbiosis leading to increased intestinal monosaccharide uptake has been associated with the development of insulin resistance [12] and an increased ratio of Bacteroidetes to Firmicutes has been significantly correlated to reduced glucose tolerance.[13] Furthermore, studies have linked increased amounts Bacteroidetes and Proteobacteria to lipopolysaccharide-induced endotoxemia [14] which is involved in the development of T2DM.[15] A clear association between T2DM and the intestinal microbiome has been demonstrated [13] but more research is necessary to determine the exact nature of this relationship.

Dysbiosis and obesity

Obesity is now considered a global health epidemic by the World Health Organization, affecting >500 million people worldwide.[3] Dysbiosis has been implicated in the development of obesity, particularly due to the role of the intestinal microbiome in metabolism. Studies conducted in obese mice [16] and humans [17] have demonstrated increases in Firmicutes and proportionate decreases in Bacteroidetes; increases in Bacteroidetes were also associated with weight loss.[17] While an increased Firmicutes/Bacteroidetes ratio has been associated with obesity by Ley et al. [16],[17] others, such as Duncan et al.,[18] reported contradictory findings. However, rodent studies have induced weight gain through the transfer of feces from genetically obese (ob/ob) mice,[19] demonstrating a clear role for the composition of the gut microbiome in obesity.

Dysbiosis and colorectal cancer

CRC is a highly common form of cancer that causes approximately 500,000 deaths worldwide every year [20] and has been linked to intestinal dysbiosis. Diet, particularly consumption of foods high in saturated fat such as red and processed meat, has been identified as a significant risk factor [21] for the development of CRC. Diet has also been demonstrated to affect the composition of the gut microbiome, leading to shifts that could potentially influence CRC risk.[22] Shifts in microbial composition associated with the aging process have also been implicated in CRC pathogenesis; older age is associated with reduced numbers of anti-inflammatory bacteria such as F. prausnitzii and Roseburia intestinalis that are protective against CRC.[23]

With the recent development of metagenomic sequencing technologies, the specific compositions of the gut microbiome in both healthy and pathological states have been characterized. However, although the nature of dysbiosis within several diseases has been previously characterized, few studies have directly compared changes in microbial composition across several disease states. As such, the purpose of this study was to compare and contrast the intestinal microbial composition in various disease states to determine whether there were any dysbiosis patterns associated with particular pathological states.

 Materials and Methods



This is a narrative review of the literature and comparative analysis. PubMed and Web of Science were searched, using keywords/search phrases such as “bacterial composition (disease),” “microbiome composition (disease),” “gut microbiome (disease)” etc., Inclusion criteria were as follows: (1) conducted in humans, (2) determined bacterial composition from fecal samples, and (3) reported percentage compositions of bacterial phyla. Exclusion criteria were as follows: (1) Use of mucosal biopsies, (2) studies lacking a control group, and (3) pediatric studies. Studies using mucosal biopsies to determine microbial composition were excluded as variability in the biopsy source makes comparisons difficult due to differences in bacterial composition throughout the GI tract.[4] Pediatric studies were excluded due to the potential for differences in bacterial composition related to age as opposed to the disease state.[4] Bacterial compositions were noted and described in terms of phyla, and if genera were reported, percentages were converted to phyla.

 Results



After applying the inclusion/exclusion criteria, 21 studies were ultimately included in the final analysis. Key characteristics of each included study, including findings, are summarized in [Table 1], [Table 2], [Table 3], [Table 4] and appraised below.{Table 1}{Table 2}{Table 3}{Table 4}

Changes within disease states

Obesity

Six studies were included investigating changes in fecal microbiota in obesity.[24],[25],[26],[27],[28],[29] Schwiertz et al.[25] found a significant decrease in Firmicutes in obese patients. Regarding Bacteroidetes, three studies found a decrease in obese patients [24],[26],[28] and Schwiertz et al.[25] found an increase. Actinobacteria were found to be increased in the obese population by Turnbaugh et al.[24] [Table 1].

