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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Sprache: Englisch
The Gut Microbiota in Health and Disease An accessible overview of the varied microorganisms of the gut The human gut contains an extraordinary array of microorganisms existing in intricate symbiosis with the body. The gut microbiota plays a crucial role in maintaining overall gut health and warding off disease. With up to 15% of the global population suffering from Irritable Bowel Syndrome (IBS) caused by improper composition of gut microbiota, understanding these organisms and their vital contribution to human health has never been more important. The Gut Microbiota in Health and Disease provides a concise, accessible introduction to gut microbiota and their contribution to human health. It offers not only an overview of the relevant microorganisms and their roles in the body, but also extended discussion of diseases caused by gut dysbiosis. It presents a crucial window into this growing body of research into a critical area of overall human health. The Gut Microbiota in Health and Disease, readers will also find: * Detailed analysis of dysbiotic health conditions including obesity, diabetes, and more * Thorough treatment of molecular techniques for the analysis gut microbial composition * Discussion of the lowering diversity of bacteria in the gut and the corresponding impact on global health The Gut Microbiota in Health and Disease is essential for researchers and clinicians working in immunology, gastroenterology, clinical microbiology, and related fields, as well as for clinical dieticians and postgraduate or medical students studying in these areas.
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The Gut Microbiota in Health and Disease
Edited by
Nimmy Srivastava
Amity University Jharkhand, India
Salam A. Ibrahim
North Carolina Agricultural & Technical State University, USA
Jayeeta Chattopadhyay
Amity University Jharkhand, India
Mohamed H. Arbab
Omdurman Ahlia University, Sudan
This edition first published 2023
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Contents
Cover
Title Page
Copyright Page
List of Contributors
1 Structural and Dynamics of Healthy Adult’s Microbiota
1.1 Introduction
References
2 Composition and Diversity of Gut Microbiota
2.1 Introduction
2.2 Composition and Diversity of Gut Microbiota Throughout Lifespan
2.3 Composition of Bacterial Community in the Different Sections of the Gastrointestinal Tract
2.4 Stability, Resilience, and Functional Redundancy
2.5 Interactions in the Gut Microbiota
2.5.1 Microbe–microbe Interactions
2.5.2 Host–microbe Interactions
2.5.3 Colonisation of the Gut Microbiota
2.6 Conclusion
References
3 Factors Affecting Composition and Diversity of Gut Microbiota: A Disease Hallmark
3.1 Introduction
3.2 Composition of Gut Microbiota
3.2.1 Gut Microbiota of Infants and Newborns
3.2.2 Gut Microbiota of Adults
3.3 Factors Affecting Gut Microbiota
3.3.1 Age and Delivery Pattern
3.3.2 Diet
3.3.3 Antibiotics
3.3.4 Oxidative Stress
3.4 Modulation of Gut Microbiota
3.4.1 Probiotics and Prebiotics
3.5 Gut Microbiota Hallmark in Disease Condition
3.5.1 Cancer
3.5.2 COVID-19
3.5.3 HIV
3.6 Conclusion
References
4 Antibiotic-Induced Changes in the Composition of the Gut Microbiome
4.1 Introduction
4.2 Gut Microbiota Composition
4.3 Antibiotic-induced Changes in the Composition of the Microbiota
4.3.1 Loss of Bacterial Diversity and Domination of Pathogenic Bacteria
4.3.2 Decrease or Loss of Certain Bacterial Species
4.3.3 Increase in Susceptibility to Infections and Diseases
4.4 Conclusion
References
5 Dysbiosis and its Varied Impacts
5.1 Introduction
5.2 Causes of Dysbiosis
5.3 Dysbiosis, Immune System, and Associated Diseases
5.3.1 Dysbiosis in the Immune-Compromised Host
5.3.2 Intestinal Bowel Disease (IBD)
5.3.3 Rheumatoid Arthritis
5.3.4 Type 1 Diabetes
5.3.5 Dysbiosis of Skin Microbiome in Carcinogenesis
5.3.6 Dysbiosis of Oral Microbiota Impacts Carcinogenesis
5.3.7 Dysbiosis of Urobiome
5.3.8 Pigmented Gallstone
5.3.9 Cholangitis
5.4 Intestinal Colonisation in Neonates and Dysbiosis
5.5 Treatment or Therapeutics
5.6 Conclusion
References
6 Connection between Dysbiosis and Diet
6.1 Introduction
6.1.1 Gut Microbiota and Dysbiosis
6.1.2 Importance of Diet in regulation of Gut Microbiota
6.2 Different Dietary Patterns Resulting in Dysbiosis
6.2.1 Breastfeeding
6.2.2 Carbohydrate-rich Diet
6.2.3 Protein-rich Diet
6.2.4 Fats and Oil-rich Diet
6.3 Future Prospects in Establishing a Healthy Connection between Diet and Gut Microbiota
6.4 Conclusion
References
7 Composition of Gut Microbiota and Clostridium difficile
7.1 Introduction
References
8 Gut Microbiota and Obesity
8.1 Introduction
8.2 Obesity Epidemic: Statistics and General Background
8.3 Gut Microbiota and Obesity
8.4 Adiposity and Gut Microbiota
8.4.1 Short Chain Fatty Acids (SCFAs)
8.4.2 AMPK and FIAF
8.4.3 Bile Acids
8.4.4 Lipopolysaccharides (LPS)
8.5 Gut Microbiota Modification
8.5.1 Diet
8.5.2 Age
8.5.3 Antibiotics
8.5.4 Probiotics
8.6 The Microbiota and Obesity Interactions
8.6.1 Immune System
8.6.2 Lipid Metabolism
8.6.3 Satiety Hormones
8.6.4 Nutrient Metabolism
8.6.5 Lymphoid Structures
8.6.6 Microbiota–Adipose Tissue Axis
References
9 Gut Microbiota and Cardiovascular Disease
9.1 Introduction
9.2 Gut Microbiota and CVD
