Gut Microbiota in Neurologic and Visceral Diseases

By Tahira Farooqui and Akhlaq A. Farooqui

Gut Microbiota in Neurologic and Visceral Diseases presents readers with comprehensive information on the involvement of microbiota in the pathogenesis of neurological disorders. Chapters cover the effect of microbiota on the development of visceral (obesity, type 2 diabetes, heart disease) and neurological disorders (Alzheimer’s disease, Parkinson’s, depression, anxiety, and autism). Sections focus on the molecular mechanisms and signal transduction processes associated with the links among microbiota-related visceral and neurological disorders. It is hoped that this discussion will not only integrate and consolidate knowledge in this field but will also jumpstart more studies on the involvement of microbiota in the pathogenesis of neurological disorders.

• Reviews the relationship between gut microbiome, diseases and disorders
• Discusses the relationship between diet, microbiota and inflammation
• Includes neurodegenerative, neuropsychiatric and cardiovascular disorders
• Covers diabetes, obesity and metabolic disorders
• Identifies molecular mechanisms and signal transduction processes
• Encompasses dietary fiber, fat, prebiotics and probiotics

• Language: English
• Publisher: Academic Press
• Release date: Mar 11, 2021
• ISBN: 9780128210406

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manuscript.

Chapter 1: Gut microbiota: Implications on human health and diseases

Tahira Farooqui    Department of Entomology, The Ohio State University, Columbus, OH, United States

Abstract

The complex communities of microorganisms colonized in the human gastrointestinal (GI) tract referred to as gut microbiota influence the host during homeostasis and disease. Animal research has demonstrated that several factors, including mode of delivery at birth, method of infant feeding, use of antibiotics, diet, and age, can contribute to the alteration of the composition of intestinal microbiota. The GI tract represents a unique challenge to the mammalian immune system. The gut microbiota influences the health of its host by providing crucial benefits in the form of immune system development, prevention of infections, nutrient acquisition, and maintaining brain and nervous system functionality. Any imbalance in the composition and diversity in microbiota (dysbiosis) contributes to low-grade inflammation and increased gut permeability, resulting in neurological and visceral diseases. This chapter discusses the classification of gut microbiota, factors responsible for changing its composition, roles, and ways by which human gut microbiota can be manipulated to treat and/or prevent diseases.

Keywords

Gut microbiota; Microbiome; Microbiome modulators; Dysbiosis; Probiotic; Prebiotic; Neurological disorders; Visceral diseases

1: Introduction

The human gastrointestinal (GI) tract harbors a complex and dynamic population of microorganisms (archaea and eukarya) called gut microbiota that has been estimated to exceed 10¹⁴. This number encompasses ~  10 times more bacterial cells than human cells.¹ Microbiota coexists in close association with humans and most of them are not harmful but rather important for the host. The microbiome is the catalog of these microbes (bacteria, fungi, archea, and viruses) living in the human lower GI tract and their genes. The number of genes in the microbiome is more than 100 times greater than the number of genes in the human genome.¹

Intestinal colonization begins after birth.²–⁴ At birth, the gut microbiota is aerobic, with small numbers and low diversity, with the most common bacteria being facultative anaerobes and members of the Enterobacteriaceae family. Within a few days, the gut environment becomes anaerobic, which favors the growth of the dominant bacterium genus, such as Bifidobacterium, in the infant gut in the first months of life. The adult-like microbiome starts developing at 6 months, dominated by Firmicutes and Bacteroidetes.⁵ The gut microbiota changes dramatically during pregnancy and intrinsic factors (such as stress), in addition to extrinsic factors (such as diet and drugs) as well as genetics, age, and hygiene factors (such as status, job security, salary, vacations, and work conditions), markedly influence the composition and activity of the gut microbiome throughout life.⁵

Under physiological conditions, a perfect equilibrium among commensals (bacteria that colonize the gut and protect the host from intruding pathogens by imposing a colonization barrier) and invasive pathogens (bacteria that bypass the epithelial barrier imposed by commensals disrupt tolerance to the resident microbiota causing stereotypic intestinal inflammation) maintains intestinal homeostasis.⁶ Any imbalance in gut microbiota composition is thought to precipitate a pathological state known as gut dysbiosis,⁷ which may be associated with the pathogenesis of many inflammatory diseases, infections, and visceral and neurological diseases. However, it is still unclear whether gut dysbiosis is a cause or consequence of these diseases.

