Microbiome Therapeutics: Personalized Therapy Beyond Conventional Approaches

Microbiome Therapeutics: Personalized Therapy Beyond Conventional Approaches addresses the current knowledge and landscape of microbiome therapeutics, providing an overview of existing applications in health and disease as well as potential future directions of microbiome modulations and subsequent translation to the global industry and market. This important reference provides the most current status of microbiome therapeutics as well as possible future perspectives through coverage of topics including the application of microbiome therapeutics; various additive, subtractive and modulatory approaches; microbiome composition of health and diseases, insights into live bio-therapeutics and the clinical data supporting their efficacy.

Case studies are provided throughout the book to further define, describe and evaluate microbiome therapeutics success and failure.

• Provides chapters focused on illness types to address the potential of microbiome therapeutics in several significant disorders
• Offers human gut microbiome explorations that have enriched the understanding of microbiome colonization, maturation, and dysbiosis in health and disease subsets
• Addresses important concepts like economic potential in the global therapeutics market as well as ethical, technical, and regulatory aspects

• Language: English
• Publisher: Academic Press
• Release date: May 17, 2023
• ISBN: 9780323993371

Book preview

Microbiome Therapeutics

Personalized Therapy Beyond Conventional Approaches

Editors

Nar Singh Chauhan

Suneel Kumar

Table of Contents

Cover image

Title page

Copyright

Contributors

Preface

Chapter 1. Microbiome therapeutics: a boon to modern therapeutics

1. Introduction

2. Microbiome therapeutics

3. Microbes maintain the well-being of various body organs

4. Conclusion

Chapter 2. Microbiome additive therapy for the human health

1. Introduction

2. Microbiome additive approaches

3. Method used to design genetic engineered microbiome additives

4. Microbiome additive therapy and clinical studies

5. Conclusion

6. Future perspective

Chapter 3. Microbiome subtractive therapy for health benefits

1. Introduction

2. Microbiome for human health and diseases

3. Brief description of microbiome

4. Subtractive approach of microbiome therapeutics

5. Phage therapy–derived microbiome subtraction

6. Bacteriocin-derived microbiome subtraction

7. Antimicrobial/bioactive metabolites–derived microbiome subtraction

8. Bottlenecks in the subtractive approach of microbiome therapeutics

9. Conclusion

10. Future perspectives

11. Declarations

Chapter 4. The modulatory approaches of microbiome therapeutics

1. Introduction

2. Human microbiome-based modulatory approaches

3. Microbiome consortia: organ-specific distribution in the human body

4. Conclusion

Chapter 5. Recent advances in microbiome engineering for therapeutic applications

1. Introduction

2. Microbiomes in the cancer microenvironment

3. The microbiome of diabetic patients

4. Fecal microbiota transplantation based therapeutics

5. Probiotic for microbiome restoration

6. Genetically engineered probiotics for target microbiome engineering

7. Conclusion and future prospects

Chapter 6. Microbial management of nonalcoholic fatty acid liver diseases

1. Introduction

2. Nonalcoholic fatty acid liver disease

3. Diagnosis of nonalcoholic fatty acid liver disease

4. Causative agents of nonalcoholic fatty acid liver disease

5. Clinical/chemical features of nonalcoholic fatty acid liver disease

6. Role of gut microbes in nonalcoholic fatty acid liver disease

7. Microbial therapies

8. Dietary management of nonalcoholic fatty acid liver disease

9. Conclusion

Chapter 7. Microbiome therapeutics in psychological disorders

1. Introduction

2. Gut microbiota

3. Gut dysbiosis

4. Skin microbiota

5. Core skin microbiota

6. Resident microbiota

7. Transient microbiota

8. Cutaneous dysbiosis

9. Gut microbiota in host physiology

10. Metabolism

11. Immunity

12. Brain–gut–microbiota–stress axis

13. Bidirectional pathways of the brain–gut–microbiota axis

14. Gut–brain axis: neuropsychology

15. The microbiota and the hypothalamic–pituitary–adrenal axis

16. Can the gut microbiota influence neural circuitry and behavior associated with the stress response?

17. Role of the gut microbiota in central nervous system physiology: behavioral and neurobiological data

18. Anxiety-like behavior

19. Cognition

20. Regulation and modulation of the microbiota

21. Administration of pre/probiotics

22. The microbiota affects the immune activation of the mucous membranes

23. Psychobiotics

24. General concepts in this chapter

Chapter 8. Microbiome therapeutics for the cancer management

1. The microbiome and disease

2. The microbiome in cancer treatment

3. Microbiome therapeutics for the cancer management

4. Effect of microbiome composition on the efficacy of anticancer therapy

5. Therapeutic strategies to modulate microbiome toward improved cancer therapy

6. Conclusion and future directions in microbiome therapeutics development

Chapter 9. A Tour-d’Horizon of microbiota therapeutics for metabolic disorders

1. Introduction

2. Maintenance of healthy gut microbiota

3. Gut microbiota and metabolic disorders

4. Gut microbiota–based therapeutics

5. Microbial therapeutics: how effective are they?

6. Future prospects

Chapter 10. Microbiome therapeutics in skin diseases

1. Introduction

2. Skin microbiome

3. Skin microbiota in health and diseases

4. Microbiome and cutaneous immune response

5. Skin diseases and microbiome intervention

6. Skin diseases and the role of probiotics

7. Clinical trials on microbiome therapeutics for skin diseases

8. Conclusion and prospects

Chapter 11. Overview of microbial therapeutics in immunological disorders

1. Introduction

2. Contribution of microbes in the development of the immune system

3. Tools to investigate and understand immunological disorders

4. Brief description of immunological disorders, etiology, role of microbes, and therapies

5. Microbe-based therapeutic approaches for treating immunological disorders

6. Limitations and challenges of microbiota-based therapy

7. Future perspectives

8. Conclusions

Appendix I

Appendix II

Chapter 12. Microbiota and its therapeutic implications in reproductive health and diseases

1. Introduction

2. Microbiota in reproductive health

3. Microbiome in sexual behavior and pregnancy

4. Microbiome in gynecological cancers

5. Microbiome as therapeutics in reproductive health diseases

6. Concluding remarks and future perspectives

Chapter 13. Personalized nutrition, personalized medicine, and microbiome therapeutics