9.2.1 Role of TMAO in Coronary Heart Disease
9.3 Gut Microbiota Composition in Cardiovascular Disease
9.4 Gut Microbiota Function in Cardiovascular Disease
9.5 Gut Microbiota as Therapeutic Strategies for Cardiovascular Disease
9.5.1 Probiotics
9.5.2 Fecal Microbiota Transplantation
References
10 Gut Microbiota and Inflammatory Bowel Diseases
10.1 Introduction
10.2 Intestinal Microbiome in IBD Patients
10.2.1 Dysbiosis in IBD
10.2.2 Genetic Factors of the Host Affecting the Pathogenesis of IBD
10.2.3 Environmental Factors in the Disruption of Gut Microbiota and Development of IBD
10.3 Interventions for the Treatment of IBD
10.3.1 Microbiome-modulating Approach in the Treatment of IBD
10.4 Conclusion
References
11 Gut Microbiota and Diabetes
11.1 Introduction
11.2 Gut Microbiota
11.3 Role of Gut Microbiota in Diabetes
11.4 Alteration in Gut Microbiota Composition in T1 and T2 Diabetes
11.4.1 T1D
11.4.2 Type 2 Diabetes
11.5 Diabetic Complications
11.5.1 Diabetic Retinopathy
11.5.2 Diabetic Nephropathy
11.5.3 Diabetic Neuropathy
11.6 Therapeutic Approaches
11.7 Conclusion
References
12 Novel Therapeutic Strategies Targeting Gut Microbiota to Treat Diseases
12.1 Introduction
12.2 Changes in the Composition of the Gut Microbiota in Patients with T1D
12.3 The Potential Role of the Gut Microbiota in the Development of T1D
12.4 Changes in the Composition of the Gut Microbiota in Patients with T2D
12.5 The Potential Role of the Gut Microbiota in the Development of T2D
12.7 Preventive and Therapeutic Perspectives Including the Gut Microbiota
References
13 Understanding the Role of Microbiota in Cancer
13.1 Introduction
13.2 Role of Microbiota in Cancers
13.2.1 Gastric Cancer
13.2.2 Colorectal Cancer
13.2.3 Liver Cancer
13.2.4 Pancreatic Cancer
13.3 Mechanism in which Microbiota Kill Cancer Cells
13.4 Microbiota that Promote Health Post Cancer Treatment
13.5 Conclusion
References
14 Impact of Gut Microbiota on Mental Health in Humans
14.1 Introduction
14.1.1 Importance of Gut Microbiota
14.1.2 The Microbiota–Gut–Brain Axis
14.2 Gut Dysbiosis and Mental Health Disorders
14.2.1 Neurodevelopmental Disorders
14.2.2 Mood Disorders
14.2.3 Depression Disorders
14.2.4 Alcohol Use Disorder (AUD)
14.3 Psychiatric Medication and the Microbiome
14.4 Probiotic Treatments for Mental Health Disorders
14.5 Future Therapeutic Approach
14.6 Conclusion
References
15 Interaction between Gut Microbiota and Central and Enteric Nervous Systems: The Gut–Brain Axis Concept
15.1 Introduction
15.2 The Neuronal Communications
15.3 Neuroimmune Regulation of Inflammation and Cellular Defence
15.3.1 Involvement of Microbiota in the Development of the Nervous and Immune Systems and Modulation of Inflammation
15.3.2 The Importance of Microbiota for the Development of the Nervous and Immune Systems
References
16 Immune-Modulation and Gut Microbiome
16.1 Introduction
16.2 Dysbiosis of the Gut Microbiome
16.3 Gut Dysbiosis and Diseases
16.3.1 Inflammatory Bowel Disease
16.3.2 Non-alcoholic Fatty Liver Disease
16.4 Gut Microbiome-Mediated Immune Modulation
16.4.1 Innate Immunity
16.4.2 Adaptive Immunity
16.5 Gut Microbiome Modulators
16.5.1 Diet
16.5.2 Diet, Gut Microbiome, and Immunity
16.5.3 Short-Chain Fatty Acids
16.6 Prebiotics
16.7 Probiotics
16.8 Galectins, Gut Microbiome, and Immune Modulation
16.9 Conclusion
References
17 Current Molecular Technologies for Assaying the Gut Microbiota: Next-generation DNA Sequencing
17.1 Introduction and Overview
17.2 Research on the Gut Microbiome Using Next-generation Sequencing
17.2.1 Amplicon Sequencing
17.2.2 Shotgun Metagenomic and RNA Sequencing
17.2.3 Comparisons between NGS Methods
17.3 Collection, Storage, and DNA Extraction Methodology
17.3.1 Sample Collection and Storage
17.3.2 DNA Extraction and Quantification
17.4 DNA Sequencing and Post-processing
17.5 Metabolic Modelling of the Human Gut Microbiome
References
18 The Role of Probiotics and Prebiotics in Gut Modulation
18.1 Introduction
18.2 Probiotics and Prebiotics: A Functional Perspective
18.3 Diet and its Effect on Gut Microbiota
18.4 Modification of Intestinal Microbiota by the Application of Probiotics and Prebiotics
18.4.1 Dysbiosis and Human Diseases
18.4.2 How Probiotics Alter the Intestinal Microbiota
18.4.3 Probiotics and Intestinal Immunomodulation
18.4.4 Probiotics and Prebiotics on Intestinal Neuroimmunology
18.5 Prebiotics and Gut Immunity
18.5.1 Effects (Direct and Indirect) of Prebiotics on the Immune System
18.6 Conclusions and Future Research
References
19 Probiotics, Prebiotics, and Synbiotics: A Potential Source for a Healthy Gut
19.1 Introduction
19.2 Prebiotics
19.2.1 Types of Prebiotics
19.2.2 Functioning of Prebiotics
19.3 Probiotics
19.3.1 Characteristics of Probiotics
19.3.2 Mechanisms of Action of Probiotic Strains
19.3.3 Applications of Probiotics
19.4 Synbiotics
19.4.1 Selection Criteria
19.4.2 Mechanism of Action
19.4.3 Therapeutic Actions
19.5 Conclusion
References
20 Current Status and Efficacy of Fecal Microbiota Transplantation for Patients Suffering from Irritable Bowel Syndrome
20.1 Introduction
20.2 Donor Selection
20.3 Safety Issues of FMT for IBS
20.4 Possible Mechanisms Underlying the Effects of FMT
20.5 Conclusion and Perspective
References
Index
End User License Agreement
List of Tables
CHAPTER 02
Table 2.1 Composition and diversity...