Gut microbiota has been reported to influence human physiology, metabolism, nutrition, and immune function, thereby modulating the health of its host by providing crucial benefits in the form of immune system development, prevention of infections, nutrient acquisition, and perhaps even brain and nervous system functionality.⁸ The microbiome has been shown to play a causal role in the development of pathologies in animal models of human disease, such as obesity (and associated pathologies), autoimmune diseases, and neurological disorders.⁹–¹⁵ However, the importance of the microbiome has recently been significantly recognized in clinical and physiological research even for the diagnosis of diseases.¹⁶–¹⁹

This chapter discusses gut microbiota, its classification, factors responsible for changing its composition, microbial metabolites, and the effects of prebiotic and probiotic supplementation on host health. It also attempts to shed a light on the molecular mechanisms involved in an altered microbiome for causing or treating visceral and neurological diseases.

2: Classification

Gut microbiota is composed of several species of microorganisms such as bacteria, yeast, and viruses. Taxonomically, bacteria are classified according to phyla, classes, orders, families, genera, and species.²⁰ It is now known that more than 1000 different species colonize the human gut, all of which belong to a small number of phyla.²¹ The most dominant gut microbial phyla are Firmicutes, Bacteroidetes, and Actinobacteria, which represent 98% of human gut microbiota communities (Fig. 1). Proteobacteria, Fusobacteria, Cyanobacteria, and Verrucomicrobia are usually less well represented phyla that account for only ~  2% of human gut microbiota communities (Fig. 1).²¹–²³ The Firmicutes (a phylum of Gram-positive bacteria) is composed of more than 200 different genera such as Enterococcus, Lactobacillus, Streptococcus, Bacillus, Clostridium, and Staphylococcus. Clostridium genera represent 95% of the Firmicutes phyla. Bacteroidetes (a phylum of Gram-negative bacteria) consists of predominant genera such as Bacteroides and Prevotella, which do not exist in equal proportion in the gut. The Actinobacteria phylum (a phylum of Gram-positive bacteria) is proportionally less abundant, and is mainly represented by the Bifidobacterium genus.²² In the less well-represented group of gut microbial phyla, Proteobacteria is a major phylum of Gram-negative bacteria, which includes a wide variety of pathogenic genera, such as Escherichia, Salmonella, Vibrio, Helicobacter, Yersinia, Legionellales, and many others. Fusobacteria is phylum of Gram-negative nonsporing bacteria similar to Bacteroides. The four species most commonly implicated as significant human pathogens are Fusobacterium necrophorum, Fusobacterium nucleatum, Fusobacterium mortiferum, and Fusobacterium varium. Cyanobacteria is a bacterial phylum (also referred to as blue-green algae and blue-green bacteria) that obtains energy through a process known as photosynthesis, but lacks a nucleus or membrane-bound organelles, like chloroplasts, but has cell walls containing peptidoglycan. There are an estimated 150 genera of cyanobacteria containing ~  2000 species. Cyanobacteria often contain a variety of cyanotoxins that can exist as both cell-associated and free forms in the surrounding water, which can be highly neurotoxic and act through a variety of mechanisms.²⁴ Lastly, the Verrucomicrobia phylum of bacteria is abundant in aquatic and soil environments, but occasionally found in the human gut. It contains only a few described species. However, high-level colonization of the human gut by Verrucomicrobia has been reported following broad-spectrum antibiotic treatment.²⁵

Fig. 1

Fig. 1 Classification of gut microbiota.