1. Introduction

2. Personalized nutrition

3. Personalized diseases diagnostics and microbiota

4. Personalized treatment and microbiota

5. Microbial signatures for personalized treatment

6. Challenges with microbiome-associated personalized medicine

7. Conclusion and future prospects

Chapter 14. Microbiome therapeutics in respiratory illnesses

1. Introduction

2. Lung microbiota

3. Challenges in the identification of lung microbiome

4. Gut–lung axis

5. Respiratory disorders

6. Use of microbes for lung health

7. Probiotics colonize the upper respiratory tract

8. Clinical implications of probiotics in the upper respiratory tract

9. Conclusion

10. Future perspectives

Chapter 15. Microbiome therapeutics as an alternative to the antibiotics

1. Introduction

2. Effect of the gut microbiome on health

3. Antibiotic effects on gut microbiota

4. Antibiotic resistance

5. Advance developed therapeutics in modulating the microbiome

6. Challenges in microbiota-based therapeutics

7. Summary

Chapter 16. Microbiome-mediated T cell regulation, inflammation, and disease

1. Introduction

2. Gut microbiome

3. Diet and gut microbiome

4. Pro- and antiinflammatory metabolites

5. Regulation of innate and adaptive immune cells by gut metabolite

6. Gut microbiome and inflammation: role in health and diseases

7. Clinical interventions and precision medicine

8. Conclusions and future directions

Chapter 17. Implementation of microbiome therapeutics: bottlenecks and their redressal using suitable delivery techniques—some case studies

1. Introduction

2. Probiotic delivery—scope and issue

3. Case studies

4. Concluding remarks and future scope

Chapter 18. Conclusion and future perspective

1. Introduction

2. Microbiome therapeutics

3. Future perspectives

Index

Copyright

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Contributors

Mirah Khalid Alshehhi,     Alforsan Holding, Abu Dhabi, United Arab Emirates

Francois Berthiaume,     Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, United States

Monika Bhardwaj,     Department of Biochemistry, Maharshi Dayanand University, Rohtak, Haryana, India

Oscar K. Bitzer-Quintero,     Neurosciences Division, Western Biomedical Research Center, Mexican Social Security Institute (InstitutoMexicano del SeguroSocial (IMSS)), Guadalajara, Jalisco, Mexico

Anirban Chattopadhyay,     Critical Care Medicine, CK Birla Hospitals Kolkata, Kolkata, West Bengal, India

Partha Chattopadhyay

INtegrative GENomics of HOst-PathogEn (INGEN-HOPE) Laboratory, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India

Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India

Nar Singh Chauhan,     Department of Biochemistry, Maharshi Dayanand University, Rohtak, Haryana, India

Mahesh Kumar Choudhary,     Internal Medicine, CK Birla Hospitals, Kolkata, West Bengal, India

Daniela L.C. Delgado-Lara,     Department of Philosophical and Methodological Disciplines, University Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico

Parneet Kaur Deol,     G.H.G. Khalsa College of Pharmacy, Ludhiana, Punjab, India

Priti Devi

INtegrative GENomics of HOst-PathogEn (INGEN-HOPE) Laboratory, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India

Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India

Aarushi Garg,     INtegrative GENomics of HOst-PathogEn (INGEN-HOPE) Laboratory, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India

Héctor González-Usigli,     Department of Neurology, Sub-Specialty Medical Unit, National Western Medical Center, InstitutoMexicano del SeguroSocial (IMSS), Guadalajara, Jalisco, Mexico

Saksham Gupta,     INtegrative GENomics of HOst-PathogEn (INGEN-HOPE) Laboratory, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India

Madangchanok Imchen,     Department of Genomic Science, Central University of Kerala, Kasaragod, Kerala, India

Shafaque Imran,     Department of Cardiac Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi, India

Kailash Jaiswal,     Department of Cardiac Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi, India

Raj Kishor Kapardar,     The Energy and Resources Institute, New Delhi, India

Tanya Kapil,     Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, India

Indu Pal Kaur,     University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India

Suneel Kumar,     Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, United States

Ranjith Kumavath

Department of Genomic Science, Central University of Kerala, Kasaragod, Kerala, India

Department of Biotechnology, School of Life Sciences, Pondicherry University, Kalapet, Puducherry, India

Haripriya J. Kungumaraj,     Department of Kinesiology and Health, School of Art and Sciences, Rutgers University, Piscataway, NJ, United States

Soumendu Mahapatra

Chromatin and Epigenetic Unit, Institute of Life Sciences, Bhubaneswar, Odisha, India

Kalinga Institute of Industrial Technology (KIIT), School of Biotechnology, Bhubaneswar, Odisha, India

Mario A. Mireles-Ramírez,     Department of Neurology, Sub-Specialty Medical Unit, National Western Medical Center, InstitutoMexicano del SeguroSocial (IMSS), Guadalajara, Jalisco, Mexico

Rasmita Mishra,     Chromatin and Epigenetic Unit, Institute of Life Sciences, Bhubaneswar, Odisha, India

Smrutishree Mohanty,     Chromatin and Epigenetic Unit, Institute of Life Sciences, Bhubaneswar, Odisha, India

Jamseel Moopantakath,     Department of Genomic Science, Central University of Kerala, Kasaragod, Kerala, India

Gagandeep Mudhar,     School of Art and Sciences, Rutgers University, Piscataway, NJ, United States

Asiya Nazir,     College of Arts and Science, Abu Dhabi University, Abu Dhabi, United Arab Emirates

Genaro Gabriel Ortiz

Department of Philosophical and Methodological Disciplines, University Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico

Department of Neurology, Sub-Specialty Medical Unit, National Western Medical Center, InstitutoMexicano del SeguroSocial (IMSS), Guadalajara, Jalisco, Mexico

Fermín P. Pacheco-Moisés,     Department of Chemistry, University Center of Exact Sciences and Engineering, University of Guadalajara, Guadalajara, Jalisco, Mexico

Rajesh Pandey

INtegrative GENomics of HOst-PathogEn (INGEN-HOPE) Laboratory, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India

Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India

Shaista Parveen,     INtegrative GENomics of HOst-PathogEn (INGEN-HOPE) Laboratory, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India

Sujata Prasad,     MLM Medical Labs, LLC, Oakdale, MN, United States

Punit Prasad,     Chromatin and Epigenetic Unit, Institute of Life Sciences, Bhubaneswar, Odisha, India

