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Human Microbiota in Health and Disease: From Pathogenesis to Therapy

Human Microbiota in Health and Disease: From Pathogenesis to Therapy

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Human Microbiota in Health and Disease: From Pathogenesis to Therapy

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2,335 pagine
45 ore
Pubblicato:
May 25, 2018
ISBN:
9780128146507
Formato:
Libro

Descrizione

Human Gut Microbiota in Health and Disease: From Pathogenesis to Therapy is a comprehensive discussion of all the aspects associated with gut microbiota early colonization, its development and maintenance, and its symbiotic relationship with the host to promote health.

Chapters illustrate the complex mechanisms and metabolic signalling pathways related to how the gut microbiota maintain proper regulation of glucose, lipid and energy homeostasis and immune response, while mediating inflammatory processes involved in the etiology of many chronic disease conditions. Details are provided on the primary etiological factors of chronic disease, the effects of gut dysbiosis and its associated disease conditions, while providing an overview of therapeutic strategies involving dietary fiber and prebiotics, fecal microbiota transplantation therapy and probiotics. Throughout the chapters, a comprehensive review of peer-reviewed animal and human studies is provided as evidence related to the history of human exposure, safety, tolerance, toxicity, nomenclature, and clinical efficacy of utilizing prebiotic fructans, s, as well as probiotic intervention, and dietary modification in the prevention and intervention of chronic disease conditions.

With common use today of pharmaceutical medicine in treating symptoms, and frequent overuse of antibiotics in chronic disease within mainstream medical practice, understanding the etiological mechanisms of dysbiosis-induced chronic disease, and natural approaches that offer prevention and potential cures for these diseases is of vital importance to overall human health.

  • Details the complex relationship between human microbiota in the gut, oral cavity, urogenital tract and skin as well as their colonization, development and impact of factors that influence the relationship
  • Illustrates the mechanisms associated with dysbiosis-associated inflammation and its role in the onset and progression in chronic disease
  • Provides the primary mechanisms and comprehensive scientific evidence for the use of dietary modification, and pro- and pre-biotics in preventing and intervening in chronic disease
Pubblicato:
May 25, 2018
ISBN:
9780128146507
Formato:
Libro

Informazioni sull'autore

Dr. Tungland is a bacteriologist/microbiologist and chemist with more than 35 years of experience in food and food ingredient research and development. He specializes in effects of dietary modification and pr0 and prebiotic use in maintaining human health. He has authored or co-authored over 50 articles in peer- and non-peer reviewed journals and trades, and contributed 6 peer-reviewed book chapters on many scientific topics. He holds several patents in areas of food ingredient and process technology application, such as reducing sugar in frozen desserts, production of bioplastics and agrochemical time-release delivery, and technology associated with reducing blood glucose response in flour-containing processed foods. He is the sole proprietor in food and health and wellness consulting company, Tungland and Associates, LLC.

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Anteprima del libro

Human Microbiota in Health and Disease - Bryan Tungland

Human Microbiota in Health and Disease

From Pathogenesis to Therapy

Bryan Tungland

Table of Contents

Cover

Title page

Copyright

Dedication

Preface

Chapter 1: Gut Microbiota, Early Colonization and Factors in its Development that Influence Health

Abstract

1.1. Commensal gut microbiota composition and body distribution

1.2. Early microbial colonization and factors affecting subsequent gut microbiota development

1.3. Consequences of an infant microbiota colonization and development on health later in life

1.4. Maternal nutrition during pregnancy and role of pro- and prebiotics in prenatal microbiota development and metabolic programing

1.5. Conclusions

Chapter 2: Short-Chain Fatty Acid Production and Functional Aspects on Host Metabolism

Abstract

2.1. Introduction

Chapter 3: Gut Microbiota Influence Lipid and Glucose Metabolism, Energy Homeostasis and Inflammation Through Effects on Bile Acid Metabolism

Abstract

3.1. Bile acid synthesis and conjugation, and their elimination or resorption

3.2. Regulation of bile acid synthesis

3.3. Bile acids as signaling molecules that regulate their synthesis, transport and energy

3.4. Bile acid signaling influences glucose and lipid, and energy metabolism

3.5. Bile acid signaling mediates cytokine expression and immune response in inflammation

3.6. Conclusions of bile acid chapter

Chapter 4: Role of Gut Microbiota in Immune Homeostasis

Abstract

4.1 Introduction

4.2. Types of T cells and their function

4.3 Gut microbiota influence innate immune homeostasis

4.4 Gut microbiota and adaptive immune homeostasis

4.5 Gut microbiota influence systemic threshold of activation of innate and adaptive cells

4.6 Commensal microbiota control immunity in distal tissues

Chapter 5: Direct Physiological Effects on Local Gi and Indirect Systemic Effects of Prebiotic Fructan Treatment, and its Role in Disease Prevention and Therapy

Abstract

5.1. Introduction

5.2. Beneficial effects of prebiotic fructan consumption on the physiology of the lower GI

Chapter 6: Intestinal-Based Diseases and Peripheral Infection Risk Associated with Gut Dysbiosis: Therapeutic use of Pre- and Probiotics and Fecal Microbiota Transplantation

Abstract

6.1. Introduction

6.2. Infection risk reduction, including C. difficile, and associated infectious diarrhea: effects of pro- and prebiotic, and fecal microbiota transplantation therapies (also refer to earlier section on effects of these therapeutic approaches in atopy and allergies)

6.3. Gastric acid-related disorders [heartburn, gastroesophageal reflux (GERD)] and effects of pro- and/or prebiotic treatment

6.4. Celiac disease and gluten intolerance: effects of pro- and/or prebiotic therapy

6.5. Irritable bowel syndrome (IBS) and effects of pro- and prebiotic, and FMT therapies

6.6. Inflammatory bowel disease (IBD) and therapeutic strategies

6.7. Pouchitis and therapeutic effects of pro- and prebiotic fructans, and FMT

6.8. Acute radiation-induced enteritis in gynecological cancer patients: effects of prebiotic fructans

6.9. Cancer: role of dysbiosis and effects of probiotic and prebiotic fructan therapy in prevention and intervention

Chapter 7: Overview of Prebiotics: Membership, Physiological Effects and their Health Attributes

Abstract

7.1. Introduction

7.2. Definitions and classifications

7.3. Mechanism of action and key metabolic benefits of the primary or classic prebiotics

7.4. Physicochemical properties and key physiological effects of classic prebiotic compounds

7.5. Physicochemical properties and physiological effects of non-conventional, candidate prebiotic compounds

7.6. Human milk oligosaccharides (HMOs)

7.7. Conclusions of prebiotic compounds

Chapter 8: Nondigestible Fructans as Prebiotics

Abstract

8.1. Chemical structure, physicochemical properties and product specifications of commercially-produced prebiotic fructans

8.2. Natural occurrence in plants and historical human exposure to prebiotic fructans

8.3. Safety and tolerance of prebiotic fructans

Chapter 9: Dysbiosis of the Microbiota: Therapeutic Strategies Utilizing Dietary Modification, Pro- and Prebiotics and Fecal Transplant Therapies in Promoting Normal Balance and Local GI Functions

Abstract

9.1. Introduction

9.2. Physiological benefits of prebiotics and strategies with or without probiotics and bacteriophage technology: significance in maintaining and restoring optimal microbial balance

9.3. Fecal microbial transplant (FMT) therapy: significance in gastrointestinal disease

Chapter 10: Oral Dysbiosis and Periodontal Disease: Effects on Systemic Physiology and in Metabolic Diseases, and Effects of Various Therapeutic Strategies

Abstract

10.1. Introduction

10.2. Systemic diseases associated with oral infection and some non-surgical strategies

10.3. Oral hygiene, non-surgical periodontal therapies and probiotics reduce and/or prevent the pathogenicity of chronic systemic disease associated with periodontitis

