Gut microbiota: Poised to assume an overarching role in a wide range of diseases

Sylvester Chuks Nwokediuko

doi:10.4103/njgh.njgh_4_21

EDITORIAL

Year : 2021 | Volume : 13 | Issue : 1 | Page : 1-5

Gut microbiota: Poised to assume an overarching role in a wide range of diseases

Sylvester Chuks Nwokediuko
Department of Medicine, University of Nigeria Teaching Hospital, Enugu, Nigeria

Date of Submission	29-May-2021
Date of Decision	29-May-2021
Date of Acceptance	29-May-2021
Date of Web Publication	30-Jun-2021

Correspondence Address:
Prof. Sylvester Chuks Nwokediuko
Department of Medicine, University of Nigeria Teaching Hospital, Ituku, Ozalla, PMB 01129 Enugu
Nigeria

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/njgh.njgh_4_21

How to cite this article:
Nwokediuko SC. Gut microbiota: Poised to assume an overarching role in a wide range of diseases. Niger J Gastroenterol Hepatol 2021;13:1-5

How to cite this URL:
Nwokediuko SC. Gut microbiota: Poised to assume an overarching role in a wide range of diseases. Niger J Gastroenterol Hepatol [serial online] 2021 [cited 2023 Mar 21];13:1-5. Available from: https://www.njghonweb.org/text.asp?2021/13/1/1/320306

Introduction

Over 2000 years ago, Hippocrates, the father of modern medicine propounded the theory that every disease starts from the gut. At the time this statement was made, research evidence as we have it today was not in good supply. However, we now know that there is an intricate relationship between gut health and the overall health of the individual.

The gut is home to a large number of microorganisms which make up the gut microbiota.^[1],[2] This is an intricate and dynamic system which has been conceptualized as a separate organ within the human body that provides many vital functions.^[3] Most of these organisms cannot be cultured with the standard microbiological techniques. Our understanding of gut microbiota has been revolutionized by advances in high throughput DNA sequencing technology and bioinformatics. Bioinformatics combines computer science, molecular biology, biotechnology, statistics, and engineering. The high throughput DNA technology utilizes omic technologies in the detection of genes, mRNA, proteins, and metabolites.

Four major phyla dominate the human gut microbiota: Firmicutes, Bacteroitetes, Proteobacteria, and Actinobacteria. The first two are the most abundant. Other minor phyla include Verrucomicrobia and Fusobacteria.^[4] The chemical, nutritional, and immunological gradients along the gut affect the density and diversity of gut microbiota. Thus, a gradient exists vertically and horizontally. On the horizontal axis is the observation that luminal organisms differ from those attached to the epithelium. Whereas the former is thought to be responsible for metabolic and nutritional activities, the latter plays greater role in immune function. Similarly, there is a vertical gradient of microbiota density in the gut,^[5],[6] with the stomach and duodenum harboring very low numbers because of gastric and pancreatic secretions and enzymes. The number gradually increases in the small bowel, reaching its highest concentration (up to 10¹¹-10¹³ bacteria/g) in the colon where anaerobes predominate.^[5],[7]

Initially, the gut microbiome was thought to have a limited role in the digestion of complex carbohydrates and in synthesizing Vitamins and nutrients. Currently, this new organ is known to govern host physiology by regulating metabolism, immunity, and gut-brain axis, through signaling of bioactive metabolites generated by the microbiome. It thus functions such as an endocrine organ secretes bioactive metabolites that can affect host physiology directly or indirectly.^[8]

Disturbance in density and diversity of gut microbiota (dysbiosis) has been reported in a wide range of medical conditions, including cancer, metabolic diseases (such as obesity and diabetes), inflammatory conditions, cardiovascular diseases, and neurodegenerative conditions. There is, thus, not only a potential diagnostic utility of this burgeoning field but also the microbiome holds great promise as an exciting new target for diet-based prevention and treatment of disease.

Physiological Functions of Gut Microbiota

Gut microbiota plays key roles in maintaining the metabolic, nutritional, structural, and immunological processes of the body.