Ankita Punetha,     Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, United States

Arun Kumar Punetha,     Kilkari Health Centre, Pithoragarh, Uttarakhand, India

Arathi Radhakrishnan,     Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, India

Javier Ramírez-Jirano,     Neurosciences Division, Western Biomedical Research Center, Mexican Social Security Institute (InstitutoMexicano del SeguroSocial (IMSS)), Guadalajara, Jalisco, Mexico

Swathi V. Reddy,     Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, United States

Sheeba Saifi,     INtegrative GENomics of HOst-PathogEn (INGEN-HOPE) Laboratory, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India

Saransh Saxena,     INtegrative GENomics of HOst-PathogEn (INGEN-HOPE) Laboratory, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India

Aditi Munmun Sengupta

Department of Physiology, University of Calcutta, Kolkata, West Bengal, India

Harvard Medical School, Boston, MA, United States

American College of Physicians—India Chapter, Kolkata, West Bengal, India

Department of Critical Care, CK Birla Hospitals, Kolkata, West Bengal, India

Garima Sharma,     University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India

Shipra,     Department of Cardiac Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi, India

Amar Singh,     Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, United States

Bandana Singh,     Mayo Clinic, Rochester, MN, United States

Gatikrushna Singh,     Department of Neurosurgery, University of Minnesota, Minneapolis, MN, United States

Mandeep Singh,     University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India

Padmasana Singh,     Department of Zoology, University of Allahabad, Prayagraj, Uttar Pradesh, India

Raj Kamal Srivastava,     Department of Zoology, Indira Gandhi National Tribal University, Anuppur, Madhya Pradesh, India

Rajpal Srivastav

Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, India

Department of Science and Technology, Ministry of Science & Technology, New Delhi, India

Aparna Swaminathan,     INtegrative GENomics of HOst-PathogEn (INGEN-HOPE) Laboratory, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India

Manoj Kumar Tembhre,     Department of Cardiac Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi, India

Blanca M. Torres-Mendoza

Department of Philosophical and Methodological Disciplines, University Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico

Neurosciences Division, Western Biomedical Research Center, Mexican Social Security Institute (InstitutoMexicano del SeguroSocial (IMSS)), Guadalajara, Jalisco, Mexico

Erandis D. Torres-Sánchez,     Department of Medical and Life Sciences, University Center ‘La Cienega’, University of Guadalajara, Ocotlán, Jalisco, Mexico

Monika Yadav,     Department of Biochemistry, Maharshi Dayanand University, Rohtak, Haryana, India

Preface

The human microbiome, the collection of microorganisms that reside in and on the human body, is a complex and dynamic ecosystem. Research in this field has revealed that imbalances or dysfunction in the microbiome can contribute to a wide range of conditions, from gastrointestinal disorders to immune-mediated diseases and even mental health disorders. In recent years, advances in technology and an increased understanding of the microbiome have led to the emergence of microbiome therapeutics as a promising new field in medicine.

This book provides a comprehensive overview of the current state of microbiome therapeutics, including the types of therapies being developed, the potential benefits and risks, and the ongoing research needed to fully understand the safety and efficacy of these therapies. It covers the basic science behind microbiome therapeutics and how it relates to human health, as well as the latest findings from ongoing research in the field. This book also delves into the various therapeutic approaches being developed, including the use of probiotics, fecal transplants, and microbial-derived molecules. This book provides case studies and practical examples of the use of microbiome therapeutics in the treatment of different human illnesses. It also covers the challenges and limitations of microbiome therapeutics, such as the need for a better understanding of the complex interactions between the microbiome and the host, and the need for more rigorous safety and efficacy testing.

This book is written by leading experts in the field and provides in-depth information on the latest research and developments in microbiome therapeutics. It is an essential resource for researchers, healthcare professionals, and anyone interested in this rapidly evolving field. With the help of this book, readers will gain a deeper understanding of the potential of microbiome therapeutics to revolutionize the treatment of a wide range of diseases, and the challenges that must be overcome to fully realize this potential.

Chapter 1: Microbiome therapeutics

a boon to modern therapeutics

Monika Bhardwaj, and Monika Yadav     Department of Biochemistry, Maharshi Dayanand University, Rohtak, Haryana, India

Abstract

Scientific explorations have enabled the microbial evaluations to describe the colonization, establishment, maturation, and role of gut microbes in human health and diseases. The significance of human microbiota in host's physiology opens new gateways for microbial augmentation as therapeutics. Gut microbes impart the health-promoting benefits to various body organs through gut–organ axis. Microbiome therapeutics strategizes to engineer the microbes with additive, subtractive, or modulatory approaches. Microbiome augmentation aims to combat the disadvantages of traditional medications and provides more promising therapeutic management of human disorders. Successful clinical trials justify the role of microbes in relieving the symptoms of various human disorders. This chapter aims to address the significant implementation of microbiome therapeutics, explains the applications of microbiome therapeutics in various human disorders, and discusses the potential future directions of microbiome modulations.

Keywords

Additive therapy; Human diseases; Microbial dysbiosis; Microbiome augmentation; Modulatory therapy; Subtractive therapy