CHAPTER 03
Table 3.1 Different classes of...
Table 3.2 WHO reporting ten pathogens...
Table 3.3 Anti-GI drugs involved...
CHAPTER 04
Table 4.1 Microbiota variation...
CHAPTER 05
Table 5.1 Some common microbiomes...
Table 5.2 Role of the probiotic for...
CHAPTER 06
Table 6.1 Role of different dietary...
Table 6.2 Breastfeeding and gut microbiota.
Table 6.3 Metabolic disorders...
CHAPTER 08
Table 8.1 Primary and secondary...
CHAPTER 10
Table 10.1 Gut microbiota variation...
Table 10.2 Traditional interventions...
CHAPTER 11
Table 11.1 Changes in the concentration...
Table 11.2 Changes in the concentration...
CHAPTER 14
Table 14.1 Gut microbiome studies...
Table 14.2 Enlisted probiotic strains...
CHAPTER 16
Table 16.1 Selected gut-microbiome...
Table 16.2 Gut microbiome modulators, effect...
CHAPTER 17
Table 17.1 Comparisons of popular...
CHAPTER 19
Table 19.1 Properties of ideal prebiotics.
Table 19.2 Examples of probiotics...
List of Illustrations
CHAPTER 02
Figure 2.1 Host–microbe interactions...
CHAPTER 03
Figure 3.1 Consequences of various factors...
CHAPTER 04
Figure 4.1 Taxonomic classification...
Figure 4.2 Overall consequences after...
Figure 4.3 The interplay of gut immunity...
Figure 4.4 Diseases in multiple organs...
CHAPTER 05
Figure 5.1 Impact of dysbiosis...
CHAPTER 06
Figure 6.1 Comparative analysis on...
Figure 6.2 Breast feeding and its...
CHAPTER 08
Figure 8.1 Obesity and dysbiosis...
CHAPTER 09
Figure 9.1 Cholesterol, gut microbiota...
CHAPTER 10
Figure 10.1 Complications in CD and UC.
Figure 10.2 The dynamic nature and...
CHAPTER 11
Figure 11.1 Disruption of the gut barrier...
Figure 11.2 Increase in butyrate-producing...
Figure 11.3 Diabetes mellitus is associated...
CHAPTER 12
Figure 12.1 The possible influence of dysbiosis...
Figure 12.2 The possible influence of dysbiosis...
CHAPTER 14
Figure 14.1 Importance of gut microbiota...
Figure 14.2 Experimental evidence showing...
Figure 14.3 Comparative illustration of healthy...
CHAPTER 16
Figure 16.1 A schematic of the gut...
CHAPTER 17
Figure 17.1 Outlines of the genome-centric...
Figure 17.2 A summary of a metagenomics...
Figure 17.3 Overview of different NGS...
CHAPTER 18
Figure 18.1 Sources and benefits of both...
Figure 18.2 Morphological structure...
CHAPTER 19
Figure 19.1 Types of probiotics.
Figure 19.2 Application of probiotics...
Guide
Cover
Title Page
Copyright Page
Table of Contents
List of Contributors
Begin Reading
Index
End User License Agreement
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List of Contributors
Mahdi Hussein AbdelrazigOmdurman Ahlia UniversitySudan
Gholamreza AbdiPersian Gulf InstitutePersian Gulf UniversityBushehrIran
Sarah Adjei-FremahWinston-Salem State UniversityWinston-SalemNorth CarolinaUSA
Israrahmed AdurVellore Institute of TechnologyTamil NaduIndia
Nahid AkhtarLovely Professional UniversityPhagwaraPunjab, India
Muhammad AltafThe Islamia University of BahawalpurPakistan
Mohamed Hussein ArbabOmdurman Ahlia UniversitySudan
Usman AtiqueChungan National UniversitySouth Korea
Aparajita BagchiVellore Institute of TechnologyTamil NaduIndia
Jutishna BoraAmity University JharkhandRanchiJharkhandIndia
Shuvam ChakrabortyVellore Institute of TechnologyTamil NaduIndia
Shahana ChowdhuryDepartment of BiotechnologyGerman UniversityBangladesh
Inderpal DevgonLovely Professional UniversityPhagwaraPunjabIndia
Ankita DeyNorth Eastern Hill UniversityShillongMeghalayaIndia
Rohan DuttaVellore Institute of TechnologyTamil NaduIndia
Sumitha ElayaperumalJSS Academy of Higher Education and ResearchMysoreKarnatakaIndia
Shakira GhazanfarPakistan Agricultural Research CouncilIslamabadPakistan
Md. Ayenuddin HaqueBangladesh Fisheries Research InstituteBangladesh
Richismita HazraAmity University KolkataWest BengalIndia
Salam IbrahimNorth Carolina Agricultural andTechnical State UniversitGreensboroNorth CarolinaUSA
Anu JacobKarunya Institute of Technology and ScienceCoimbatoreIndia
Vishal JoharLovely Professional UniversityPhagwaraPunjabIndia
Parneet KaurShoolini University of Biotechnology and Management SciencesSolanIndia
KhushbooLovely Professional UniversityPhagwaraPunjabIndia
Saurabh KulshreshthaShoolini University of Biotechnology and Management SciencesSolanIndia
Kunal KumarAmity Institute of BiotechnologyAmity University JharkhandRanchiIndia
Jissin MathewKarunya Institute of Technology and ScienceCoimbatoreIndia
Tahir ul Gani MirLovely Professional UniversityPhagwaraPunjabIndia
Hriiziini MonicaNorth Eastern Hill UniversityShillong, MeghalayaIndia
Sagnik NagVellore Institute of TechnologyTamil NaduIndia
Shaimaa H. NegmPort Said UniversityPort Fouad CityEgypt
Jessica PandoheeTelethon Kids InstituteNedlandsWestern AustraliaAustralia
Ajit PrakashUniversity of North CarolinaChapel HillNorth CarolinaUSA
Ridashisha RymbaiNorth Eastern Hill UniversityShillong, MeghalayaIndia
Rohan Samir Kumar SachanLovely Professional UniversityPhagwaraPunjabIndia
Abu SaeidNPI University of BangladeshManikganjBangladesh
Ankita SainiUniversity of DelhiNew DelhiIndia
Harshit SajalJSS Academy of Higher Education and ResearchMysore KarnatakaIndia
Bushra ShaidaSharda UniversityGr. Noida, U.P.India
Rajani SharmaAmity Institute of BiotechnologyAmity UniversityJharkhandRanchiIndia
Vandana SinghSharda UniversityGr. Noida, U.P.India
Dwaipayan SinhaGovernment General Degree CollegeMohanpurPaschim MedinipurIndia
Yuvaraj SivamaniCauvery College of PharmacyMysuruKarnatakaIndia
Nimmy SrivastavaAmity Institute of BiotechnologyAmity University JharkhandIndia
Lisa F. M. Lee Nen ThatRMIT UniversityVictoriaAustralia
Ab Waheed WaniLovely Professional University PunjabIndia