10.4. Summary of periodontal disease and systemic health and therapeutic strategies

Chapter 11: Intestinal Dysbiosis in Obesity, Metabolic Syndrome and Related Metabolic Diseases: Therapeutic Strategies Utilizing Dietary Modification, Pro- and Prebiotics, and Fecal Microbial Transplant (FMT) Therapy

Abstract

11.1. Introduction

11.2. Effects of diet on microbiota diversity, inflammation, weight gain and glycemia and insulinemia: therapeutic effects of pro- and prebiotic, and FMT treatment

Chapter 12: Gut Microbiota in Brain Development and Disorders of the CNS: Therapeutic Strategies Involving Dietary Modification, Pro- and Prebiotic Intervention, and Fecal Microbiota Transplantation (FMT) Therapy

Abstract

12.1. Introduction

12.2. Gut microbiota and pre- and postnatal brain development

12.3. Interactive bidirectional signaling between the gut microbiota and brain

12.4. Dysbiosis and CNS disorders: effects of probiotic and prebiotic (psychobiotic), and FMT intervention therapy

12.5. Conclusions

Chapter 13: The Gut-Brain-Skin Axis and Role of Intestinal Dysbiosis in Acne Vulgaris: Therapeutic Effects of Pro- and Prebiotic Use

Abstract

13.1. Introduction

13.2. The gut-brain-skin axis

13.3. Pathophysiology of acne vulgaris

13.4. Dietary modification and pro- and prebiotics intervention therapy in acne vulgaris

13.5. Conclusions of dysbiosis in acne and effects of natural therapeutic strategies

Chapter 14: Microbiota and the Urogenital Tract, Pathogenesis, and Therapies

Abstract

14.1. Introduction

14.2. Normal microbiota of female and male urogenital tracts

14.3. Effects of lactic-acid-producing bacteria and race/ethnicity on vaginal microbiota

14.4. Polymorphisms in cytokine gene complex and effects on vaginal microbiota alterations and pregnancy issues

14.5. Microbial–host interactions in the lower genital tract (vaginal immunity)

14.6. Pathophysiology of UTIs and their risk factors

14.7. Therapeutic treatments for urogenital tract infections

14.8. Conclusions

Index

Copyright

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Dedication

To mankind, who through lack of knowledge or misguided choices suffers from chronic disease.

To my wife Linda and my children, who through their kindness, love, and continual devotion to help others have inspired me to enlighten and empower others to take control of their health and wellness.

Preface

The life expectancy in the United States is on the decline. It declined in 2015 (78.9–78.8 years) for the first time since 1993, when it dropped from 75.6 to 75.4 years. According to the National Center for Health Statistics (2016), the death rate rose 1.2 percent in 2015, marking its first increase since 1999 and resulted in more than 2.7 million deaths in the United States. About 45% of these were due to heart disease or cancer, the two leading causes of death in the United States. Recent data also showed increases in virtually every cause of death, including those for eight of the top 10 leading causes of death, which include heart disease, diabetes, stroke, kidney disease, chronic respiratory diseases and Alzheimer’s disease. The latter, Alzheimer’s disease, showed the largest rate jump for any cause of death, which went from 25.4 to 29.4 deaths per 100,000 people, almost a 14% rise.

Obesity plays a major role in many of these diseases. Data from 1,800 sets worldwide showed that excess weight played a role in 4 million deaths in 2015, from heart disease, diabetes, kidney disease, and other related factors (Gregg and Shaw, 2017). Based on defining obesity as a body mass index (BMI) of 30 or more and overweight as a BMI from 25 to 29, nearly 604 million adults and 108 million children worldwide are obese. According to the Global Burden of Disease (GBD) study (2015), in 2015 nearly one-third (2.2 billion) of the world’s population is obese or overweight and more than 10% of the world’s population is obese, a marked rise over the past 30 years. Investigating 195 countries, essentially the world’s population, the study found that rates of obesity at least doubled in 73 countries, including Turkey, Venezuela, and Bhutan, from 1980 to 2015. These rates are particularly rising in countries such as Latin America, Africa, and Southeast Asia. Systemic inflammation increases with age, and age-associated inflammation drives macrophage dysfunction and tissue damage. As you will come to understand throughout this book, all of the aforementioned diseases, including obesity, have as one of its primary etiological factors, an imbalance in the population of microbiota, termed dysbiosis, particularly in the gut, that promotes a permeable gut barrier, called leaky gut syndrome. This condition promotes systemic inflammation, leading to immunological dysfunction that ultimately triggers metabolic and neurological dysfunction and the pathophysiologic progression of disease.

Gut microbiota and human health are intertwined, represented as a symbiotic relationship that is responsible for the overall health of the host. The human gastrointestinal (GI) tract is residence to approximately 10¹³–¹⁴ microorganisms, predominately bacteria but also fungi, viruses, archaea, and protozoa (Sekirov et al., 2010a,b) collectively referred to as microbiota, while their collective genomes constitute what is known as the microbiome. Most of these gut microbiota reside in the large intestine (colon), containing an estimated 10¹¹–¹² CFU/g of content. The gut microbiota include commensal microbiota, or bacteria that live in a symbiotic relationship with their host, and others that have potentially pathogenic characteristics. The commensals are essential for completing host digestion including the complete breakdown of complex carbohydrates, such as dietary fiber, and proteins. The host depends heavily on their gut microbiota to extract maximum nutritional value from their diets. In addition to digestion, the commensal microbiota are also responsible for the production of short-chain fatty acids and the synthesis of vitamins. Gut microbiota also determine host susceptibility to GI infections. Other beneficial effects of the commensal microbiota in the gut include extraction of nutrients, maintenance of gut barrier integrity and function, and stimulation of the immune system. As a consequence, the gut microbiota composition has the ability to influence host metabolic functions.

Mounting research evidence from human and germ-free mice now supports that alterations or shifts in the complex microbial system, resulting in dysbiosis, can lead to a cascade of physiological consequences that modulate the expression of genes in host tissues such as the liver, adipose tissues, intestine, muscle, and brain. This in turn may drive or lessen the development of fat tissue and metabolic disturbances associated with the gut barrier function and the systemic immunity, and even influence the process of nerve myelination. Inflammation is often generated from these metabolic disturbances to the gut barrier and has consequences on immune response and risk of developing chronic metabolic diseases. Evidence is clear that dysbiosis of the gut microbiota is associated with the pathogenesis of both intestinal and extraintestinal disorders. Intestinal disorders include inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, celiac disease, and colorectal cancer, while extraintestinal disorders include allergy, asthma, autoimmune disease, metabolic syndrome, obesity, Type 1 and Type 2 diabetes, cardiovascular disease, hypertension, bacterial vaginosis, fatty liver disease, and even brain demyelination. It also influences brain activity that triggers effects in autism, attention deficient disorder, depression, and anxiety. In addition, dysbiosis of distal tissues, such as skin, oral cavity, and urogenital tracts, also contributes to significant local disease situations, such as atopic dermatitis, psoriasis, eczema, acne vulgaris, periodontitis, bacterial vaginosis, and candidiasis. Dysbiosis of oral cavity can also have significant association with systemic disease, such as cardiovascular disease; oral, head, neck, and skin cancers; pregnancy complications; Alzheimer’s disease and Parkinson’s disease; respiratory tract diseases; and renal dysfunctions.

In view of the growing body of evidence linking diet, gut dysbiosis, and diversity of the gut microbiota to the development of metabolic diseases, approaches aimed at restoring the gut microbiota are emerging as potential and intriguing therapies. In addition to dietary modification to reduce high-fat red meats and sugars in the diet, one approach to modulate the gut microbiota is through the ingestion or administration of probiotics, which are live microorganisms that after entering the gut can exert beneficial health effects on the host by improving its intestinal microbial balance. This book shows that published literature provides significant evidence of their use in treating dysbiosis, markers of inflammation, and many chronic diseases. The most common of these microorganisms are strains of Lactobacilli and Bifidobacteria. An alternative therapeutic approach uses bacteriophage therapy. It has recently shown promise in in vitro and animal studies to increase the efficiency of probiotic use, and provide benefits in acute cases of dysbiosis. However, another alternative, possibly the best overall strategy, is to prevent dysbiosis through dietary modification by reducing fat, digestible starch and refined sugars, in combination with long-term prebiotics use. Although, if a dysbiotic condition exists, the use of probiotics for a short term, and potentially with the use of bacteriophage cotherapy, followed by the dietary modifications and daily use of prebiotics alone, with occasional probiotic use, may be effective in preventing reoccurrence.