1. Introduction

The human body is the shelter for immense microorganisms consisting of bacteria, fungi, protozoa, and viruses (Khayyira et al., 2020; Chauhan, 2022a). Broadly, all these entities are referred to as the microbiota, and the genomes from these microbes are collectively called the microbiome. In the human microbiome, bacteria are largely present in the gastrointestinal tract (Gilbert et al., 2018; Sharma et al., 2021a,b,c). Besides it, they colonize the skin, saliva, oral mucosa, nasopharyngea, skin, vagina, urogenital tract, conjunctiva, and other body sites as well (Kirby et al., 2021). The microbes colonizing the human intestines are different in composition and influenced by nutriment and antibiotics revelation. Each of these niches is distinct, and depending upon the locality in the body, they are mutually related to the host. The microbes in their niches play a role in nervous system development, maintaining energy homeostasis, human physiology, immunity, and providing nutrition. The arrangement and role of gut microbes are determined by environmental, geographical parameters, nutritional, genetic, physiological factors, meals, medication, and anxiety. The microbial communities have a major impact on human health. It is seen in recent research that microbes interact mutually and cross-talk with the human host creating bifacial cooperation that influences the host execution. Due to their key role in human health, researchers are being influenced and utilizing their properties to cure major diseases and are being recognized as therapeutics for several diseases (Bui and de Vos, 2021; Yadav et al., 2020a,b). Reduction in microbiota heterogeneity is the result of a lack of fiber intake in food and the effect of antibiotics taken for various diseases that differ, from an allergy to sensitivity to viral, bacterial, and fungal infections (Sorbara and Pamer, 2022; Mittal et al., 2020). The defensive role of intestinal microbes is frequently impaired by disturbance of the previously mentioned elements or by other exterior elements that forehead to various contagious modifications in the host body, resulting in various severe diseases (Rawls et al., 2006; Kumar et al., 2020a,b). Dysbacteriosis is an imbalance of microbial colonies that have been the suspicious basis of acute and chronic inflammatory diseases such as irritable bowel syndrome, inflammatory bowel disease, metabolic disorders such as diabetes, obesity, neurological illness, allergic diseases, and other harmful microbial and parasitic infections (Cani et al., 2008; Joossens et al., 2011; van den Elsen et al., 2017; Warner et al., 2016; Mittal et al., 2019). The persistence of antibiotics is vital for fabulous healthcare while the loss of favorable symbiotic bacteria is the result of antibiotic dosage that comes up with the scale of nasty outcomes. These negatives are offset by the positive results of antibiotics in decreasing the mortality rate of infectious diseases (Sorbara and Pamer, 2022). To reverse the harmful effects associated with microbiome depletion, the restoration of the symbiotic bacterial population that is accidentally diminishing should be addressed. The most potent target for restoration of the microbiome is the macropopulation treated with abroad scale of antibiotics (Sorbara and Pamer, 2022; Kumar et al., 2018a,b). Devilishly, the upgradation of the microbiome is sighted as a primary thinkable subordinate to recent and upgrowing medical cures. Unveiling the role of microbiota composition in diseases susceptibility is helping to develop therapeutic treatment of human illnesses (Eng and Borenstein, 2019; Ahmed et al., 2013). We are focusing on the methods through which microbiota can be manipulated in a way that increases disease resistance or cures the disease. Description of the fundamental procedures is the basis for the implication of therapeutic approaches. Therapies that are blueprinted to retard harmful microbes and organize healthy microbes are microbiome therapeutics. The gut microbiome is now the center of attention for its contribution to disease pathology and its role in microbiome dysbiosis which is common in disorders such as obesity (Sanmiguel et al., 2015; Ahmed et al., 2015), cardiovascular disease (Tang et al., 2017), diabetes (Singer-Englar et al., 2019), bipolar disease (Dickerson et al., 2017; Ahmed et al., 2014b), and many others (Kasselman et al., 2018; Pundir et al., 2008). CNS (e.g., Parkinson's disease and Alzheimer's disease, etc.) is the only disease that has an immediate association with the gut through the gut–brain axis (Mars et al., 2021; Ahmed et al., 2014a). For diseases such as liver cirrhosis, types of cancer, neurological disorders, urological disorders, and skin problems, microbiomes serve as the crucial magic bullet. Our rising concern regarding symbiotic microbial species and the benefits of ecological principles and machine learning are stipulating with the inspiring fortuity for microbiome-based therapeutics to ascend from fecal microbiota transplantation to the incorporation of sharply explained and clinically authenticated symbiotic microbial consortia that fine-tune resistance against disease. Through this chapter, we will discuss the various diseases related to microbiome dysbiosis and their cure by various advanced techniques by taking microbes and their beneficial properties into consideration (Table 1.1).

2. Microbiome therapeutics

The use of microbes along with the associated metabolites and other factors to disrupt the harmful microbial content and improve the beneficial microbes is called microbiome therapeutics (Yadav and Chauhan, 2022). The development of drug/antibiotic resistance and broad-range actions of traditional medications endorsed the efforts of the development of microbiome therapeutics (Greene and Reid, 2012; Pundir et al., 2009). The augmentation of microbes as therapeutic agents may help to overcome the ill manifestations of the traditional medicines on human body. As the microbes reside naturally in the human system, their use as therapy facilitates the disease management without posing any deteriorating impact on the human body. Efforts are now being done to engineer the microbes to improve their therapeutic efficiency. The human gut microbiota has already been explored for its health-promoting benefits (Ogunrinola et al., 2020). Any alteration in the gut microbiota composition induces the disease development (Yadav et al., 2018). Microbes directly communicate with the host to prevent disease onset (Thaiss and Elinav, 2017). Microbes help in reducing the cognitive behaviors (Cowen, 2020). Various genera belonging to Akkermansia help in reducing metabolic abnormalities and aid in the cancer treatment (de la Cuesta-Zuluaga et al., 2017). Various other microbes of the same genus protect the host from cardiovascular disorders and maintain the intestinal integrity (Li et al., 2016). The gut microbes also help in the management of cancer (Cheema et al., 2016), Crohn's disease (Joossens et al., 2012), and the intestinal disruptions due to dietary fats (Schroeder et al., 2018). The significance of gut microbes in promoting human health augments their use for improved diagnostics and treatment of various disorders (Jones, 2016). The microbes are now being modulated with exogenous microbial factors and components (Cully, 2019). The interactive role of microbes and the host benefits the microbial therapy (Mimee et al., 2016). Various methods are now being followed for microbial augmentation as therapeutics (Mimee et al., 2016). Additive, subtractive, and modulatory mechanisms including addition, subtraction, and modulation of microbial strains are being implemented for the development of microbial therapeutics (Marchesi et al., 2016) (Fig. 1.1).

Table 1.1

Figure 1.1  Microbiome augmentation for a healthy life.Various environmental factors lead to microbial dysbiosis that lead to disease onset. Augmentation of microbes as therapeutics helps in maintaining the normal gut microbiota that ultimately leads to a healthy life.

2.1. Additive microbial therapy

Additive therapeutics involves the addition of a single natural/engineered microbe or group of microbes for the host's health promotion (Khoruts and Sadowsky, 2016). The microbes may be administered through fecal microbiota transplantation (FMT) or probiotics (Marchesi et al., 2016) (Fig. 1.2).