Type 2 diabetes mellitus

Five studies were included which investigated fecal microbiota changes in T2DM.[29],[30],[31],[32],[33] Regarding Firmicutes, Larsen et al.[30] found a decrease in T2DM cases, whereas Sedighi et al.[32] found an increase. Sedighi et al.[32] was the only study to report for Actinobacteria for which they found a decrease in T2DM cases. Wu et al.[31] did not report statistical significance for bacterial abundances, making their results difficult to interpret. All studies had a reduced F/B ratio in cases as compared to controls, but statistical significance was not always available [Table 1].

Irritable bowel syndrome

Three studies were included investigating fecal microbiota changes in patients with IBS.[34],[35],[36] Bacteroidetes were found to be significantly decreased in the IBS population by Jalanka-Tuovinen et al.[36] and Rajilic-Stojanovic et al.[35] Jalanka-Tuovinen et al.[36] found also found a significant decrease in Actinobacteria in the IBS population, which was not reported by other studies [Table 2].

Colorectal cancer

Five studies reported changes to bacterial composition in CRC.[37],[38],[39],[40],[41] Regarding Bacteroidetes, Wang et al.[37] found a decrease in the CRC population, whereas Zeller et al.[40] found an increase. Firmicutes were found to be increased in the CRC population by Zeller et al.[40] and Allali et al.[39] Proteobacteria were found to be increased in the CRC population by Allali et al.[39] and Wang et al.,[37] while Zeller et al.[40] found a reduction in Proteobacteria [Table 3].

Crohn's disease

Three studies were included which investigated bacterial changes in CD.[42],[43],[44] Two of these studies did not report statistical significance at the phylum level,[42],[43] and Wills et al. did not find any differences in the abundance of bacteria between remission and exacerbation [44] [Table 4].

Changes across disease states

Decreases in Firmicutes were noted in studies of CD, and one study in obesity. However, while there were no opposing results found for these diseases, other studies did not find any statistically significant changes in Firmicutes, making these findings very uncertain. While some studies reported concordant increases or decreases in various phyla, no consistent pattern of dysbiosis emerged across the various disease states.

 Discussion



We did not find highly consistent changes in the microbial composition of the intestine within or between disease states. While some studies within diseases were concordant for increases or decreases within a phylum, the magnitude of changes often differed, and no two studies reported the same changes in all phyla. As such, while some shifts in the microbial composition may recur within studies of a particular disorder, there do not seem to be common dysbiosis changes between diseases. However, this variability may be accounted for when considering the heterogeneity of included studies, as well as variations in the characteristics and environmental exposures of study participants.

Diet has been shown to modify the composition of the gut microbiome in several studies [22],[45] with some demonstrating differences at the phylum level between those consuming a typical Western diet compared to one based primarily on plant carbohydrates.[45] Included studies were conducted in a variety of Eastern (e.g., China, Japan, Taiwan) and Western (USA, Spain, Germany, Denmark, Finland) countries, such that different dietary habits may have affected the type of dysbiosis present in a particular disease state. For example, the three studies investigating intestinal dysbiosis in IBS were conducted in China, Finland, and England such that differences in dietary habits and the associated modifications to the microbiome composition could have potentially confounded any changes related to IBS, or influenced the response of the microbiome to a particular disease state. In fact, examining only the studies by Jalanka-Tuovinen et al.[36] and Rajilic-Stojanovic et al.[35] (England and Finland, respectively) shows concordant findings for Firmicutes and Bacteroidetes, while Chung et al.[34] (China) found no statistically significant changes for any phyla. Indeed, Duncan et al. noted that discrepancies in the findings between various studies may be due to host physiology or dietary habits [18] making the determination of true dysbiosis patterns more difficult if they do exist. Schwiertz et al.,[25] who found a decrease in the F/B ratio that contradicted our other included studies [24],[26] as well as previous findings,[16],[17] also noted that uncontrolled dietary and lifestyle factors such as exercise habits or body mass index (BMI) (in studies unrelated to obesity/T2DM) could potentially limit the conclusions drawn from studies undertaken with unrestricted human volunteers.