Atif Khurshid WaniLovely Professional University PhagwaraPunjabIndia
Mulumebet WorkuNorth Carolina Agricultural and Technical State UniversityGreensboroNorth CarolinaUSA
1 Structural and Dynamics of Healthy Adult’s Microbiota
Mahdi Hussein Abdelrazig
Professor of Hematology, Omdurman Ahlia University, Sudan
1.1 Introduction
Microbiota are the range of microorganisms that may be commensal, symbiotic, or pathogenic found in and on all multicellular organisms, including plants. Microbiota include bacteria, archaea, protists, fungi, and viruses [1–3], and have been found to be crucial for immunologic, hormonal, and metabolic homeostasis of their host.
The term microbiome describes either the collective genomes of the microbes that reside in an ecological niche or within the microbes themselves [4–6]. The microbiome and host emerged during evolution as a synergistic unit from epigenetics and genetic characteristics, sometimes collectively referred to as a holobiont [7, 8]. The presence of microbiota in human and other metazoan guts has been critical for understanding the co-evolution between metazoans and bacteria [9, 10]. Microbiota play key roles in the intestinal immune and metabolic responses via their fermentation product (short-chain fatty acid), acetate [11]. All plants and animals, from simple life forms to humans, live in close association with microbial organisms [12]. Several advances have driven the perception of microbiomes, including:
the ability to perform genomic and gene expression analyses of both single cells and entire microbial communities in the disciplines of
metagenomics
and
metatranscriptomics
[
13
];
databases accessible to researchers across multiple disciplines [
13
]; and
methods of mathematical analysis suitable for complex datasets [
13
].
Biologists have come to appreciate that microbes make up an important part of an organism’s phenotype, far beyond the occasional symbiotic case study [13]. Commensalism, a concept developed by Pierre-Joseph van Beneden (1809–1894), a Belgian professor at the University of Louvain during the nineteenth century [14], is central to the microbiome, where microbiota colonize a host in a non-harmful coexistence. The relationship with their host is called mutualistic when organisms perform tasks that are known to be useful for the host [15, 16], and parasitic when disadvantageous to the host. Other authors define a situation as mutualistic where both benefit and commensal where the unaffected host benefits the symbiont [17]. A nutrient exchange may be bidirectional or unidirectional, may be context dependent, and may occur in diverse ways [17]. Microbiota that are expected to be present, and that under normal circumstances do not cause disease, are deemed normal flora or normal microbiota [15]; normal flora may not only be harmless, but may be protective of the host [18]. The human microbiota includes bacteria, fungi, archaea, and viruses. Micro-animals, which live on the human body, are excluded. The human microbiome refers to their collective genomes [15].
Humans are colonized by many microorganisms; the traditional estimate was that humans live with ten times more non-human cells than human cells; more recent estimates have lowered this to 3:1 and even to about 1:1 [19, 20]. In fact, these are so small that there are around 100 trillion microbiota on the human body [21]. The Human Microbiome Project sequenced the genome of the human microbiota, focusing particularly on the microbiota that normally inhabit the skin, mouth, nose, digestive tract, and vagina [15]. The Project reached a milestone in 2012 when it published initial results [22]. Organisms evolve within ecosystems so that the change of one organism affects the change of others. The hologenome theory of evolution proposes that an object of natural selection is not the individual organism, but the organism together with its associated organisms, including its microbial communities; coral reefs. The hologenome theory originated in studies on coral reefs [23]. Coral reefs are the largest structures created by living organisms, and contain abundant and highly complex microbial communities. Their innate immune systems do not produce antibodies, and they should seemingly not be able to respond to new challenges except over evolutionary time scales. The puzzle of how corals managed to acquire resistance to a specific pathogen led to a 2007 proposal that a dynamic relationship exists between corals and their symbiotic microbial communities. It is thought that by altering its composition, the holobiont can adapt to changing environmental conditions far more rapidly than by genetic mutation and selection alone. Extrapolating this hypothesis to other organisms, including higher plants and animals, led to the proposal of the hologenome theory of evolution [23]. As of 2007, the hologenome theory was still being debated [24]. A major criticism has been the claim that V. shiloi was misidentified as the causative agent of coral bleaching, and that its presence in bleached O. patagonica was simply that of opportunistic colonization [25]. If this were true, the basic observation leading to the theory would be invalid. The theory has gained significant popularity as a way of explaining rapid changes in adaptation that cannot otherwise be explained by traditional mechanisms of natural selection. Within the hologenome theory, the holobiont has not only become the principal unit of natural selection, but the result of other step of integration that it is also observed at the cell (symbiogenesis, endosymbiosis) and genomic levels [7].