3: Factors affecting the composition of the gut microbiota

The microbial composition is host specific, evolving throughout an individual's lifetime in response to various intrinsic and extrinsic factors. Actually, it starts at the gestational age in mothers’s womb. The development of the perinatal gut microbiota is influenced by multiple factors, such as gestational age, mode of delivery, maternal microbiota, infant feeding method, genetics, and environmental factors/stressors. The intrinsic factors include pregnancy, mode of birth, age, and genetic factors, whereas extrinsic factors include types of diet, drugs (e.g., antibiotics), infections, lifestyle, and environmental stressors (Fig. 2). Moreover, other stimuli including many other characteristics of the host, such as ethnicity, region of habitation, geography, and/or socioeconomic status, affect gut microbial composition (Fig. 2).

Fig. 2

Fig. 2 Various intrinsic and extrinsic factors that are responsible for influencing gut microbiota composition.

The gut microbial communities of the mother influence fetal development during pregnancy, which consequently affect the health of the offspring.²⁶ At birth, the initial microbiota composition is affected by the mode of delivery (vaginal or caesarean).²⁷–²⁹ Babies delivered by natural birth show greater gut bacterial counts at 1 month of age than those delivered by caesarean section, implicating that gut colonization by microbes begins during pregnancy and is enhanced by natural birth, having a dramatic effect on the health of the infant.²⁷–²⁹ Moreover, vaginally delivered infants acquire bacterial communities resembling their own mother's vaginal microbiota, dominated by Lactobacillus, Prevotella, or Sneathia spp., whereas infants delivered by C-section harbor bacterial communities similar to those found on the skin surface, dominated by Staphylococcus, Corynebacterium, and Propionibacterium spp.³⁰

Whether a baby is breast-fed or formula-fed plays an important role in the infant’s gut microbiota.³¹–³³ Breast-fed infants show a predominance of Bifidobacteria and Lactobacilli, whereas bottle-fed infants develop a mixed flora with a smaller number of Bifidobacteria.³³ The growth and development of a robust gut microbiota is important for the development of the immune system, which continues during breast-feeding (an important stage in which the transfer of immunity from mother to child that begins in the uterus is continued), and provides a nurturing environment required for the long-term health of the baby.³⁴–³⁶ Subsequently, another significant shift in the composition of the gut microbe community occurs when the infant switches to solid food and varied diet.

It has been increasingly evident based on molecular analyses, including The Human Microbiome Project, that there are differences found in the composition of gut microbiota among each stage of human life (infants, toddlers, adults, and the elderly). This suggests that each individual has a distinct combination of gut microbial species. In fact, gut microbiota is strictly linked to the chronological age of each individual (Fig. 2). Bacteria of the Bacteroidetes phylum tend to dominate numerically during youth, but numbers decline significantly by old age. The reverse trend occurs for bacteria of the Firmicutes phylum.³⁷

Diet has a dominant role over other possible variables, such as ethnicity, sanitation, hygiene, geography, and climate, on the microbial diversity in individual adults.³⁸ Interindividual differences in populations of gut microbiota may lead to different capacities to utilize dietary components and to different levels of disease risk. For example, the consumption of modern Western diets (containing high fat and low fiber due to low consumption of vegetables) in one group of adults tends to result in the loss of some important microbial species. A high-fat diet is considered a risk factor for disorders including obesity, diabetes, and metabolic syndrome, which are associated with profound modifications of gut microbiota composition.³⁹ In contrast, a different group of adults consuming a more healthy diet (containing high fiber and low fat) tends to have a smaller amount of pathogenic bacteria but a large amount of beneficial microbes, implicating that the gut microbiota and its composition can be altered by type of diet and its components.⁴⁰–⁴² Nearly 90% of the bacteria in the human gut can be mapped to just two phyla (Bacteroidetes and Firmicutes). However, the relative proportions of these two dominant phyla vary and can be influenced by a range of factors.⁴³ Both short-term and long-term dietary variations influence gut microbiota composition.⁴⁴