2.1.1. Fecal microbiota transplantation

FMT includes the addition of microbes through the transfer of healthy human feces. The fecal transfer is done through various modes. For the safety assessment of the administered microbes, the donors must be screened well (Cammarota et al., 2017; Mehta et al., 2021). Before FMT, the stool as well as blood of the donor must be examined to reduce the risk of transfer of any infection from donor to the recipient. To improve the immune acceptance of the administered microbes by the recipient, any close relative of the recipient must be chosen as fecal donor (Bakken et al., 2011). To prevent the transfer of genetic ailments, the donor must be unrelated to the recipient (Kelly et al., 2015). The fecal suspension was found suitable for the management of Clostridium difficile infection (CDI) (Zuo et al., 2018). Similarly, FMT was found suitable for the treatment of recurrent CDI induced through antibiotic treatment (Quraishi et al., 2017; Sharma et al., 2021a,b,c). The successful recovery from CDI fascinated the use of FMT for the treatment of other diseases (Allegretti et al., 2019). The fecal slurry was found effective in the treatment of diabetes (Vrieze et al., 2012). Recurrent infections associated with the urinary tract were healed after treatment with fecal microbes (Tariq et al., 2017). FMT restored the gut Bacteroidetes lost due to excessive alcohol consumption (Ferrere et al., 2017; Yadav et al., 2021a,b). Even the FMT was efficient in the transfer of immune cells (T-cells) to the patients with liver cirrhosis and alcoholic hepatitis (Gao et al., 2018). Successful clinical trials were reported for the management of alcoholic hepatitis and fibrosis (https://clinicaltrials.gov/). Similarly, FMT was found successful in the treatment of neural diseases (Finegold et al., 2002), cancer (Sweis et al., 2016) and ulcerative colitis (Paramsothy et al., 2019). The success of FMT is dependent on the lateral transfer of the microbes that are transferred (Hall et al., 2017). The ill effects such as the transfer of bad stools urged the need for some other approach. Alternatively, artificial stools containing gut commensals grown in laboratory conditions and designed into living form are now being used for disease management (Petrof and Khoruts, 2014).

Figure 1.2  Additive microbiome therapeutics.Probiotics lead to pathogen eradication through colonization resistance, enrichment of the host with enhanced gut barrier functions, and reducing the colon inflammation through immunomodulatory approach. Fecal microbiota transplantation also improves the host's immune functions through immune modulation.

2.1.2. Probiotics

Probiotics are the live microbes administered within the host for providing health benefits. The microbes that are administered may be natural or genetically engineered. Probiotics should be harmless, suitable, specific, and able to survive within the host (Guslandi et al., 2003). Microbes such as Bifidobacterium, E. coli, and Lactobacillus were successfully used for disease management (Cuello-Garcia et al., 2015). Probiotics improve the gut microbial composition (Depommier et al., 2019) and remove the pathogens through competitive exclusion, production of antimicrobial compounds such as bacteriocins, and alteration of microbial functions (Kesarcodi-Watson et al., 2008). Probiotics also help in stimulating the host immune system (Varankovich et al., 2015). Probiotics were found to successfully treat cancer (Uccello et al., 2012), Crohn's disease (Jonkers et al., 2012), diarrhea (McFarland, 2006), and IBD (Coqueiro et al., 2019). Probiotics are effective in healing the intestinal membrane disrupted due to IBD (Podolsky, 1999). Biotherapeutics are being developed nowadays through probiotic engineering for efficient disease diagnostics and treatment. Thus, probiotics improve the gut environment through addition of improved functional characteristics. As the fecal slurry involves multiple microbes with unique adaptive mechanisms, the fecal microbial survival within the host supports the functioning of FMT as superprobiotics.

2.2. Subtractive microbial therapy

Subtractive therapy works by deleting the harmful microbes from the microbial consortium through antimicrobial compounds such as bacteriophages and bacteriocins (Lu and Collins, 2009). The traditional medications such as antibiotics due to their broad range activity affect the untargeted microbes. Thus, alternative approach including use of bacteriocins and bacteriophages with targeted activity is now being used as therapeutics (Fig. 1.3).

2.2.1. Bacteriocins

Bacteriocins are synthesized by ribosomes to exhibit the antimicrobial functions (Klaenhammer, 1988). Bacteriocins eradicate the harmful microbes by rupturing the cell through the destruction of cell membrane as well as affecting the cell respiration (Mahlapuu et al., 2016). The antimicrobial range of the bacteriocins depends on their constituency of lanthionine (Ołdak and Zielińska, 2017). The bacteriocins with lanthionine, such as enterocin, nisin, etc., work against Bacillus, Clostridium, and Geobacillus (Egan et al., 2016), while bacteriocins that are devoid of lanthionine possess antibacterial activity against Clostridium, Enterococcus, Lactobacillus, Leuconostoc, and Pediococcus (Umu et al., 2017). Bacteriocins are naturally produced by certain gut microbes belonging to Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria (Douillard and Vos, 2014). Bacteriocins are used by the commensals for successful colonization within the human gut (Kommineni et al., 2015). Bacteriocins are being successfully used for food preservation (Ramu et al., 2015). Additionally, they are being used in maintaining oral hygiene (Zoumpopoulou et al., 2013) as well as skin health (Kang et al., 2009). Bacteriocins find their use in the treatment of various human disorders such as ulcers (Kaur et al., 2012), pathogenic infections (Perez et al., 2014), and vaginosis (Kaur et al., 2013). Despite the significant role of bacteriocins, the microbes may produce resistance against them and even degrade them to deteriorate the host's health (Dicks et al., 2018). Significant efforts are required to develop highly potent bacteriocins for designing effective microbial therapies.

Figure 1.3  Subtractive microbiome therapeutics.All three classes of bacteriocins lead to cell lysis either through cell penetration, receptor-mediated recognition, or direct cell contact, and ultimately cause the pathogenic cell's death. Bacteriophages are engineered with exogenous therapeutic genes to insert and express desired therapeutic functions to the host.