Microbial therapeutics, including fecal microbiota transplants (FMTs), bacterial consortia, and probiotics are increasingly being tested in patients with Clostridium difficile (C. diff) infections and other gastrointestinal (GI) disorders [25] including inflammatory bowel disease (IBD), and more recently, non-GI indications such as autism [25, 26] and cancer. In parallel to microbial therapeutics, microbial signatures are being evaluated as a novel class of biomarkers, applied for stratification of efficacy and safety in clinical trials across multiple indications [28]. This rapid increase in microbial therapeutics and biomarkers notably demands a rigorous reevaluation of the factors influencing an individual’s personal gut microbiome over time. Such understanding is essential for optimizing clinical trials with any microbial component. For example, without a complete understanding of the factors influencing the gut microbiome in health and disease, we cannot determine whether the optimal FMT should be sourced from a patient who previously responded to a therapy or a healthy donor who is matched for age and sex. In this text, we present a comprehensive assessment of the gut microbiome of 946 well-defined healthy French donors from the Milieu Interieur (MI) Consortium, with 1359 shotgun metagenomic samples. Designed to study the genetic and environmental factors underlying immunological variance between individuals, the MI Consortium comprises 500 women and 500 men evenly stratified across five decades of life, from 20 to 69 years of age, for whom extensive metadata, including demographic variables, serological measures, dietary information, and systemic immune profiles are available and easily accessible [28]. Integrating these data with those from cancer patients, we demonstrate clear evidence for altered microbial communities in cancer patients across multiple non-GI indications. To build on the findings of several landmark microbiome studies [29], many of which relied on an older reference library for taxonomic classification of microbial sequence reads [30], we leveraged an expanded set of reference genomes with a novel taxonomy that corrects many misclassifications in public databases to discover new biological insights, particularly around age and sex [31]. An independent dataset was used for replication of many of the findings [32]. Study of short-term longitudinal samplings from half the donors found that individuals are more similar to themselves over time compared with others [33]. However, the degree of stability between individuals was quite variable and was influenced by lifestyle factors as well as baseline composition. Overall, the aims of the study are threefold. First, we introduce a new microbiome analysis approach that uses an expanded set of reference genomes with a novel taxonomy to discover new, statistically robust insights into host/bacteria biology that will enable personalized medicine approaches for microbial therapeutics and biomarkers. Second, we provide the rich metadata and 1000-plus deep shotgun metagenomic samples described here as a resource on which future microbiome studies can test and build new computational tools, as well as be compared against disease cohorts. Finally, while demonstrating the utility of this resource as a control population, we define global shifts in the gut microbiomes of patients with non-GI tumors compared with healthy donors normalised based on relative evolutionary divergence [31]. The impact of this procedure was particularly prominent for species of the genus Clostridium, which were split into 121 unique genera spanning 29 families [31]. This could be especially meaningful for analysis of gut microbiome samples, as Clostridium species are prevalent community members and often emerge in association studies. The RefSeq sequences and taxonomic tree from the GTDB, including its naming conventions, were used to build a reference database for the k-mer-based program Kraken2 [33] and read-reassignment step [34]. This custom Kraken2/GTDB pipeline was applied to 1359 quality-controlled samples from 946 MI donors and compared using both the marker gene-based tool Metaphlan2 [35] and Kraken2, with the same 23 505 reference genomes using their original NCBI taxonomies. Consistently, more bacterial taxa were identified per sample with Kraken2 than Metaphlan2, a result of the updated reference database and higher sensitivity of this k-mer-based approach. Between the two Kraken databases (GTDB and NCBI), richness varied depending on how taxa were redistributed by GTDB. For example, GTDB split 2397 NCBI genera into 3205, while it collapsed 18 795 NCBI species into 13 446. Despite finer-level differences, the overall distribution of phyla across the three approaches was similar, indicating that Kraken2/GTDB pipeline results would be consistent with previous analyses. As such, a combination of k-mer-based read assignment and genome-based taxonomy allows higher resolution analysis of shotgun metagenomic samples. Using variable gut microbiomes in a restricted geographical region to complement our optimized taxa-based approach and further use of the resolution afforded by shotgun metagenomic sequencing, we applied HUMANn2 to identify the functional potential of microbial pathways present in the MI samples. Using both the Kraken2/GTDB and HUMANn2 pipelines, we identified a broad range of diversity across the 946 individuals in this geographically restricted cohort of healthy French adults. This diversity was observed in terms of metabolic pathway richness (282 ± 40, mean ± SD), species richness (248 ± 32), and Shannon diversity (3.7 ± 0.35), which account for both richness and evenness (Data S1, table 2). Across donors, our GTDB pipeline confirmed Firmicutes and Bacteroidota (formerly Bacteroidetes) as the most abundant phyla in the gut, but enabled distinction among the original Firmicutes phyla, which was further divided in the GTDB into 12 distinct categories; Firmicutes, Firmicutes_A, Firmicutes_B, … Firmicutes_K (Data S1, table 1). Notably, throughout the GTDB, the group containing type material (if known) kept the original unsuffixed name. Of those, seven were present in this cohort, with Firmicutes_A the most abundant, followed by Firmicutes and Firmicutes, highlighting the finer granularity, even at the phylum level, provided by GTDB-based taxonomic calls. Subsequent application of the Bray–Curtis (BC) distance metric is a means to assess species presence/absence in addition to relative abundance.