The relevance of using prebiotics in the management of chronic disease in humans is supported by extensive human and animal studies, as shown throughout this book. A prebiotic is a selectively fermented nondigestible food ingredient that brings about specific changes in the composition and/or activity of the GI microbiota to then confer benefits upon host well-being and health. Among the few prebiotic agents are the nondigestible fructans, a group of naturally occurring polymeric carbohydrates that contain chains of fructose monomers linked together by nondigestible β-2,1-linkages, or in combination with β-2,6-fructofuranosyl linkages that go by the scientific names of inulin, oligofructose, fructooligosaccharides, or agavins or graminans. These molecules are preferentially utilized by health-promoting commensal microbiota, most specifically the lactic-acid bacteria, such as the Lactobacilli and Bifidobacteria, are found in over 36,000 plants worldwide and in many commonly consumed fruits and vegetables. They have been isolated in pure form for commercial use as dietary supplements or in processed food development from chicory root, Jerusalem artichokes and agave. By selectively feeding these health-promoting commensal bacteria, they help establish a intestinal environment that favors the growth of these health-promoting microbiota, allowing them to compete more effectively to reduce or eliminate the growth of more pathogenic opportunistic microbiota that increase the risk of disease. The nondigestible fructans have been consumed by humans for more than 10,000 years, are naturally prebiotic, safe, and well tolerated. They are novel potential targets relating diet with gut microbes in the prevention and treatment of gut dysbiosis-induced inflammation and aberrant immune responses, which trigger ill-effects on human health and disease.

In addition to these therapies, fecal microbiota transplantation therapy is another highly successful treatment, particularly for recurrent, more severe cases of Clostridium difficile infection. The therapy has also been utilized in the treatment of chronic constipation, IBDs, such as Crohn’s disease and ulcerative colitis, enterocolitis, IBS pouchitis. The therapy has also seen use in nongastroenterologic conditions, including autoimmune disorders (idiopathic thrombocytopenic purpura), neurological conditions, such as multiple sclerosis, Parkinson’s disease, cerebral cavernous malformations and cognitive impairment from hepatic encephalopathy, chronic fatigue syndrome, metabolic syndrome, and Type II diabetes with variable success.

This book discusses in detail the aspects associated with gut microbiota colonization, its development and maintenance, and its symbiotic relationship with the host to promote its health. The various chapters explain and illustrate the complex mechanisms related to how the gut microbiota maintain proper regulation of glucose, lipid and energy homeostasis and immune response, while mediating inflammatory processes involved in the etiology of many chronic disease conditions. The chapters further detail the effects of gut dysbiosis and its associated disease conditions, while providing comprehensive review of the scientific evidence related to the clinical significance of utilizing dietary modification, pro- and prebiotic and fecal transplantation therapy in the prevention and intervention of chronic disease conditions.

As chronic disease continues to escalate worldwide, new knowledge of the roles microbiota play in inflammation and the pathogenesis of disease and its therapy, provides targets for combating declining global life expectancy. Our world cannot afford to continue down a trajectory of ill-fated choices, while losing valuable members of our communities to diseases that can be largely prevented through appropriate dietary interventions.

References

Global Burden of Disease Study Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet (London, England). 2015;386(9995):743–800. doi: 10.1016/S0140-6736(15)60692-4.

Gregg EW, Shaw JE. Global health effects of overweight and obesity. NEJM. 2017;doi: 10.1056/NEJMe1706095.

NCHS (National Center for Health Statistics) (CDC) Death rates and life expectancy at birth. : https://data.cdc.gov/NCHS/NCHS-Death-rates-and-life-expectancy-at-birth/w9j2-ggv5 (retrieved 9.5.17).

Sekirov I, Russell S, Antunes CM, et al. Gut microbiome in health and disease. Physiol. Rev. 2010;90:859–904.

Sekirov I, Russell S, Caetano L, Antunes M, Finlay B. Gut microbiota in health and disease. Physiol. Rev. 2010;90(3):859–904. doi: 10.1152/physrev.00045.

Chapter 1

Gut Microbiota, Early Colonization and Factors in its Development that Influence Health

Abstract

The intestinal microbiota is a relevant aspect of human health. Human microbial colonization begins prior to birth, in utero and continues to develop, and microbial diversity increases and converges toward an adult-like microbiota by the end of the first 3–5 years of life. Perinatal factors play a significant role in microbial colonization, such as mode of delivery, diet (breastfeeding or formula), genetics, and intestinal mucin glycosylation. Once established, the intestinal microbiota composition is relatively stable, throughout adult life, although it can be altered by bacterial infections, antibiotic treatments, lifestyle, stress, surgery, through dietary choices and strenuous exercise. Early-life microbiota development is a significant factor in predisposition to many inflammatory-related diseases, such as inflammatory bowel diseases, metabolic diseases related to obesity, and allergic responses, such as asthma. This chapter reviews the impact of factors affecting microbiota development and its influence on human health throughout life.

Keywords

Human microbiome

commensal gut microbiota

infant

colonization

infant health

probiotics

prebiotics

cesarean section

breastfeeding

diet

immunity

early programing

antibiotics

inflammatory diseases

1.1. Commensal gut microbiota composition and body distribution

The human gastrointestinal tract is residence for approximately 10¹³–¹⁴ microorganisms (predominately bacteria) (Grenham et al., 2011), collectively referred to as microbiota, while their collective genomes constitute what is known as the microbiome. As one travels from the esophagus to the distal rectum, there is a marked difference in diversity and the number of bacteria ranging from 10 per gram of contents in the esophagus and stomach to 10¹² per gram of contents in the colon and distal large intestine (Ohara et al., 2006), as depicted in Fig. 1.1.

Figure 1.1   Distribution of commensal human gastrointestinal microbiota.

Streptococcus appears to be the dominant genus in the distal esophagus, duodenum, and jejunum (Pei et al., 2004; Justesen et al., 1984), while nonpathogenic Helicobacter pylori is the dominant bacteria present in the stomach and determines the entire microbial environment of the gastric microbiota. When commensal H. pylori dominates the stomach, the stomach is inhabited by a diverse population of other dominant species such as Streptococcus (the most dominant), Prevotella, Veillonella, and Rothia, but the diversity disappears once H. pylori acquire a pathogenic phenotype (Blaser, 1999; Andersson et al., 2008). The large intestine (colon) microbiota make up over 70% of all microbes found in the body, out numbering body cells by a factor of 10 (Qin et al., 2010; Rodríguez et al., 2015). The bacteria isolated from the large intestine are shown in Table 1.1, with their gram reaction, fermentation substrate, and principle end products. The bacteria located within the large intestine are estimated to number 10¹¹–¹² colony forming units (CFU) per gram of content (Leser and Molbak, 2009), making up about a half a pound of bacteria (Whitman et al., 1998), which functions as if they were another human organ. Although it was once thought that the gut microbiota comprised between 500–1000 different species that contributes 3.3 million unique microbial genes in the GI tract (Eckburg et al., 2005; Ramakrishna and Krishman, 2007; Proctor, 2011), Frank et al. (2007) reported that the collective human gut microbiota is composed of over 35,000 bacterial species. Furthermore, from a bacterial gene perspective, recent Human Microbiome Project and the Metagenome of the Human Intestinal tract studies suggest that there could over 10 million nonredundant genes in the human gut microbiome for this level of bacterial diversity.