2.2.2. Bacteriophages

These are the viruses that are produced by bacteria. They are host-specific and work through targeted approach against the pathogens only. Bacteriophages work by integrating their genomic content into pathogens and causing their lysis (Weynberg and Jaschke, 2020). The bacteriophage engineering with CRISPR-Cas improves the pathogen specificity (Bikard et al., 2014). They are being employed for the treatment of various disorders (Lin et al., 2017). They are mainly applied to destruct the microbes that are resistant to certain antibiotics. The bacteriophage was successfully used to treat osteomyelitis (Abedon, 2016), which developed due to Staphylococcus aureus that was found resistant to methicillin (Drilling et al., 2017). The bacteriocins φNH-4 and φMR299-2 were found effective in treating lung disorders (Alemayehu et al., 2012; Gupta et al., 2021) and skin problems (Brown et al., 2016). Bacteriophages were found effective in relieving inflammatory disorders (Vahedi et al., 2018), colitis (Galtier et al., 2017), ulcers (Fish et al., 2018), etc. The main advantage of the phages is their ability to avoid resistance through mutation. Despite this certain microbe develops phage resistance through certain mutations and modulatory mechanisms (Oechslin, 2018), the phage therapy suffers various challenges due to the gastrointestinal conditions within the host (Elbreki et al., 2014).

2.3. Modulatory therapy

Modulatory therapy includes the modulations of microbes as well as their interactions with the host. The microbes must be restored to normal composition for a healthy well-being. Lifestyle modifications through the reduction in medications, change in diet, as well as introduction of intensive physical workouts can help in maintaining the healthy gut microbes (Bhalodi et al., 2019). Diet as well as exercise directly modulates the content of short-chain fatty acid (SCFA)–producing microbes (Allen et al., 2018), which have a major role in maintaining healthy physiology (Allen et al., 2018). Protein-enriched diet modulates the gut microbiota (Clarke et al., 2014; Yadav et al., 2020a,b). Similarly, athletes were found to possess healthy gut microbes including Veillonella (Scheiman et al., 2019). A healthy diet must include fibers (Makki et al., 2018), proteins (Clarke et al., 2014), and balanced sugar content (Sloan et al., 2018). An imbalanced diet compels the microbes to use the host mucosal glycans, which disrupts the intestinal integrity (Birchenough et al., 2019). Additionally, the balanced diet helps in maintaining the content of SCFA-producing microbes (Bindels et al., 2015). As the balanced diet reduces the content of harmful microbes and improves the content of commensals (Chen et al., 2015), dietary manipulations have been used for relieving the symptoms of various disorders such as diabetes (Zhao et al., 2018; Yadav and Chauhan, 2021) and epilepsy (Lindefeldt et al., 2019). Administration of antioxidants in diet can help in reducing obesity (Li et al., 2013). Additionally, the inclusion of alcohol (Hernández-Quiroz et al., 2020), cigarettes (Lee et al., 2018a,b), medications (Martinez et al., 2019), etc. may negatively impact the gut microbes (Fig. 1.4).

Figure 1.4  Modulatory microbiome therapeuticsExcessive sugar and high-fat diet leads to the development of disease through gut dysbiosis. A modulation of dietary habits, reduction of antibiotic consumption, and inclusion of exercise lead to healthy gut and well-being through increased immunity.

3. Microbes maintain the well-being of various body organs

3.1. Skin health and microbiome

Human skin is an inhabitant of a large number of microbes and is the largest organ providing an immunologic and physical hurdle to the incoming pathogens. Microbes flourish and distribute differently in different areas and atmospheres such as sebaceous areas, hair follicles, and glandular structures, eccrine, as well as apocrine glands. These areas provide different cutaneous microenvironments, which contribute to the growth of microbes (Grice et al., 2014). Microbes are present not only in the outer skin but also deeper inside the epidermis, dermis, and dermal adipose tissues. The topmost layer stratum corneum of the epidermis accommodates a huge microbial richness, which favors the barrier properties to the skin. The metabolites produced by commensal microbes lead to homeostasis. Human skin is a harsh habitat with acidic pH, a cool environment, and the presence of host defense molecules (such as antimicrobial peptides and lysozyme) (Woo and Sibley, 2020; Kumar et al., 2020a,b). Regardless of these circumstances, human mucosal surfaces and skin lodge spare microbes larger than eukaryotic cells in the body. Skin microbiome represents around 19 phyla including Bacteroidetes (6.3%), Proteobacteria (16.5%), Firmicutes (24.4%), and Actinobacteria (51.8%). Corynebacterium, Propionibacterium, and Staphylococcus are found commonly at the genus level. Recently, it was observed that the imbalance in microbiota and host result in the initiation of various clinical diseases and lead to proinflammation (Woo and Sibley, 2020). Dysbiosis results in several skin disorders such as acne vulgaris, atopic dermatitis, chronic wounds, psoriasis, rosacea, and seborrheic dermatitis.