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2 Composition and Diversity of Gut Microbiota
Lisa F.M. Lee Nen That1 and Jessica Pandohee2
1 School of Science, RMIT University, Bundoora, Victoria, Australia 2 Telethon Kids Institute, Nedlands, Western Australia, Australia
2.1 Introduction
The human gastrointestinal tract, which has a surface of 250–400 m2, is home to a rich, complex, and diverse microbial community which is evaluated at 100 trillion [1–3]. The community containing fungi, archaea, viruses, bacteria, and helminths constitute the gut microbiota [4]. Initially, the bacterial population was estimated to be 1014 bacterial cells, which is 10 times more than human cells and had 100 times more genes than the human genome [3, 5, 6]. However, an updated estimate indicated that the ratio of bacteria to human cells is 1:1 [7].
A co-dependent relationship has evolved leading to mutualistic interactions between the host and the microbial community as the microorganisms have provided many health benefits to the host [1]. Moreover, strong host selection and coevolution have shaped the diversity of the gut microbiota. Indeed, the relationship between mammals and the bacteria present in the gut is ancient and suggests coevolution due to the presence of several groups of similar and related bacteria in different mammals. This also highlights the beneficial impact on the host as both parties cooperate for a functionally stable ecosystem [1]. Humans have certainly benefited from interactions with the gut microbiota, as they prevent infections caused by pathogens [8, 9], allow synthesis and absorption of nutrients and metabolites [10, 11], and protect the gut barrier in behavioural disorders [12].
Previously, the study of the microbial community in the gastrointestinal tract relied on culture-based methods. However, advanced technology gave rise to new methods that allowed the amplification of conserved regions, such as the 16S rRNA gene using universal primers, and the amplified products may be compared to sequences in databases for identification [13]. Two large-scale projects, namely MetaHit and The Human Microbiome Project, have also contributed to our understanding and further characterised the microbial communities associated with humans [14, 15]. This chapter aims to provide an overview of the recent advances on the composition and diversity of the gut microbiota.
2.2 Composition and Diversity of Gut Microbiota Throughout Lifespan
The bacterial community in the gastrointestinal tract undergoes several changes over a lifespan [3, 16]. From infant to adulthood, diversity in gut microbiota increases and becomes more complex [17]. At adulthood, the composition remains stable and as they age, interindividual variation is greater and there are shifts in the composition of the gut microbiota. Table 2.1 gives an overview of the bacterial composition at different life stages.
Table 2.1 Composition and diversity of gut microbiota throughout a lifespan.
Stages of lifespan
Composition and diversity of gut microbiota
Fetus
The gut microbiome starts developing before birth and is shaped by the mother’s diet.
Microorganisms detected in the placenta, amniotic fluid, fetal membranes, and cord blood.
Community in placenta: Firmicutes, Tenericutes, Proteobacteria, Bacteroidetes, and Fusobacteria and resembles oral microbiome.
Baby
Preterm
Increase in pathogens, bacterial diversity is reduced compared to healthy term baby.
Most abundant: facultative anaerobe; Enterobacteriaceae, Enterococcaceae, Lactobacillus.
Less abundant: Bifidobacterium, Bacteroides, Atopobium.
Delivery mode
Vaginal delivery: 72% similarity between infant and mother’s fecal microbiota. High number of Lactobacilli. Early colonizers: facultative anaerobes (Staphylococcus, Streptococcus, Enterococcus, Enterobacter); obligate anaerobes (Bifidobacterium, Bacteroides, Clostridium).
Caesarean birth (C-section): less bacterial diversity, bacterial community similar to skin and hospital environment. Increase in Clostridium difficile, absence of Bifidobacterium and Bacteroides.
Difference in bacterial communities between elective and emergency C-section.
At birth
Lower diversity and high interindividual variation. Dominant: Firmicutes, Proteobacteria, Actinobacteria. Less abundant: Bacteroidetes.
Diet
Breast-fed babies: Bifidobacteria and Lactobacillus are dominant. Decrease in Firmicutes and Proteobacteria.
Bottle-fed babies: Higher diversity. Increase in Bacteroidetes, Clostridium coccoides, Staphylococcus. Less abundant: Bifidobacteria,
Infant (first year)
Weaning
Microbiota becomes more complex, most abundant: Bifidobacterium, Bacteroides.
Increase: Clostridia (Clostridium coccoides). Decrease: facultative anaerobes.
Children
Main phyla: Bacteroidetes and Firmicutes, Interindividual variation in ratio of the 2 phyla, increase in diversity and similarity with adult microbiota increases.
First four years: Enrichment in Proteobacteria and Actinobacteria.
At 2.5 years, adult-like microbiota in terms of composition and diversity. Functional capabilities mostly involved in physical development.
Preadolescent children: Increase in butyrate-producing bacteria (Roseburia spp., Faecalibacterium spp., Ruminococcus spp.), Alistipes spp., Bacteroides vulgatus and Bacteroides xylanisolvens.
Adolescents (11–18 years)
High level:
Bifidobacterium
and
Clostridium
spp.
Adults
Most abundant: Firmicutes, Bacteroidetes, and Actinobacteria. Less abundant: Proteobacteria, Verrucomicrobia. Stability is relatively unchanged in adulthood. Dominant: Lachnospiraceae and Ruminococcaceae (10‒45% of total fecal bacteria), Bacteroidaceae and Prevotellaceae (remaining 12‒60%).