Table 1.1

Abbreviations: (Acet) acetate; (Prop) propionate; (Succ) succinate; (But) butyrate; (Lact) lactate; (Fom) formate; (EtOH) ethanol.

A recent study of the gut microbiome and its function by Le Chatelier et al. (2013) used 123 nonobese and 169 obese individuals to develop a concept of high gene count and low gene count to derive implications in health and disease. The high gene count microbiome included Anaerotruncus colihominis, Butyrivibrio crossotus, Akkermansia sp., and Fecalibacterium sp.; with a high Akkermansia (Verrucomicrobia): Ruminococcus torque/gnavus ratio. The key defining element favoring digestive health of the high gene count microbiome included increased proportion of butyrate-producing organisms, increased production of the fermentation gas, hydrogen, development of a methanogenic/acetogenic ecosystem, and reduced production of hydrogen sulfide, which would be indicative of proteolytic fermentation by pathogenic bacteria. The individuals with a high gene count had more robust microbiome and lower prevalence of metabolic disorders and obesity than those with a low gene count. Individuals with higher populations of proinflammatory bacteria such as Bacteroides and R. gnavus, both known to be associated with inflammatory bowel disease (Swidsinski et al., 2005; Joossens et al., 2011). Among other key members of the low gene count group included Parabacteroides, Campylobacter, Dialister, Prophyromanas, Staphylococcus, and Anaerostipes sp. In addition, bacterial groups making up the low gene count individuals lack metabolic systems for the degradation of β-glucuronide, aromatic amino acids, or nitrite reduction, all known to have damaging effects on DNA and potential for carcinogenesis.

Overall, the human microbial system is highly variable, with every individual having a distinct gut microbial composition; however, a healthy gut microbiota is dominated by the phyla Firmicutes and Bacteroidetes, followed by the phyla Actinobacteria and Proteobacteria, with occasional observation of the phylum Verrucomicrobia (Benson et al., 2010; Dethlefsen et al., 2008; Dubourg et al., 2013). More than 99% of the microorganisms identified in the colon are from the Bacteroidetes and Firmicutes phyla of bacteria, out of the dozens of possible bacteria phyla that exist (Gill et al., 2006; Ley et al., 2008). Traditionally, the Firmicutes:Bacteroidetes ratio has been implicated in predisposition to disease states, with a higher ratio being recognized as more disease related (Ley et al., 2006). Besides genera from the phyla Firmicutes and Bacteroidetes, the human colon also consists of primary pathogens, such as the species Campylobacter jejuni, Salmonella enterica, Vibrio cholera, and Escherichia coli, as well as Bacteroides fragilis, which can be classified as being commensal or pathogenic depending on the circumstance. Although these species typically have low populations (0.1% or less of the entire gut microbiome) (Human Microbiome Project Consortium, 2012; Gillespie et al., 2011). In particular, the levels of the phylum Proteobacteria is very low, with its absence along with high populations of Bacteroides, Prevotella, and Ruminococcus suggest a healthy gut microbiota (Hollister et al., 2014). In addition to this difference, a healthy gut microbiome also has characteristic axial differences from the lumen to the mucosal intestinal epithelial surface. By example, as Bacteroides, Bifidobacterium, Streptococcus, Enterococcus, Lactobacillus, Ruminococcus, Clostridium, and Enterobacteriaceae bacteria are predominant luminal genera, only bacteria from the genera Clostridium, Lactobacillus, Enterococcus, and Akkermansia are associated with the mucus layers and epithelial crypts of the small intestine (Swidsinski et al., 2005).

The intestinal microbiota all possess diverse enzymes that execute highly varied metabolic processes in the intestine, for example, converting substances into compounds that could either be beneficial to the hose or those that could be harmful to the host, Table 1.2.

Table 1.2

Generally, tissue metabolism, particularly hepatic metabolism, is represented by oxidative and biosynthetic processes with glucuronic and sulfuric acid conjugation. These processes lead to water-soluble, polar substances. However, by contrast, intestinal microbiota metabolism is primarily associated with reduction and hydrolysis reactions, resulting in compounds that are harmful to the host, such as putrefactive compounds (ammonia, H2S, amines, phenols, indoles, p-cresols, etc.), as well as secondary bile acids. These putrefactive substances often result in direct intestinal damage or are partially absorbed throughout the host’s life to contribute to cellular aging and geriatric diseases, such as carcinoma, liver disorders, autoimmune, and immunosuppressive diseases, atherosclerosis, hypertension, and cardiovascular disease. The substances may also influence nutrition and metabolism, and host’s infection resistance.

Three generalized groups of intestinal microbiota have been postulated (Mitsuoka, 1992, 2014), Fig. 1.2. Group I consists of microorganisms that are symbiotic to the host and constitute the predominant microbiota, Group II consists of ubiquitous microorganisms from the Enterobacteriaceae, such as E. coli or from the Enterococcus group, but in normal relatively healthy individuals, these do not predominate, and Group III bacteria that consist of recognized pathogenic microbiota, which typically are in low numbers, but sometimes produce infection.

Figure 1.2   Changes in the fecal microbiota with increased age.

Those commonly recognized and studied as being Group I and dominant and beneficial microbiota include Bifidobacterium and Eubacterium, although individuals have other distinct genera, such as Peptococcus and Bacteroides that are known to provide beneficial effects and promote health, such as synthesizing vitamins and protein, assisting in digestion and absorption by producing digestive enzymes, such as proteases and lactase, preventing colonization of pathogens through competitive inhibition, and stimulating proper immune response. E. coli, some Enterococci and Veillonella are known to produce putrefaction compounds as mentioned above, carcinogens and toxins and contribute to diarrhea, constipation, hypercholesterolemia, hypertension, autoimmune disease, cancers, hepatic dysfunction, and immune suppression, while Group III bacteria, such as Clostridium perfringens, Staphylococcus aureus, Proteus, and Pseudomonas aeruginosa produce putrefactive compounds, carcinogens, toxins, and pathogenicity that contribute to aging and premature death. The individual gut microbiota composition is characteristic of each individual but fluctuates based upon nutrition, environmental, and psychological factors and affects the homeostasis of the individual (Guarner and Malagelada, 2003). The composition of the intestinal microbiota, particularly differs by age classifications (Odamaki et al., 2016; Mitsuoka, 2014; Zoetendal et al., 2006), Fig. 1.2. By example, Drasar and Roberts (1989) recognized that fecal microbiota of breast-fed infants is dominated by populations of bifidobacteria (phylum Actinobacteria), with only 1% enterobacteria. Recently, Odamaki et al. (2016) used high-throughput sequencing of amplicons derived from the V3–V4 region of the 16S rRNA gene to investigate the long-term, sequential changes in intestinal microbiota composition. By analyzing fecal samples from 367 healthy Japanese subjects between the ages of 0 and 104 years, the researchers determined that certain transition types of microbiota were enriched in infants, adults, elderly individuals, and both infant and elderly subjects. In agreement with previous studies, the microbiota composition included four predominant phyla, Actinobacteria (containing the Bifidobacteria and Atopobia among others), Bacteriodetes (containing the genera Bacteriodes among others), Firmicutes (containing the Clostridia, Eubacteria, Roseburia, and Bacilli among others), and the Proteobacteria, which contains the family Enterobacteriaceae, a family of Gram-negative pathogenic bacteria, including, Salmonella, E. coli, Yersinia pestis, Klebsiella, and Shigella. Other disease-causing bacteria in the Enterobacteriaceae family include Proteus, Enterobacter, Serratia, and Citrobacter. Firmicutes was determined to be the most predominant phylum postweaning, although bacteria from this phylum was found to be in lower numbers in children <4 years, as compared with children >4 years. In subjects greater than 70 years, Bacteriodetes, β-Proteobacteria and, δ-Proteobacteria. In addition, Odamaki et al. (2016) reported that the relative abundance of Bacteriodetes was not sequentially changed, but its population increased stepwise after 70 years of age.