Older adults have substantially different GI tract communities than younger adults, which indicates that gut microbiota changes throughout life. Gut microbiota composition is also affected by various genetic factors (Fig. 2), transfering from mother to child.⁴⁵, ⁴⁶ Major concerns are the long-term use of drugs (e.g., antibiotics), which could result in long-term alteration of normal healthy gut microbiota (Fig. 2), and horizontal transfer of resistance genes, which could result in a reservoir of organisms with a multidrug-resistant gene pool.⁴⁷ Long-term use of antibiotics can bring changes in commensal bacteria associated with various conditions such as development of asthma, eczema, atopic dermatitis, other allergic senitization, and autoimmune encephalitis.⁴⁸ Therefore, the individual microbiota pattern is highly variable due to varying extrinsic and intrinsic factors, indicating a strong influence on the balance of the bacterial community.

4: Functional aspects of the gut microbiota

The GI tract is the main site where environmental microorganisms and antigens interact with the host through intensive cross talks. The gut microbiota benefits the host in many ways, including protecting against pathogenic colonization, which is essential for the maintenance of intestinal epithelial integrity (exerting trophic effects on the intestinal epithelium by favoring the development of intestinal microvilli), modulating host physiology and metabolism by harvesting of energy from ingested food but not digested by the host, playing a fundamental role in the maturation of the host's innate and adaptive immune responses, and regulating energy homeostasis and neurobehavioral development (Table 1).²¹, ⁴⁹–⁵³,

Table 1

A compound that is foreign to a living organism (Xenobiotic); Nuclear receptor farnesoid X receptor (FXR); antimicrobial products (AMPs); hypothalamic-pituitary-adrenal axis (HPA), corticotropin-releasing factor (CRF); toll-like receptors (TLRs); microbe-associated molecular patterns (MAMPs); Nod-like receptors (NLRs); gastric inhibitory peptide (GIP); G protein-coupled receptors (GPCRs, such as GPR41 and GPR43); a class of antidiabetic agents that mimic the actions of the glucagon-like peptide (GLP-1); paraventricular nucleus of the hypothalamus (VN); adrenocorticotropic hormone (ACTH); fatty acid (FA); short-chain fatty acids (SFAs), SCFA receptors (SCFARs), monounsaturated fatty acid (MUFA), microbiota-accessible carbohydrates (MACs), polyunsaturated fatty acids (n-6 PUFAs), biologically active proteins (BAPs) like trypsin and chymotrypsin inhibitors.

4.1: Protection against pathogenic colonization (colonization resistance)

On one hand, gut microbiota protects the host from infection by pathogenic microorganisms and contributes to both nutrient metabolism and the development and function of the GI immune system. On the other hand, the host provides a nutritious and hospitable environment to ensure the survival of resident microbial communities, thereby implicating a symbiotic relationship between gut microbiota and host. In addition to metabolic benefits, symbiotic commensals provide the host with several functions that promote immune homeostasis, immune responses, and protection against pathogen colonization.⁵³,⁵⁴ The ability of symbiotic commensals bacteria to inhibit pathogen colonization is called colonization resistance (CR), which is mediated via two mechanisms: (1) direct mechanisms (such as direct killing, competition for limited nutrients, as well as space) and (2) indirect mechanisms (including stimulation of innate or adaptive immune system, as well as by other nonimmune defenses).⁵³ In direct mechanisms, symbiotic bacteria scavenge nutrients that would otherwise be available to pathogens. Bacteriophages, type VI secretion systems (T6SS), and bacteriocins may target and kill pathogens. Microbiota-dependent digestion supports the growth of the bacterial community and generates byproducts that are utilized by the host, such as short-chain fatty acids (SCFAs), which can inhibit pathogen growth. Symbiotic bacteria produce enzymes that convert conjugated, primary bile acids (BAs) to secondary BAs, which can kill some pathogens. However, in indirect mechanisms, microbes can compete with one another indirectly by acting on the host.⁵³,⁵⁴