3.1.1. Atopic dermatitis

7% of the general population is affected by severe morbidity, and a dreadful disease is an atopic dermatitis (Woo and Sibley, 2020; Singh, 2020). Bacteria such as Staphylococcus and Corynebacterium colonize damp and/or occluded skin areas, as these organisms prefer high humidity in their habitat (Grice et al., 2014; Chauhan et al., 2018). These species are halotolerant and thrive in damp environments, where they get their nitrogen from perspiration (Lunjani et al., 2019; Ahmed et al., 2018). It releases adherents and proteases that release nutrients, and promotes bacterial adhesion to the skin. Genetic origins of atopic dermatitis are linked to a loss in function of the filaggrin gene of the functional skin barrier. The filaggrin gene is present in the epidermal differentiation complex that contains genes, which are involved in the differentiation of keratinocytes and proteins for the cornified envelopes. Filaggrin is composed of nonfunctional precursor serine proteases caspase 14. A decrease in the level of the filaggrin gene facilitates Staphylococcus growth and disruption of corneocyte structures, which results in higher skin pH and decreased antimicrobial peptides (Sroka-Tomaszewska and Trzeciak, 2021). 10%–30% of atopic dermatitis with loss in function of filaggrin gene is detected in caucasian patients (Musthaq et al., 2018; Verma et al., 2018). Due to atopic dermatitis, there is a loss of integrity in the stratum corneum, a decrease in expression of structural proteins, a difference in lipid composition, pH of the skin, abnormal antibody response that facilitates S. aureus explosion. Its overgrowth reduces skin commensal taxa Staphylococcus epidermidis and other commensal microbes such as Proteobacteria, Prevotella, Propionibacterium, Corynebacterium, Streptococcus, and Acinetobacter (Baurecht et al., 2018; Kumar et al., 2016). Epidermis yeasts, such as Malassezia species, may cause or worsen atopic dermatitis cutaneous irritation (Langan et al., 2020; Kumar et al., 2017). Virulence factors from S. aureus release proteases, toxins, and superantigens, activate inflammatory pathways by activating interleukin-mediated T cell response, and lead to the pathogenesis of atopic dermatitis (Cho et al., 2001; Foster et al., 2014; Geoghegan et al., 2018; Alomar, 2012; Liu et al., 2017). S. aureus δ-toxin degranulates the mast cells and α-toxin causes monocytes to produce IL-1β (Hodille et al., 2016; Kumar et al., 2018a,b), which can enhance Th17 responses or CD4+ T cell production of IL-17 (Nakagawa et al., 2017; Gupta et al., 2017). S. aureus enters the dermis due to defective skin barrier and interacts with the immune system, which leads to the production of cytokines IL-4, IL-13, IL-22, and TSLP (Nakatsuji et al., 2016). The skin barrier disrupts when inflammation is initiated by Th2-type immune cells; it decreases the tissue production of AMP human β-defensins (HBD)-2, cathelicidin LL-37, and hBD-3, reducing pathogen clearance. Cross-talk between the human body and the skin microbiome is a leading idea that is generally called the gut–skin axis (Lee et al., 2018a,b; Marrs and Flohr, 2016; Salem et al., 2018). The processes due to which the gut–skin axis affects skin homeostasis are unknown. However, it regulates the effect of gut bacteria synergistics on systemic immunity (O'Neill et al., 2016). For example, Bacteroides fragilis, Faecalibacterium prausnitzii, and metabolites (retinoic acid, polysaccharide A) might stimulate the formation of Th-cells and regulatory T-cells, which enhance proinflammatory and antiinflammatory responses separately (Forbes et al., 2016). Several studies are presently underway to investigate the therapeutic value of manipulating the skin microbiota. Research on gut–skin axis effects on the physiopathology of skin diseases is required for further mechanisms to understand. Skin microbiota transplantations, similar to fecal microbiota transplantation therapy for C. difficile infections (van Nood et al., 2013), could be used to reduce S. aureus colonization and AD symptoms without the use of antibiotics, which foster resistance. Most patients are colonized with S. epidermidis, implying a more hostile connection between coagulase-negative Staphylococcus and S. aureus (Nakatsuji et al., 2017). Furthermore, it appears that Cutibacterium acnes has an antagonistic interaction with S. aureus (Francuzik et al., 2018). The administration of probiotics through mouth has also been investigated. Some strains of Bifidobacterium and Lactobacillus can lessen atopic dermatitis in newborns throughout pregnancy and after birth. In children, the use of a combination of probiotic strains was demonstrated to decrease the topical steroid use and Scoring Atopic Dermatitis index (SCORAD) (Li et al., 2019; Navarro-Lopez et al., 2018). In atopic eczema patients, pharmacological measures such as topical corticosteroids, calcineurin inhibitors, or even moisturizers and emollients may restore barrier function and balance the skin microbiota (Sroka-Tomaszewska and Trzeciak, 2021). The narrow-band ultraviolet B therapy is used to lower S. aureus concentrations and superantigen production considerably (proinflammatory peptides) (Woo and Sibley, 2020). Some antibacterial strains of Staphylococcus hominis and S. epidermidis were introduced in the medium, and this combination was topically inserted in lesions, which reduced the S. aureus persistence at the site of application (Nakatsuji et al., n.d.; Myles et al., 2018). Besides it, Roseomonas mucosa was topically transplanted in adults and pediatric patients; they did not find the previous existence of gram-negative Bacilli. In a randomized comparison trial, 60 individuals with intermediate atopic dermatitis were treated either with Vitreoscilla filiformis supplemented biomass or with an emollient without biomass two times a day for a month (Luger et al., 2021). AD scores were more in patients who got the enhanced emollient than those who received the control emollient (Luger et al., 2021). This shows that the added emollient regulates the skin microbiota and decreases the number and acuteness of AD flares (Luger et al., 2021). AD patients were treated with topical application for 4–8 weeks consisting of Lactobacillus reuteri DSM 17938, which improves the Local SCORAD and SCORing AD (Luger et al., 2021). According to the National Institute of Health, R. mucosa strains offered clinical benefits to lesioned skin in both children and adults (Luger et al., 2021). S. aureus colonization was reduced when the strains of coagulase-negative Staphylococcus were reintroduced on the skin of AD patients (after separation from healthy people and patients with AD). More research on the gut–skin axis and its impact on skin disease physiopathology are needed. Innovative medicines that target the gut to benefit skin health need understanding to gain knowledge of these pathways. These findings form the foundation for the rational development of bacteriotherapy.