1.2. Early microbial colonization and factors affecting subsequent gut microbiota development

The fetus, once thought sterile prior to birth, is now increasingly thought to be seeded before birth, with maternal microbiota forming the first microbial inoculation (Tapiainen et al., 2006; Rautava et al., 2012). Recent studies on intrauterine environment (Jiménez et al., 2005;  2008; DiGiulio et al., 2008) suggest that the meconium of the fetus may be colonized prior to birth in utero (Dominguez-Bello et al., 2010; Madan et al., 2012; Moles et al., 2013; Hu et al., 2013; Gosalbes et al., 2013; Ardissone et al., 2014). The presence of bacterial species in the meconium such as E. coli, Enterococcus faecium, and Staphylococcus epidermidis could result from the translocation of the maternal gut microbiota via the bloodstream (Jiménez et al., 2008), but more recent studies of the infant’s meconium, indicate that the neonatal’s bacteria closely resembles microbes from the mother’s oral cavity (Hu et al., 2013; Aagaard et al., 2014). The microbiota characterizing the meconium and fecal material of preterm infants during the first 3 weeks of life has recently been determined (Moles et al., 2013; Gosalbes et al., 2013). Analysis of the meconium of neonates by 16S rRNA-based sequencing studies has shown that its microbiota differ from those observed in early fecal samples from early life. These studies have shown that bacteria from the phylum Firmicutes were in the majority in the meconium, while Proteobacteria were the main bacteria in early fecal samples. In addition, studies showed that Shigella, Staphylococci, Leuconostoc, Lactococcus, and Streptococcus predominated in meconium, while enterococci and potentially pathogenic Gram-negative bacteria were also abundant in fecal samples. Microassays determined a high prevalence of bacteria such as Streptococcus mitis and Lactobacillus plantarum in meconium, whereas in infant feces, bacteria such as the gram negative E. coli, Enterococci, and Klebsiella pneumoniae and Serratia marcescens predominated. As bacteria have been shown to differ from those in the fetus, as compared with the feces in early-life sample, it is thought that maternal colonization may take place, seeding the fetus in utero prior to birth. In order to determine if maternal gut bacteria can be translocated to fetuses in utero, two studies investigated if oral administration of a genetically labeled E. faecium to pregnant mice resulted in its presence in amniotic fluid and meconium of term off-spring after sterile cesarean section (Jiménez et al., 2005;  2008). The studies showed that the labeled E. faecium was found in the amniotic fluid and in the meconium of pups from their mothers, but not in control mice, confirming that maternal microbial transmission in mammals is possible.

From the first maternal microbiota contact, the microbial diversity increases rapidly, converging toward adult-like complexity by the end of the first 2–5 years of life (Rodríguez et al., 2015; Koenig et al., 2011; Palmer et al., 2007), when it becomes more stable, to resemble that of an adult (Rodríguez et al., 2015; Mackie et al., 1999). However, there is little evidence about the identity and number of microbes that traverse the placenta, or whether they persist in the infant or whether their presence has short- or long-term health consequences.

Palmer et al. (2007) and Avershina et al. (2014) showed that newborn gut microbiota composition is widely characterized by high interindividual diversity. The composition of the human gut microbiota from early infancy through old age has been characterized in a few studies (Mitsuoka, 1990; Palmer et al., 2007; Claesson et al., 2011). From birth, the colonic environment is rapidly colonized (O’Toole and Claesson, 2010), with many different microbes, with its diversity being influenced by several factors including gestational age, mode of delivery (vaginal birth vs. C-section) (Adlerberth and Wold, 2009; Dominguez-Bello et al., 2010), feeding method (breast-fed or formula-fed) (Orrhage and Nord, 1999), and environmental factors such as sanitation, health care, nutrition, and antibiotic treatment (Adlerberth and Wold, 2009; Marques et al., 2010). Bifidobacteria colonization generally occurs within the first 4 days of life. Bifidobacterium longum is only found in breast-fed newborns, and bifidobacteria is the primary form of beneficial bacteria in the newborn’s gut (Bezirtzoglou et al., 2006; Mariat et al., 2009). This bacterium feeds on nondigestible galactooligosaccharides (GOS) found in human breast milk. The Bifidobacteria are commonly found in the feces of infants and has been shown to colonize the colonic epithelium of the infant and protect it from pathogenic bacteria (Bezirtzoglou et al., 2006; Thum et al., 2012; Zivkovic et al., 2011). By contrast, formula-fed infants have a more complex microbiota, more typifying adult forms of bacteria, with bifidobacteria, Bacteroides, clostridia, and streptococci all prevalent (Gibson and Roberfroid, 1995). The intestinal microbiota of neonates is characterized by low diversity and a dominance of the phyla Proteobacteria and Actinobacteria (which contains the Bifidobacteria). If delivered vaginally, human neonates are colonized within the first few days by organisms from the maternal vagina and rectum to contain large numbers of enterobacteria such as E. coli, and Streptococci, Lactobacilli, and Prevotella (Bäckhed, 2011; Cooperstock, 1987; Cooperstock and Zedd, 1983; Conway, 1997; Mackie et al., 1999). These facultative anaerobic microbiota generate conditions that favor the subsequent establishment of greater microbiota diversity with obligate anaerobes predominating; thus, the bacteria originally colonized during the birthing process become fewer in number. The obligate anaerobes include, members of the phylum Bacteroidetes, and continue to develop as time progresses from postnatal weaning from breast milk onto a solid diet rich in plant polysaccharides (Eckburg et al., 2005; Qin et al., 2010; Bäckhed, 2011). During this same period, obligate anaerobes such as Bacteroides and Clostridium species increase in number, ultimately becoming dominant genera of the adult gut microenvironment. By contrast, in cesarean delivery mostly the maternal skin bacteria colonize the newborn’s intestine, as evidenced by the dominance of Streptococcus, Corynebacterium, and Propionibacterium (Dominguez-Bello et al., 2010; Mackie et al., 1999). Generally, development of the gut microbiota is delayed for up to several weeks in Cesarean-delivered infants, who have slower acquisition of Bifidobacterium and Bacteroides (Frylund et al., 1992; Gronlund et al., 1999). In preterm infants, intestinal colonization with bifidobacteria is delayed (Blakey et al., 1982; Sakata et al., 1985). From the initial colonization, the infant gut microbiota is unstable and lacks diversity, but by the end of their first year, infants have a distinct microbial profile that is individually characteristic of them. This early period is defined as the window of opportunity to modify the gut microbiota for the ultimate long-term health of the host, Fig. 1.3. With addition time the microbiota profile stabilizes, diversifies, and acquires 40–60% similarity with adult microbiota, converging within 2–5 years of age, toward microbiota complexity of an adult in composition and diversity (Palmer et al., 2007; Koenig et al., 2011; Yatsunenko et al., 2012). This unique, individual composition and diversity is their microbiota profile for life, unless altered by stress, antibiotics treatment, or dietary modification with pro- and/or prebiotics, etc. As such, the first 3 years (1000 days) of life are critical for dietary interventions to improve child growth and development.

Figure 1.3   Epigenetic factors that influence intestinal colonization of the gut microbiota.

Green—beneficial modification. Red—modification considered negative for health.