Age is another factor that could potentially be associated with the variations in microbial compositions. While it has been proposed that the adult gut microbiome remains relatively stable between the ages of 30 and 70,[46] the proportion of Firmicutes tends to decrease. Furthermore, the elderly tend to have more variable intestinal microbiomes than younger individuals.[46] In the included study by Kasai et al.,[26] cases were significantly older than controls (P = 0.001), such that shifts in the microbiome due to aging could have confounded any compositional changes. Furthermore, several included studies [25],[30],[35],[37],[42] reported using participants of various ages, potentially leading to variation in bacterial compositions among cases and controls that is unrelated to the disease state.

Differences in disease severity or other comorbidities between studies could also potentially account for some of the variation in microbial composition. For example, Kasai et al.[26] used BMI ≥25 as their benchmark for obesity, whereas most literature considers obesity to be defined as a BMI ≥0.30. Furthermore, they report that only one of their participants had BMI ≥30, which could account for some of the discrepancies noted in their data compared to the others. However, while many studies have found differences in the gut microbial compositions of obese compared to lean participants,[13] it is notable that Schwiertz et al.[25] did not find significant differences in the microbiome compositions of obese and overweight (BMI 25–30) participants. As such, the effect of differing degrees of obesity in included studies is unclear. However, patient BMI is another factor that could affect reported findings. Larsen et al.[30] for example, included both cases and controls with a range of BMIs in their study, with average BMIs of 30 and 28, respectively. While obesity and T2DM are closely related,[47] the degree of obesity could affect compositions reported between studies. Furthermore, 3 of the studies investigating CRC [37],[40],[41] included patients with Stages I-IV and Wang et al.[38] included patients with stages II-IV; however, none of them investigated the effect of disease severity on microbiome composition. While different bacteria may be related to different aspects of cancer progression, it is still unclear how this may change or whether intestinal dysbiosis is a cause or effect of CRC.

Characterizing dysbiosis in various disease states is of both diagnostic and therapeutic importance. Attempts have been made to use the microbiome as a potential biomarker of disease,[19] and a better understanding of the relationship between microbiota and disease may be used to develop targeted treatments.[48],[49] However, the inconsistency of our present findings suggests that compositional changes are variable between diseases, potentially due to factors unrelated to disease states such as participant characteristics, environmental exposures, and lifestyle factors.

To the best of our knowledge, this is the first attempt of comparing changes in the composition of the gut microbiome across multiple disease states. However, it has several limitations. Only 21 studies were included across five disease states in this small, exploratory review; as this was not a systematic review, our findings may be subject to selection bias. Moreover, the included studies were variable and may have been subject to issues of internal validity such as uncontrolled confounders or comorbidities and inadequate study populations, as well as different methods of sequencing and data analysis that limit their potential for comparison. Furthermore, we looked exclusively at stool specimens, which have been shown to differ from mucosal-associated microbiota,[50] as well as the microbiome of more proximal regions in the GI tract.[4] As such, it is possible that patterns of compositional changes in the investigated diseases may not be reflected by the microbes present in collected specimens. Therefore, the findings of this review warrant further exploration into microbiome compositional differences in various disease states in proximal GI regions as well as in mucosal-associated microbiota, and exploration of any associations which may exist between these different sampling methods. This work also highlights the limitations associated with studies determining microbiome composition in uncontrolled human population-future studies should attempt to control for variables such as diet, age, and lifestyle as possible.

 Conclusions



The composition of the gut microbiome in CD, obesity, T2DM, IBS, and CRS as compared to healthy controls, suggests that common changes to bacterial genera in these chronic disorders do not exist. However, uncovering patterns of dysbiosis associated with disease state highlighted the promising implications for better understanding their pathogenesis, as well as the potential for novel diagnostic and therapeutic interventions.

Authors' contributions

The authors were assigned specific sections to draft, these were developed into a single manuscript which was reviewed and approved by all authors. First and second authors made equal contributions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Compliance with ethical principles

Not applicable. None of the authors reported human or animal studies.

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