CR is carried out by secretion of antimicrobial products (AMPs), nutrient competition, bacteriophage deployment, and support of gut barrier integrity (Table 1).⁵⁴–⁵⁶ Moreover, changes in microbiota composition and potential subsequent disruption of CR can also be caused by various drugs, such as antibiotics, proton pump inhibitors, antidiabetics, and antipsychotics, thereby providing opportunities for exogenous pathogens to colonize the gut and ultimately causing infection.⁵⁷ In addition, the most prevalent bacterial enteropathogens, including Clostridioides difficile, Salmonella enterica serovar Typhimurium, enterohemorrhagic Escherichia coli, Shigella flexneri, Campylobacter jejuni, Vibrio cholerae, Yersinia enterocolitica, and Listeria monocytogenes, can employ a wide array of mechanisms to overcome colonization resistance.⁵⁷

4.2: Maintenance of the intestinal epithelium integrity

The gut intestinal epithelial layer forms the major barrier that separates the host body from the external environment. Gut microbiota are known to influence epithelial homeostasis by preventing pathogenic bacterial invasion by maintaining intestinal epithelium integrity (Table 1).⁵⁷–⁶⁰ The first layer of defense in the epithelium of the gut is formed by a mucus layer, which is critical for limiting the exposure of epithelial cells to the microbiome. The absence of a highly glycosylated polymeric protein (mucin) in the mucus layer makes the host vulnerable to intestinal inflammation. The intestinal epithelial system is also home to immune cells, including dendritic cells, T cells, B cells, and macrophages, which function in close relation with the intestinal epithelial cells (IECs) to maintain intestinal homeostasis.⁵⁸ Gut microbiota maintains a symbiotic relationship with immune cells. The maintenance of the intestinal epithelial barrier is the essential function of the IECs, which integrate positive and negative interactions from the microbiota living in the gut and signal the immune cells to accommodate the microbiota, thereby perpetuating the normal function of the body.⁵⁹

The intestinal epithelial monolayer is composed of different types of specialized epithelial cells (such as enterocytes, Paneth, goblet, endocytes, and microfold cells), each with a distinct function. The most abundant of these are IECs or enterocytes, which plays a major role in maintaining epithelial barrier integrity. Paneth cells are only found in the small intestine, particularly in the ileum. Paneth cells can directly sense enteric bacteria via cell-autonomous MyD88-dependent toll-like receptor (TLR) activation, triggering expression of multiple antimicrobial factors. They can synthesize and secrete AMPs, such as α-defensin, to impede microbial entry to the intestinal lumen. Goblet cells secrete mucus, trefoil peptides, and resistin-like molecule-β, which are central to both the defense and repair of the epithelial layer, and play significant roles in epithelial homeostasis. Endocytes regulate incoming antigens, whereas microfold cells secrete IgA, which, in addition to goblet cells, helps present bacterial antigens to dendritic cells. IECs are capable of phagocytosis and can sequester and neutralize bacterial toxins. Moreover, they recognize bacterial-derived molecules known as prokaryotic-associated molecular patterns (PAMP) with the help of the Toll-like receptors (TLRs) on the cell surface and the nucleotide-binding oligomerization domain-like receptors (NODRs) in the cytoplasm, which activate defense mechanisms by the secretion of AMPS.