The fecal material of children and adults has Bacteroidaceae, Eubacteria, and Peptococcaceae that outnumber bifidobacteria, which constitute 5–10% of the total microbiota. The numbers of Enterobacteriaceae and Streptococci in children and adults are also less than Bacteroides, eubacteria, Peptococcaceae, and bifidobacteria, decreasing to less than 10⁸ CFU/g of fecal material. Lactobacilli and Veillonella are also present in children and adult fecal material, but in numbers that usually are less than 10⁸ CFU/g (Mitsuoka, 1990). In elderly persons, the proportions of Bifidobacteria, Firmicutes, and Fecalibacterium prausnitzii tend to decrease or completely disappear, with an increase in Enterobacteriaceae such as E. coli, Proteobacteria, and Staphylococcus (Biagi et al., 2010; Claesson et al., 2011; Mariat et al., 2009). Putrefactive bacteria like clostridia, including C. perfringens, also significantly increase. In addition, lactobacilli and streptococci, also significantly increase. Mariat et al. (2009) further reported that total bacteria counts from infants were nearly 10-fold lower in log10 values (10.7) than in adults or seniors (11.5 and 11.4, respectively). Further, the dominant roles of bacteria from the phyla Firmicutes and Bacteroidetes remain unchanged during different life stages; however, the ratio of Firmicutes microbiota to Bacteroidetes evolves, to be respectively 0.4, 10.9, and 0.6 for infants, adults, and elderly individuals, respectively.

Early colonization of the gut microbiota, and resulting microbiota composition, once established, helps establish the health and disease potential of an individual throughout life. Its composition is relatively stable throughout adult life, but can be altered by several epigenetic factors including the original mode of infant delivery (Collado et al., 2012b; Gregory, 2011; Salam et al., 2006; Thavagnanam et al., 2008; Penders et al., 2006), as a result of bacterial infections (Dethlefsen et al., 2006), antibiotic treatment (Greer and O’Keefe, 2011; Jakobsson et al., 2010; Tanaka et al., 2009), age (Hopkins et al., 2002), stress (O’Mahony et al., 2009; Molina et al., 2009; Bailey et al., 2004), degree of hygiene (Schmidt et al., 2011), alcohol misuse (Kvietys et al., 1990; Wang et al., 2010), toxic pollutants (Kramer, 2002; Leshchuk et al., 2011), neonatal nutrition (Le Huërou-Luron et al., 2010; Hoffmann and Falvo, 2004; Bode, 2012; Penders et al., 2005), and adhering to a long-term Western diet high in red meat, saturated fats, refined sugar, and starch and low in fermentable fiber (Newmark et al., 2001; Turnbaugh et al., 2009), particularly prebiotic fiber, Fig. 1.3.

1.2.1. Fetal delivery method and pregnancy term

Regarding method of fetal delivery, recent evidence shows that vaginally delivered infants are colonized by maternal vaginal and fecal bacteria, including the health-promoting, probiotic bacterium Lactobacillus, Bifidobacterium spp., Prevotella, or Sneathia (Dominguez-Bello et al., 2010), while infants born via C-section are generally colonized by microbes associated with skin and the hospital environment, such as Staphylococcus, Corynebacterium, Propionibacterium, E. coli, and K. pneumoniae and other potentially pathogenic bacteria. Bifidobacterium numbers were significantly lower in cesarean born children, and the overall diversity of their microbiota also appeared lower (Bäckhed et al., 2015; Biasucci et al., 2010; Dogra et al., 2015; Jakobsson et al., 2014). Data from investigations to show long-term effects of the delivery mode have suggested that microbiota of C-section-delivered infants may be disturbed for months or even years (Salminen et al., 2004; Jakobsson et al., 2014). Infant populations have seen progressive increases in metabolic and immune mediated diseases that may be related to a parallel increase in the rates of C-section delivery, which have increased significantly beyond the 15% recommended by the World Health Organization (WHO). C-section deliveries have been associated with allergies and asthma, autoimmune diseases, such as type 1 diabetes, celiac disease, and obesity (Thavagnanam et al., 2008; Decker et al., 2010; Barros et al., 2012; Cho and Norman, 2013). Allergies are the most common chronic disease of children, while obesity, diabetes, and autoimmune disorders are highly significant nutrition issues in cultures consuming a Western diet (see sections on these conditions for further information).

The microbiota of preterm infants is also different to those delivered after a full-term pregnancy. Berrington et al. (2013) noted that in preterm infants, the microbiota are characterized by higher levels of facultative anaerobes and have lower diversity, with lower levels of short-chain fatty acids (SCFAs) and a delayed acquisition of the normal anaerobic gut microbiota including the bifidobacteria. The colonization of the microbiome within the gut of premature infants proceeds through a progression from bacilli to gamma-Proteobacteria to clostridia, with the rate, but not the sequence being influenced by antibiotic use, diet, age, or whether the infant was delivered vaginally or by Caesarean (LaRosa et al., 2014). Recent data by Mai et al. (2013) also suggest that preterm infants are more susceptible to mortality-inducing diseases such as necrotizing enterocolitis (NEC) and late onset sepsis.

1.2.2. Development of gut microbiota after birth and consequences of antibiotic treatments

Research has shown that antibiotics whether administered to the mother prior to birth or the infant, or during colonization or development, have shown significant bactericidal and bacteriostatic activity against pathogens, but a significant body of evidence also has shown that they have drastic short- and long-term implications on the gut microbiome, reducing bacterial diversity, while allowing opportunistic pathogens to flourish, resulting in increased susceptibility to allergic asthma, allergic sensitization, allergic rhinitis, and peripheral blood eosinophilia in the childhood, as well as other immunological dysfunctions (Abrahamsson et al., 2013; Azad et al., 2016; Bisgaard et al., 2011; Buffie et al., 2012; Cho and Blaser, 2012; Peterson and Round, 2014; Russell et al., 2012; Ubeda et al., 2010). However, antibiotics commonly prescribed can have significantly different influences on the microbiome. Several factors determine the potential for influencing gut microbiota, which are related to their spectrum of activity (Gismondo, 1998), pharmacokinetics, dosage (Nord, 1990), and length of administration (Nord and Edlund, 1990). Regarding an antibiotics activity and its potential to influence gut microbiota, an antibiotic that has a broad spectrum, such as ampicillin, ciprofloxacin (Cipro), cefbuperazone, cefoperazone, cefixime, ceftriaxone, or imipenem/cilastatin, relating to its ability to inhibit the growth of both Gram-positive and Gram-negative bacteria, will have greater impact on the intestinal microbiota than an antibiotic that is gram-reaction specific (Gismondo, 1998; Peterson and Round, 2014). The rate of intestinal absorption, a factor in pharmacokinetics, also plays a significant role, in addition, whether the antibiotic is excreted in its active form in bile or saliva also is important, as these factors determine the concentration of the antibiotic in the intestinal lumen, and thus, the severity of the microbiota alteration (Gismondo, 1998). Generally, oral antibiotics that are well absorbed from the small intestine have limited impact on the colonic microbiota, whereas those poorly absorbed can elicit significant gut microbiota alterations. In addition, antibiotics administrated parenterally can be secreted in their active forms in bile, saliva, or from intestinal mucosa, and result in significant microbiota alterations (Nord and Heimdahl, 1986). Further, the dosage and length of administration of an antibiotic determines the magnitude of impact on the gut microbiota. In general, the greater the dosage and length of administration, the larger is the impact on the microbiota (Nord and Edlund, 1990). Many antibiotics have long-lasting effects on the microbiota, leading to permanent loss of some organisms, while others overgrow and persist. By example, the broad-spectrum antibiotic, amoxicillin, a β-lactam antibiotic that inhibits peptidoglycan synthesis, has been shown to alter the gut microbiome by reducing diversity, particularly reductions in Bifidobacteria, and community-wide loss of Lactobacilli, Enterococcus, and Enterobacteriaceae in neonatal mice (Mangin et al., 2010; Sekirov et al., 2008). Another broad-spectrum antibiotic, vancomycin, that inhibits peptidoglycan crosslinkage, has been shown to significantly reduce microbiome diversity, by reducing a wide variety of microbial communities in mice, such as Lactobacilli, Enterococci, Group D Streptococcus (Sekirov et al., 2008), Bacteriodales, Ruminobcoccaceae, Lachnospiraceae, and Clostridiales in both adult and neonatal mice (Russell et al., 2012), and Tenericutes and Turicibacteria in neonatal mice (Russell et al., 2012). In clinical study, Vrieze et al. (2013) also demonstrated that vancomycin significantly lead to community loss of L. plantarum, Faecalibacterium prausnitzii, Eubacterium hallii, Clostridium cluster IV and XIVa, E. coli, Haemophilus spp., and Serratia. Of further consequence of vancomycin use is that it also allowed community expansion of several microbiota groups known to even potentially greater importance while also allowing the expansion of several communities having reported pathogenic or detrimental effects on the host (i.e., Enterobacteriaceae, Verrucomicrobiaceae, Panenibacillaceae, Firmicutes, and Anaeroplasmataceae) (Sekirov et al., 2008; Russell et al., 2012). Another broad-spectrum antibiotic, Cipro, that inhibits bacterial DNA replication, has been shown in clinical study to result in community-wide reductions in bacterial diversity, particularly losses of Clostridiales and Fecaelibacterium spp. (Dethlefsen et al., 2008; Sekirov et al., 2008).