Nutrition and metabolism

Both the microbiome and host genome participate in encoding for metabolites, with the former contributing much more than the latter. Specific functions of gut microbiota include extraction of energy from otherwise indigestible polysaccharides as well as promotion of uptake of nutrients. Extraction of energy from dietary polysaccharide and fiber leads to the production of short-chain fatty acids (SCFAs), Vitamins, and essential amino acids.^[9],[10]

SCFAs serve as nourishment for the microbiota and host intestinal cells and regulate immunity, energy metabolism, and expansion of adipose tissue. They also acidify the intestinal lumen, thus preventing the growth of pathogenic organisms.^[11],[12] The major SCFAs are acetate, butyrate, and propionate. Acetate is a substrate for gluconeogenesis and lipogenesis while butyrate and propionate regulate gut physiology and immunological processes. Gamma aminobutyric acid, tryptophan, serotonin, and catecholamines are other metabolic products of gut microbiota that function essentially as signaling molecules. Other functions of SCFAs include modulation of appetite regulation and energy intake,^[13] and maintenance of epithelial integrity through the action of interleukin-18.^[14]

Bile acids from dietary cholesterol are also metabolized by gut microbiota to prevent excessive weight gain and development of nonalcoholic fatty liver disease (NAFLD),^[15] reduce insulin resistance^[16], and also reduce diet-induced obesity.^[16],[17]

Defense against pathogens

Gut microbiota defends the host against pathogens through diverse mechanisms, including the production of antimicrobial compounds and colonization resistance.

Structural function

Gut microbiota plays a key role in the development, maturation and maintenance of the sensory, motor, intestinal barrier, and immune functions of the mucosa. Through the mechanism of competitive exclusion by the occupation of sites of attachment, competition for nutrients and production of antimicrobial compounds, the gut microbiota acts as a physical barrier to in-coming pathogenic organisms. Furthermore, gut microbiota stimulates the host to produce a wide range of antimicrobial compounds such as defensins, cathelicidins, and C-type lectins.^[18],[19]

Immunological function

The intestinal mucosa presents a very wide surface for interaction with antigen from the external environment. The dense microbiota in contact with the mucosa accounts for the bulk of antigens that confront the native immune cells. The immune system develops tolerance to overlying microbiota while at the same time controls the microbiota to prevent its overgrowth, translocation, and systemic dissemination.

Bacterial colonization of the gut is a fundamental requirement for the development and activation of the gut-associated lymphoid tissue.^[20],[21] Such colonization is associated with an increase in the number of immunocompetent cells (B-cell, T-cells, and dendritic cells). The complex mutually beneficial interaction between the gut microbiota and the host results in several immunological responses that ensure a dynamic equilibrium between the two partners. Typical examples of such responses include immunoglobulin A secretion and the release of antimicrobial peptides.

Gut-brain axis

Gut microbiota regulate mood and behavior of the host. The brain is able to sense gut bacteria (gutbrain axis). The vagus is thought to play a key role in this bidirectional flow of information.^[22]

Control of appetite

There is a complex interaction of genetic, environmental, and behavioral factors in the pathogenesis of obesity.^[23] Control of appetite is another function of gut microbiota. Dietary fiber has a complex structure and thus resists digestion in the upper gut, reaches the colon where it is fermented to release SCFAs. Some SCFAs can stimulate the release of appetite-suppressing hormones glucagon-like peptide-1 and peptide YY. Domestic and industrial food processing distorts food structure, leading to the production of energy-dense, more digestible, and easily absorbable products in the upper part of the gut. Bacterial fermentation is thus reduced with attendant loss of benefits derived therefrom.

Gut Microbiota in Disease

The factors that affect the density and diversity of gut microbiota are multiple, including mode of delivery, feeding methods, especially in infancy, level of nutrition, age, diet, drugs, living arrangements, and host immunization.^{[24],[25],[26],[27],[28],[29]} The processes involved are complicated. For instance, the process of aging is associated with a reduction in the propensity of gut microbiota to produce SCFAs with consequent reduction in amylolytic capability of the host. This state may in turn promote inflammatory changes in the gut.^[30],[31]

Dysbiosis is associated with a wide range of changes in the health of the host. These changes are underpinned by changes in energy absorption and changes in microbial metabolites such as choline, SCFAs, bile acids, and disturbance of the gutbrain axis.