IECs also maintain two-way communication with the underlying immune cells to regulate the inflammatory response against bacterial toxins. In conjunction with the mucosal layer (chemical barrier) and specialized cells, the epithelial layer forms a well-equipped, intricately regulated, and stringent barrier with continuous scrutiny by immune cells to create an immune-silent environment. IECs form a layer that functions as a physical barrier facilitated by tight connections between each cell. The tight junction proteins (such as occludin, claudins, and zonula occludens) are crucial for maintaining epithelial barrier integrity. To allow the transport of essential molecules and restrict harmful substances, the intracellular signaling transduction system involves a number of extracellular stimuli (such as cytokines, small GTPases, and posttranslational modifications), which markedly modulate the tight junction protein complexes. Any imbalance in these regulations, or dysfunction of IECs, may result in compromised barrier integrity causing several diseases. Thus, IECs maintain barrier integrity by allowing the permeability of essential ions, nutrients, and water, but restricting the entry of bacterial toxins and pathogens.⁶⁰ Moreover, genetic susceptibility, diet, and a number of environmental conditions may also affect the maintenance of the intestinal epithelium integrity directly or indirectly through changes in microbiota.

4.3: Modulation of host metabolism

As the gut microbiota encodes a substantively larger number of genes than its human host, it follows that they undertake a variety of metabolic functions that humans are unable to do or are only able to do in a limited capacity. The GI microbiota is crucial to the de novo synthesis of essential vitamins. Lactic acid bacteria are key organisms in the production of vitamin B12, which cannot be synthesized by either animals, plants, or fungi.⁶¹, ⁶²Bifidobacteria are main producers of folate, a vitamin involved in vital host metabolic processes.⁶³ Gut microbiota also synthesize vitamins such as vitamin K, riboflavin, biotin, nicotinic acid, pantothenic acid, pyridoxine, and thiamine (Table 1).⁶⁴ Moreover, GI microbiota also synthesizes all essential and nonessential amino acids, and carries out biotransformation of BAs (Table 1).⁶⁵

BAs are hydroxylated steroids, synthesized in the liver, from cholesterol. BAs are ligands for the nuclear farnesoid X receptor (FXR) as well as a G protein-coupled receptor (TGR5). BAs are synthesized under negative feedback control through activation of the FXR in the ileum and liver (Table 1). BAs appear to inhibit hepatic phosphoenolpyruvate carboxykinase (PEPCK) activity. PEPCK allows hepatic parenchymal cells to produce glucose from pyruvate derived from amino acid metabolism. Primary BAs, such as cholic and chenodeoxycholic acids, are synthesized from cholesterol in the liver, conjugated to glycine, taurine, or sulfate. Glycine from glycocholic acid serves as an energy, carbon, and/or nitrogen source, whereas taurine from taurodeoxycholate serves as a sulfur source. Deconjugation reaction (hydrolysis of the C-24 N-acyl amide bond) is catalyzed by bile salt hydrolase (BSH) enzymes, detected in several bacterial genera, including Clostridium, Bifidobacterium, Lactobacillus, Bacteroides, and Enterococcus. Deconjugation of bile salts makes them less soluble and less efficiently reabsorbed.⁶⁶ While most BAs are efficiently absorbed and recycled back to the liver, only about 5% of the total pool of BAs serve as a substrate for bacterial metabolism in the GI tract, then constitute the major route for cholesterol excretion from the body.⁶⁶, ⁶⁷ The composition and size of the pool of BAs can be altered by intestinal microbiota via the biotransformation of primary bile acids to secondary bile acids, subsequently killing some pathogens. BA-activated FXR plays important roles in synthesis of BAs and metabolism, glucose and lipid metabolism, and even hepatic autophagy. The distribution of BAs in the small and large intestine can also affect the bacterial community dynamics in the gut. Primary BAs, such as taurocholate, can provide homing signals to gut bacteria and promote germination of spores, and may facilitate recovery of microbiota after dysbiosis induced by antibiotics or toxins. On the other hand, reduced levels of BAs in the gut may play an important role in allowing pro-inflammatory microbial taxa to expand, implicating the role of BAs in shaping the GI microbiota. Gut microbial enzymes contribute to BAs metabolism, generating unconjugated and secondary BAs that act as signaling molecules and metabolic regulators to influence important host