Even more focused, narrow spectrum antibiotics can result in wide-spread community bacterial loss and expansion. The antibiotics cephalosporin, a β-lactam antibiotic, similar in activity to amoxicillin, and streptomycin, an aminoglycoside that inhibits peptide synthesis have been shown to reduce gut microbiota diversity, result in community loss and community expansion of certain microbiota. Perez-Cobas et al. (2013) showed that cephalosporin significantly reduced bacteria from the phylum Firmicutes, while also contributing to the community loss of Actinobacteria (Slackia and Bifidobacteria), beta-Proteobacteria, Streptococcus spp., Roseburia, and Eubacterium, bacteria with reported health-promoting properties. Sekirov et al. (2008) also reported that streptomycin significantly diminished the more health-promoting Lactobacillus spp., Enterococcus spp., and Group D Streptococcus, while allowing the expansion of more pathogenic Enterobacteriaceae.

Research evidence has also determined that if birth is preterm or antibiotic treatment has taken place during the early colonization period, these conditions are likely to have long-term implications for microbial diversity and consequent health. By example, Tanaka et al. (2009) showed that antibiotic therapy in infants was associated with higher proportions of enterobacteria and enterococci, and lower proportions of bifidobacteria, some of the differences remained 1 month after the cessation of treatment. Barrett et al. (2013) also characterized the gut microbiota in preterm infants as having reduced diversity and higher levels of potentially pathogenic bacteria, such as Enterococcus, together with Proteobacteria, and lower numbers of more health-promoting Bifidobacterium and Bacteroides compared with full-term infants (Moles et al., 2013). Investigators have also determined that even short-term antibiotic treatment can significantly affect the evolution of the infant gut microbiota. A significant consequence of such treatment is the colonization pattern of Bifidobacterium, which appears to be particularly disturbed up to 8 weeks after antibiotic treatment, while Proteobacteria are consequently increased (Fouhy et al., 2012a). High levels of Proteobacteria have recently been linked to NEC, a severe inflammatory intestinal disorder commonly associated with preterm delivered infants (Wang et al., 2009). Antibiotic therapy of mothers, either prenatal or during breastfeeding, is also associated with lower proportions of Bacteroides, Atopobium, and a lower number of total gut microbiota in neonates and infants (Fallani et al., 2010). Collectively, studies that indentified causality between dysbiosis and disease progression have provided the means to categorized dysbiosis into three different categories, including (1) loss of beneficial microbiota, (2) expansion of pathobionts or potentially harmful microorganisms, and (3) loss of overall microbial diversity. Often more than one type occurs at the same time.

Studies have also shown that multidrug resistant bacterial genes were prevalent for thousands of years before the advent of antibiotics, indicating exposure to environmental molecules having antimicrobial properties and effects on resistance genes (Dethlefsen et al., 2008). Although this could be secondary to the effects of an imbalance in the commensal microbiota, which could augment the development of resistant genes, resulting in a disruption of the symbiotic relationship between the host intestinal environment and the healthy gut microbiota (Kersten et al., 2011). One of the primary mechanisms the commensal microbiota has to prevent pathogenic proliferation is through competitive inhibition. By example, disturbing the populations of lactic-acid bacteria has significant consequences on acid production and luminal pH, as these bacteria are responsible for producing high levels of SCFA that lower the pH of the luminal contents below the level compatible for pathogen growth. In addition, disruption of the commensal gut microbiota diversity may also potentially increase the abundance of host-derived sialic acid, a growth promoter for pathogens such as Salmonella typhimurium and Clostridium difficile (Ng et al., 2013; Hurley and Nguyen, 2002). In addition to proliferation of opportunistic pathogens and decreased growth of health-promoting microbiota, such as the Bifidobacteria, which produce significant levels of SCFAs, the decrease in SCFA production can result in electrolyte imbalances and diarrhea (Bengmark, 1996; Mortensen and Clausen, 1994). SCFAs also contribute to host health in many other ways, as described in detail in following sections, such as improving blood flow in the colon and liver (Topping, 1996), increasing calcium solubility and absorption (Coudray et al., 1997), increasing absorption capacity of the small intestine (Clausen, 1998), maintaining colonic mucosal integrity (Sakata, 1997), decreasing the risk of developing gastrointestinal disorders, cancer, and cardiovascular disease by serving as signaling molecules for many metabolic processes (Wong et al., 2006).

Studies involving even short-term use of antibiotics have resulted in major changes in the gut microbiota, and resulting in diminished microbiota diversity and the persistence of the changes in many of the treated individuals. By example, Jernberg et al. (2007) showed that only a 7-day course of a broad-spectrum antibiotic, clindamycin, resulted in a persistent nonrecovery of Bacteroides diversity that lasted up to 2 years. Jakobsson et al. (2010) further showed that a short-term course of the antibiotic clarithromycin to eliminate a H. pylori infection resulted in a dramatic reduction in the diversity of Actinobacteria with a 1000-fold increase in the ermB resistance gene, which persisted for over 4 years in a percentage of the treated patients. A more recent study by Panda et al. (2014) showed that a 7-day course of Cipro and β-lactams, that primarily target Gram-positive microorganisms, reduced microbial diversity by 25% and microbiota taxa from 29 to 12 with an increased in the Bacteroidetes:Firmicutes ratio. However, the greatest concern on human health from the use of broad-spectrum antibiotics is not associated with alteration of the commensal gut microbiota diversity per se, but rather the potential these antibiotics have on propagating a resistant strain via horizontal gene transfer (HGT) (Frost et al., 2005; OECD, 2010; Gyles and Boerlin, 2014). Using HGT, bacterial species can transfer mutant genetic information across different species via conjugation, phage transduction, natural transformational mechanisms, or transposons and integrins. In fact, it could be envisaged that HGT may occur between pathogenic and probiotic bacteria in the gut, where pathogens could receive genetic elements from probiotics that enhance the pathogen’s colonization in the gut. HGT may also allow for the acquisition of virulence genes by probiotics from neighboring gut pathogens (Capozzi and Spano, 2009), resulting in a reservoir state of resistance genes. Thus, broad spectrum antibiotics should only be used with extreme care, and with significant consideration to the possible deleterious outcomes from their use. Decreasing excessive use of antibiotics, while increasing the use of pro- and prebiotics can be effective in preventing several important infant diseases such as NEC, atopic eczema as well as improving short- and long-term health (Wall et al., 2009).