Older adults
With age, both Firmicutes and
bifidobacteria
decline. Increase in Bacteroidetes and Proteobacteria. High interindividual variation. Diversity varies according to residence such as community, long-term care, hospital. Less diversity in adults in long-term care than those residing in community.
Centenarian
Increase: Fusobacterium, Bacillus, Staphylococcus, Corynebacterium, and Micrococcaceae family.
Decrease: Butyrate-producing bacteria (Faecalibacteriumprausnitzii, Eubacterium rectale, Eubacterium hallii, Eubacterium ventriosum).
2.3 Composition of Bacterial Community in the Different Sections of the Gastrointestinal Tract
The composition and abundance of bacteria varies along the digestive tract due to the different environmental conditions within each section [18]. More than 90% of the bacteria found in the gastrointestinal tract belong to the phyla Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria [3]. These microorganisms are usually found in the lumen, which is the gap in the digestive tract, and the mucosal layer of the digestive tract [16].
It has been estimated that saliva contains 109 cfu/ml [19, 20]. The cheeks, tongue, tooth surfaces, and saliva represent microenvironments in the oral cavity for a diverse community of bacteria which include Streptococci, Clostridia, fusobacteria, actinobacteria, proteobacteria, Prevotella, and Bacteroides [19]. In the esophagus, the most common microorganisms identified include Streptococcus, Prevotella, and Veillonella spp, and they only reside in the esophageal wall temporarily [16, 21]. Other bacteria such as Veillonella, Clostridium, and Neisseria may also temporarily reside in the stomach [22]. Helicobacter pylori which is not acid-tolerant and has optimum growth conditions at pH 7 could be considered as an endemic gastric bacterium, as it has adapted to the harsh conditions inside the stomach, and resides mostly close to the antrum within the mucus layer where it has created its own suitable environment. There have been few studies carried out in the small intestine where the bacterial population is considered the lowest [16, 20]. Indeed, the duodenum had an estimated 103 cfu/ml of viable bacteria. Although it contains mostly acid-tolerant bacteria from incoming stomach content, other bacteria such as Bacteroides, Bifidobacterium, Veillonella, Staphylococcus, and Enterobacteria have also been identified in lesser numbers. The jejunum has similar microbial composition as the duodenum. The bacterial population in the ileum is more diverse and increases to 106‒108 cfu/ml, as there is lesser movement and a neutral pH [20]. The bacteria present are mostly facultative anaerobes and aerobes [23]. The colon is home to one of the most populous and diverse microbial communities in nature with 300‒1000 bacterial species present [16, 20]. Obligate anaerobes including Bacteroides, Eubacterium, and Bifidobacterium predominate the colon (90% of cultivable bacteria in the colon) followed by facultative anaerobes such as Streptococcus and enterobacteria [21].
The existence of community types in the gut microbiota has been demonstrated and are distinct in bacterial composition [24]. A study by Arumugam et al. has identified in individuals from 6 nationalities that the microbial can be grouped into three distinct enterotypes, namely Bacteroides, Prevotella, and Ruminococcus [25]. These enterotypes are distinguished by the different methods used for energy production from fermentable resources in the colon. Bacteroides break down carbohydrates and proteins to generate energy, while degradation of mucin glycoproteins is mainly caused by Prevotella. As for Ruminococcus, it is involved in mucin degradation and its uptake as the bacteria is involved in membrane transporters. It was argued that the term faecotypes would be more appropriate instead of enterotype, as enterotypes were identified by analysing fecal samples, and composition differs at different sections in the gastrointestinal tract [26].
There have been a few studies that questioned the existence of the three distinct enterotypes [27]. Wu et al. reported that in a long-term study looking at the effect of diet [28], there was a distinction between the two enterotype Prevotella and Bacteroidetes brought about by diet, and other genera responsible for the differences were Alistipes, Parabacteroides, Paraprevotella, and Catenibacterium. Ruminococcus, the third enterotype was not distinct and was associated with Bacteroidetes. Long-term diet strongly correlated with the enterotypes. The Bacteroides enterotype was characterised by animal protein and saturated fats, while Prevotella was mostly associated with a diet rich in carbohydrates and simple sugars.
Further research has also suggested that instead of three distinct enterotypes, bacterial communities may vary along a gradient and may be led by either Prevotella on one end or Bacteroides on the other [29, 30].
2.4 Stability, Resilience, and Functional Redundancy
Although diversity has been considered necessary for a stable ecosystem, many different and unrelated bacteria fulfil similar roles in the gut microbiota leading to functional redundancy, where taxonomic diversity varies among individuals while the functional stability is still maintained [1, 31]. Indeed, a study looking at obese and lean twins has revealed that a core functional group was present at the level of genes in bacteria that is crucial for several metabolic activities [32]. The existence of this functional group allows the resident bacteria to carry out a wide range of metabolic activities making the community functionally diverse [33]. Functional redundancy has also been considered a determinant in the stability and resilience of the gut microbiota, especially in response to perturbations. The stability of the gut microbiota depends on how the community can revert to its original state making it resilient [34]. Despite a change in taxonomic diversity, this is possible because more than one group of bacteria can carry out functions to restore to the state prior perturbation. Maintaining the core functional microbiota is important for health and any disruption may lead to diseases. The core microbiome is involved in various pathways including metabolism of amino-acid and carbohydrates [32]. Dysbiosis occurs when the gut microbiota fails to return to its original state and is usually dependent on how resilient and stable the gut microbiome is [32].