A proinflammatory state in the gut can be induced by a permanent change in the composition or function of gut microbiota which in turn leads to alteration in intestinal permeability, visceral hypersensitivity, intestinal motility, and alteration in immune and metabolic functions with the potential of initiating certain diseases such as diabetes mellitus, obesity, neurodegenerative and autoimmune diseases.^[32],[33]

Although it is difficult to prove causation for many diseases in which gut microbiota plays a role, a number of epidemiological studies have revealed that a reduction in the diversity of gut microbiota is associated with some diseases, including NAFLD, asthma and inflammatory diseases, diabetes and obesity, allergies, inflammatory bowel disease, and irritable bowel syndrome.^{[34],[35],[36],[37],[38],[39]} Others include autism, cancer, anxiety, and depression.^{[40],[41],[42]}

Therapeutic Applications

A reliable approach to the management of diseases related to gut microbiota is to restore the individual from the dysbiotic state to a healthy gut microbiota.^[43] The most rational therapeutic options include antibiotics, prebiotics, probiotics, and fecal microbiota transplantation (FMT). FMT has been satisfactorily proven to be efficacious in the management of recurrent Clostridium difficile

ection (CDI). The use of FMT in this condition is associated with about 90% therapeutic success and a very good safety profile.^[44] Efficacy of FMT in other diseases remains to be established. Protocol standardization for each disease and rigorous evaluation of gut microbiota profile of donors and recipients are variables that will most likely improve outcomes.

The gut microbiome holds promise as an exciting new target for interventions that are diet-based. Accurate glucose response prediction to specific diets is possible through the use of personal and microbiome features.^[45] This was made possible through the use of a machine-learning algorithm that integrates blood parameters, dietary habits, anthropometrics, physical activity, and gut microbiota measured in a cohort. The result was an accurate postprandial glycemic response to real-life meals.

The overarching place of gut microbiota in human disease was brought to the fore recently in a seminal viewpoint expressed by Finlay who proposed the hypothesis that diseases that were hitherto classified as noncommunicable, that cannot be transmitted from person to person might actually be transmissible.^[⁴⁶^] Conventionally, these noncommunicable diseases (NCDs) are thought to be propagated by genetic, lifestyle, and environmental factors, rather than microbial involvement. Examples include hypertension, diabetes mellitus, obesity, and cancer. Dysbiosis is an underlying factor in these NCDs and in animal experiments, transplantation of the abnormal microbiota of NCD models into healthy animals results in disease in the recipient. Based on this observation, it is plausible to posit that NCDs could have a microbial component, which in this case is the microbiota. In support of this is the fact that people who live together such as spouses tend to have similar microbiota.^[47] However, the confounding effect of diet and other environmental factors remains a formidable research frontier.

Gut microbiota, together with new generation sequencing and omics technologies are an emerging flagship in the prevention, diagnosis, and treatment of a wide range of human diseases. However, many questions remain unanswered. The concept of “good” and “bad” gut microbiome remains elusive. It has been difficult to classify these microbiota-driven disorders, and screening methods for recognition of affected persons are yet to be developed. Furthermore, the question of the chicken and the egg is also being re-enacted in this complex relationship. Is dysbiosis the cause or effect of the disease with which it is associated? Answers to these pertinent questions are likely to become available as more results of mechanistic research become available.

Conclusion

The human gut microbiota is a complex colony of diverse micro-organisms whose role in the maintenance of healthy living and causation of a wide range of diseases has become an interesting field of medical research. In health, the microbiota has a unique density and diversity, through which it is able to perform certain metabolic, nutritional, structural, and immunological functions. Perturbations of this uniqueness result in disease. Microbial replacement therapies rely on the deliberate manipulation of this milieu to restore balance. To date, FMT for the treatment of recurrent CDI is the only condition in which microbiome replacement therapy has recorded significant efficacy. Granted that many questions arising from the intricate nature of this subject remain unanswered, the surge in research output in the field confers on gut microbiota an overarching status in disease prevention, diagnosis, and treatment.

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