1.2.3. Environmental and lifestyle factors, geography and host genetics

Environmental and lifestyle factors, and host genetics, can play a significant role influencing infant gut microbiota colonization. Research has also shown that geographical location can also play a role on the microbiota, as microbiota differences are related to dietary patterns and lifestyle in a specific area (Fallani et al., 2010; Suzuki and Worobey, 2014). In studying the influence of geography on infant microbiota composition, the investigators reported that infants from Northern Europe have higher levels of Bifidobacterium spp. and some Clostridium spp., and Atopobium spp., while infants from Southern Europe had higher levels of Eubacteria, Lactobacilli, and Bacteroides. Comparisons between the microbiota of infants from regions of close proximity, such as from Estonian and Sweden (Grześkowiak et al., 2012), or Finland, and Germany (Sepp et al., 1997), have also shown significant differences. It is also interesting to note that the incidence of obesity seems also to be geographically linked. Suzuki and Worobey (2014) using meta-analysis of six previous studies, involving 1020 healthy individuals drawn from 23 populations in Africa, Europe, North and South America, and Asia, found that the proportion of bacteria from the phylum Firmicutes increased with latitude, while the proportion of bacteria from the phylum Bacteroidetes decreased with latitude, regardless of sex, age, or detection methods. African-Americans showed the same patterns as Europeans and North Americans, not the pattern observed for Africans living in tropical areas. The fact that body size increases with latitude for many animals, including humans, Bergmann’s rule, it is thought to be an adaptation for dealing with cold environments. As current human gut microbiota were found to follow Bergmann’s rule may suggest that our microbiota are influenced by ancestral human microbial ecology, noting that Firmicutes bacteria have been shown to have greater ability to extract energy from food. The authors speculate that changes to the gut microbiota are important for allowing populations to adapt to different environmental conditions. Furthermore, the gut microbiota of healthy infants from the Amazonas of Venezuela, rural Malawi, and metropolitan US was compared (Yatsunenko et al., 2012). Data show that patterns of gut microbiome development were shared during the first year of life in all populations, and bifidobacteria was determined to be the most prevalent group, dominating the infant microbiota of all three locations during this period of development.

A recent study of the gut microbiota of a large cohort of Asian children (7–11-year olds) showed that the microbiota of the children were largely representative of the country of their residence, likely as a consequence of different dietary habits and lifestyles, as suggested by predictive metagenomic analysis. Data show that the majority of children from China, Japan, and Taiwan harbored bacteria from a Bifidobacterium/Bacteroides cluster, while those children from Indonesia and Khon Kaen in Thailand predominantly harbored Prevotella spp. (Nakayama et al., 2015).

In addition to geography, psychological stress also results in gut microbiota alteration. Early research by Lizko (1987), while investigating the effects of psychological stress on intestinal parameters in cosmonauts, determined that upon return from space flight their microbiome had significantly lower fecal Bifidobacteria and Lactobacilli populations. The alteration in microbiota led to a subsequent decline in colonization resistance, resulting in increased levels of pathogens, and a significant reduction in mucin production and a significant decrease in acid mucopolysaccharides on the mucosal epithelium. Lizko reported that exposure to stress decreases immunoglobulin A production, a key regulator in bacterial adhesion, increasing the potential for pathogen colonization. In early research with infant (6–9 months) rhesus macaques (Macaca mulatta), Bailey and Coe (1999) found that separation from their mothers resulted in an initial shedding of Lactobacilli on the first day of separation, and significant die-off, and decrease of Lactobacilli in the feces. They also observed a significant inverse relationship between the fecal concentrations of shed pathogens (Shigella spp.) and (Campylobacter spp.), and shed Lactobacilli (P = 0.07). In later research, O’Mahony et al. (2009) determined that male rat pups separated from their mothers for 3 h daily between postnatal days 2 and 12, had increased numbers of fecal coli and plasma corticosterone, a higher systemic immune response to bacterial lipopolysaccharide challenge than unstressed control rat pups. In research with mice, Bailey et al. (2011) determined that when their society is disrupted the stability and structure of the microbiota is altered, resulting in fewer Bacteroides spp., while significantly increasing the relative abundance of Clostridium spp. This change led to bacterial translocation and an increase in the presence of the circulating proinflammatory cytokines, IL-6 and MCP-1, which are correlated with stressor-induced changes in three bacteria genera (i.e., Ceprococcus, Pseudobutyrivibrio, and Dorea). Dinan and Cryan (2012) also reported that stress induces increased intestinal permeability and bacterial translocation, leading to bacterial antigens crossing the epithelial barrier to activate the innate mucosal immune responses, which in turn alters the composition of the microbiome and leads to enhanced hypothalamic–pituitary–adrenal axis drive.

In addition to the environment and lifestyle, host genetics has been know for more than 60 years to play a key role in intestinal colonization, immunity, and pathogenicity (Sherlock et al., 1963; Felsen and Wolarsky, 1955). Recent genome-wide association studies (GWASs) have identified genes that confer greater susceptibility to disease. GWAS have linked risk loci with genes involved in the interaction between host and commensal microorganisms. By example, one of the first genes implicated in Crohn’s disease susceptibility was nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a cytosolic pattern recognition receptor that has genetic variants strongly associated with the disease. In addition, multiple genes involved in autophagic clearance of bacteria have also been identified by GWAS, such as immunity-related GTPase family M protein gene (IRGM), autophagy-related protein 16-1 gene (ATG16L1), and unc-51 like autophagy activating kinase 1 gene (Franke et al., 2010; Henckaerts et al., 2011; Parkes et al., 2007; Prescott et al., 2010; Burton et al., 2007; Rioux et al., 2007). Autophagy is a cellular process where cytosolic components are enveloped by a double membrane, which then fuses with the lysosome for degradation of its contents. Autophagy is the main mechanism the body uses for recycling of proteins, organelles, and is very important for clearance of intracellular pathogens. Researchers have determined that deficiencies in ATG16L1 and IRGM genes result in diminished ability to clear Salmonella and E. coli (Rioux et al., 2007; Kuballa et al., 2008; Lapaquette et al., 2010), and for IRGM, mycobacteria, Listeria monocytogenes, and Toxoplasma gondii (Singh et al., 2006; Collazo et al., 2001). In addition, NOD2 gene variants have been shown to have less effective autophagy-mediated bacterial clearance (Cooney et al., 2010; Travassos et al., 2010; Homer et al., 2010), likely by a decrease in the ability to recruit the protein, ATG16L1, to the plasma membrane, resulting in ineffective clearance of intracellular Shigella and Salmonella infection in multiple cell types, including mouse embryonic fibroblasts, primary macrophages, and dendritic cells (Cooney et al., 2010; Travassos et al., 2010; Homer et al., 2010). These researchers have determined that variants of these genes influence autophagy, which, in turn, leads to impaired clearance of pathogenic bacteria and dysbiosis, resulting in triggers to impaired immunity response and inflammation associated with Crohn’s disease and other immune- and autoimmune-related disorders.

1.2.4. Structure and integrity of gut mucosal layer

In addition to the effects that birth term and antibiotic treatment have on gut microbial colonization, the structure, and composition of the host mucus layer and its development may also play a significant role in the colonization and succession of bacteria in the gut microbiota. Bacteroides thetaiotaomicron by example is reported to induce expression of the small proline-rich protein 2A, which is necessary for maintenance of desmosomes at the epithelial villus (Lutgendorff et al., 2008a). The mucus layer, made of mucin, a family high molecular weight, heavily glycosylated proteins (glycoconjugates) produced by the epithelial tissues (Marin et al., 2007), covers the intestinal epithelium and forms the site that the microbiota first encounter the host. Mucin has the ability to form gel-like secretions, serving functions from protection, lubrication, hydration to the intestinal lining, and also plays a significant role in maintaining intestinal homeostasis through complex interactions with commensal bacteria (Marin et al., 2007). The mucosal layer binds to pathogens as part of the immune system to enhance immune modulation (Shan et al., 2013) (see also section on immunomodulation). The mucosal layer varies by its thickness, composition, structure, and glycosylation pattern along the GI tract, correlating with the association of distinct microbial communities at the different GI epithelial areas (Hooper and Gordon, 2001; Kleerebezem and Vaughan, 2009). Currently, at least 20 different human mucins are identified by cDNA cloning, and are either classified as membrane-bound due to the presence of a hydrophobic membrane-spanning domain, favoring retention in the plasma membrane, or those that are secreted as principal components of mucus by mucous membranes or are

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