Specific functions may still be confined to certain groups of bacteria, which makes them keystone species. In the gut microbiota, keystone species play important roles in keeping the diversity and community structure by interacting with other resident bacteria [35, 36]. As they are usually relatively low in numbers, their loss would have a profound impact on the community. In a study looking at the amylolytic activity of four bacteria, namely Eubacterium rectale, Bacteroides thetaiotaomicron, Bifidobacterium adolescentis, and Ruminococcusbromii, the bacterium R. bromii had the most superior degradative ability when co-cultured with each of the four bacteria although it was inoculated in a medium that limited its growth [37]. This highlights the importance of R. bromii as a keystone species as many bacteria depend on it for provision of substrates. Akkermansiamuciniphila may be considered as another keystone species as it breaks down mucin to provide energy source, leading to increased growth of other bacteria in co-cultures [38].
2.5 Interactions in the Gut Microbiota
In the gut microbiota, no bacteria can survive on its own, and interactions between microbes and with the host are important to shape the community (Figure 2.1). Microbial interactions such as competition, predation, and cooperation in the gastrointestinal tract are constantly happening, and bacteria have had to adapt to tolerating surrounding bacteria while resisting invading pathogens, leading to a healthy state of the gut microbiota.
Figure 2.1 Host–microbe interactions and microbe–microbe interactions occurring in the gastrointestinal tract.
2.5.1 Microbe–microbe Interactions
Cooperation has been observed in bacteria such as congeners Bacteroides ovatus and Bacteroides vulgatus [39]. B. ovatus is a symbiont found in the gut that breaks down a large quantity of substrates such as inulin for B. vulgatus at its own expense. By doing so, the fitness of B. ovatus increases as it receives benefits from its congener, which may include generation of growth promoting factors.
Facilitation occurs because the presence of a closely related species, i.e., belonging to the same family in the gut microbiota, may also increase the chances of colonisation of a specific novel bacteria [2]. Factors that promote abundance of the related species may also encourage invasion of the bacterial species. A study by Stecher et al. showed that high levels of E. coli may have promoted the invasion of Salmonella as they require similar environmental conditions and are closely related [2]. Another example of facilitation occurred when rats with intestinal Lactobacilli were administered Lactobacillus reuteri and within 5 days, the population of L. reuteri was significantly increased and correlated with high levels of intestinal Lactobacilli.
Competition among bacteria has been reported when they occupy same ecological niche or require similar resources for survival [20]. When the gut microbiota is rich and diverse with the range of ecological niches filled, invading pathogens that compete for similar requirements may be less likely to invade. Resident bacteria such as Bacteroides fragilis have developed mechanisms such as toxin production or possess type IV secretion systems to combat other bacteria [40–42].
Bacteria in the gut are also subjected to predation by bacteriophages and other bacteria [43]. All these interactions indicate how complex and dynamic the microbial community in the gut is.
2.5.2 Host–microbe Interactions
Bacteria in the gastrointestinal tract has also developed a commensal and symbiotic relationship with the host whereby they coexist without harming each other and where one provides benefits to the other [44]. They also interact with each other to create a stable and healthy environment in the gastrointestinal tract, and resist any invasion from pathogens. Interaction with the host occurs through the modulation of the gut epithelium or when influencing the immune system [45].
Moreover, production of short chain fatty acids (SCFA) by resident bacteria from dietary fibres are energy sources for the intestinal epithelial cells and the gut microbiota. These SCFA play an important role in immunity and host physiology. A study by Maslowski et al. demonstrated that as the SCFA bind to a G-protein coupled receptor 43, it triggers an anti-inflammatory response that lead to modulation of apoptotic pathways [46].
The intestinal epithelium is covered by a layer of mucus made of glycoproteins to protect against pathogens such as Salmonella. It is also a food source for a select group of bacteria such as Bacteroides fragilis, Akkermansiamuciniphila, and Bifidobacterium bifidum as they produce enzymes that break down glycoproteins to release monosaccharides [47].
The mucus layer of the epithelium and the gut microbiota also work in concert to prevent pathogenic invasion [48]. Some bacteria also release toxins and antimicrobial peptides.
2.5.3 Colonisation of the Gut Microbiota
During the first years in a human lifespan, the process by which early colonisers settle and establish in the gut is termed ecological succession [20]. The community grows in complexity, diversity, and composition until it reaches a climax and remains stable throughout adulthood. Colonisation resistance occurs as residential bacteria protect the gut against pathogens.
Secondary succession is defined as the process by which the microbial community goes through a recovery phase after a perturbation such as antibiotic administration [49, 50]. The recovery stage is characterised by a complex process in multiple stages with interactions among bacterial species [51]. The presence of keystone taxa acts as a catalyst as it triggers a response that leads to restoration of the entire ecosystem. Moreover, 21 bacterial species have been linked to recovery and breakdown of complex polysaccharides and mucin is an important determinant for ecosystem recovery. Four ecological processes are also being considered to understand the microbial succession, namely dispersal potential, availability of resources, changes in environmental stresses, and predation by bacteriophages [52].
Chng et al. reported similar results from a meta-analysis of effect of antibiotic treatment on gut microbiota [51]. The initial step in the recovery phase includes the presence of rapid-growing facultative anaerobes that degrade complex substrates leading to biomass recovery, followed by aerotolerant bacteria that degrade fibre and mucin [50, 51]. At this stage, there is possibly functional redundancy in the community. Finally, the obligate anaerobes that break down fibre and other bacteria also return leading to stability and diversity in the ecosystem.
2.6 Conclusion
This chapter has highlighted the progress made in characterising the composition and diversity of the gut microbiota and demonstrated how the bacterial community has developed a close relationship with the host. Understanding the many processes that occur in the gut microbiota can allow us to translate the information into clinical practice and develop diagnostic strategies. As there are interindividual variations in the gut microbiota, and considering the important role of the microbiota in diseases, personalised medicine could become a new avenue and lead to development of next-generation tools [53, 54].
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