3.1.2. Psoriasis vulgaris

Psoriasis is a severe rebellious skin disease that involves rapid cell growth, resulting in plaques of thicker skin, coated in scales (Visser et al., 2019). Psoriasis vulgaris (PV) (plaque psoriasis) prefers drier areas of the skin, such as the elbows, knees, and trunk. Psoriasis is caused by a breakdown in immunological tolerance to microbiota (Grice et al., 2014). Psoriasis impacts between 1% and 3% of the population. It causes thickened, scaly plaques as a result of epidermal hyperproliferation, hyperkeratosis, dermal inflammation, and angiogenesis (Musthaq et al., 2018). PV is the result of miscommunication between the inborne and acquired immune system, with the tumor necrosis factor-alpha (TNF-α) and interleukin-23/interleukin-17 (IL-23/IL-17) axis. Psoriatic lesions comprise a higher abundance of proteobacteria, Schlegelella, Rhodobacteraceae, Firmicutes, Acidobacteria, Moraxellaceae, Campylobacteraceae, and Streptococcaceae, but Propionibacterium and Actinobacteria species are less in number (Musthaq et al., 2018). Due to the presence of specific bacteria, two types of psoriasis were discovered: type 1 with a Proteobacteria phylum and type 2 with Firmicutes and Actinobacteria phylum. The Actinobacteria to Firmicutes ratio was altered by conventional and biological systemic treatments (e.g., cyclosporin A, retinoic acids, fumarates, methotrexate, adalimumab, and ustekinumab) (Pessemier et al., 2021; Ferček et al., 2021). The reduction in Propionibacterium acnes stimulates the Th-1 cytokine immune response by overactivation of the cutaneous antibody response (Musthaq et al., 2018). Psoriasis pathogenesis is the effect of multiple factors such as environmental infections, UV and X-rays, stress, smoking, thermal and chemical burns, drinking alcohol, and trauma, and immunological and genetic predispositions, causing keratinocytes to secrete proinflammatory cytokines (Polak et al., 2021). Keratinocytes and dendritic cells play key roles during skin immune system activation (Visser et al., 2019). T lymphocytes are activated in an antigen-independent manner, producing TNF-α, vascular endothelial growth factor (VEGF), IL-1, IL-2, IL-6, IL-8, IL-12, IL-17, IL-23 p19/p40, INF, granulocyte–macrophage colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF), which disturbs blood vessels and keratinocytes, resulting in hyperaugmentation of keratinocyte, parakeratosis (maturation process of keratinocytes get reduced inside epidermis), and aberrant angiogenesis (in the place of skin disease brittle and twisted capillaries formed with increased permeability) (Visser et al., 2019). Genetic components relevant to the metabolism of vitamins, cofactors, and lipid metabolism were more frequent in unaffected skin areas. Metabolism and biodegradation of naphthalene, lysine, and benzoate involve the biological (KEGG) pathways and were found to be increased in psoriatic lesions (Ferček et al., 2021). F. prausnitzii is a major source of protective SCFAs inside the gut; loss of this bacterium loses the Th-17 cell generation and function. Psoriasis is linked in a chain with gut dysbiosis, Th-17-mediated inflammation, and SCFAs in the disease mechanisms (Yu et al., 2020). Many immunosuppressive drugs have been used to treat psoriasis. The tumor necrosis factor (TNF) seems to have a relevant role in the pathogenesis of psoriasis so antiinterleukin-17 is considered successful in treating psoriasis (Cottone et al., 2019). Oral therapy of Bifidobacteria infantis is used to treat psoriasis as its effect is seen in psoriasis patients where its dose for 8 weeks reduced inflammatory CRP and TNF levels, while it is unclear if this was accompanied by clinical improvements. Lactobacillus pentosus GMNL-77 administered orally in a mouse model of psoriasis reduced IL-23/IL-17 axis-associated cytokines and TNF, which was linked to less erythematous scaling lesions. An animal model of psoriasis administered with Lactobacillus sakei ethanol extract and inhibiting the inflammation when correlated with clobetasol is being currently used as standard therapy (Knackstedt et al., 2020; Kundu et al., 2018). Narrow-band UV B light therapy lowers the Staphylococcus, Firmicutes, Clostridium, Anaerococcus, Finegoldia, Gardnerella, Peptoniphilus, and Prevotella in the lesions of psoriasis patients (Pessemier et al., 2021). Further research in the function and the modification of the microbiome for psoriasis vulgaris would be a welcome addition to the several antibody-mediated treatment trials already underway (Yu et al., 2020).

3.1.3. Acne vulgaris

Acne is now a persistent skin condition of the pilosebaceous unit, a complex miniorgan of the body with a wide range of microbiological, morphological, and metabolic variability depending upon the location of the skin (O'Neill and Gallo, 2018). It is characterized by hormonal hyper seborrhea, altered keratinization, immunological and inflammatory processes, and the growth and deposition of P. acnes in hair follicles in the back, chest, face, and neck (Goodarzi et al., 2020). Acne refers to a group of microorganisms that live on the surface of the skin. They are vital to healthy skin function when in harmony with defensive mechanisms since they prevent bacterial overgrowth and infectious strains involved in various dermis illnesses. The stability of the epidermis of the skin, the microflora of the epidermis, and the sebaceous gland all play a role in the pathophysiology of acne (Rocha and Bagatin, 2018). Comedones or noninflammatory lesions, inflammatory lesions, pustules, papules, cysts, and nodules are the clinical hallmarks of acne (Kim et al., 2021). The resident microbiome contains both S. epidermidis and C. acnes (previously known as P. acnes), while S. aureus is found in the transitory microbiome (Dréno et al., 2020; Chauhan, 2019b). C. acnes are frequently seen in locations where there is a lot of sebum. In contrast to popular belief, acne is not linked to an increase in the number of C. acnes. Indeed, in metagenomics studies, the load of C. acnes reported in patients having acne and healthy individuals was found to be similar, with somewhat higher levels in healthy participants. Instead, it appears that a decline in microbial heterogeneity and an imbalance between C. acnes phylotypes play a role in acne triggering (Dréno et al., 2020; Kumar et al., 2015). Acne patients' skin is primarily colonized by bacteria from the genus Staphylococcus and Firmicutes, mainly S. epidermidis and the Proteobacteria, with Actinobacteria being absent (Ferček et al., 2021; Chauhan, 2019a). P. acnes is thought to be a beneficial commensal for skin health. It maintains a low skin pH by releasing free fatty acids from triglycerides and inhibits the colonization of harmful microorganisms such as S. aureus and Streptococcus pneumonia (Xu and Li, 2019). The genera Gamella, Streptococcus, Granulicatella, Neisseria, and Fusobacterium are on the skin of acne patients, most likely due to the parallel abundance of Cutibacterium bacteria, which limits the surge of other bacteria (Kelhälä et al., 2018). Acne etiology is thought to be influenced by both bacterial causes and inflammation. Antibiotics were the most prominent treatment against acne for over 40 years, even though acne is not a prevalent pathogenic condition. P. acnes are treated with topical antibiotics having bactericidal properties. Oral antibiotics contain both antibacterial and antiinflammatory properties, which spot P. acnes as well as the immune system of the host (Xu and Li, 2019; Goyal et al., 2019). First-line medication for the extreme proliferative reaction in acne is tetracyclines, macrolides, and clindamycin (Eichenfield et al., 2013). Nitrosomonas eutropha is an oxidizing bacterium. It oxidizes ammonia to nitrite, nitrate, and nitric oxide. Nitrates are an important link in metabolic pathways. They synthesize the nitro lipids and also influence inflammation during the activation of the immune system. N. eutropha has many therapeutic properties, which were earlier utilized by humans due to its presence on a person's skin. Because of modern cleanliness practices, the use of various antibacterial bathing bars has depleted its presence and deprived humans of utilizing its medicated therapies resulting in inflammation. Its repercussions can be reversible by reintroducing its strain on human skin to avail its benefits (Trivedi et al., 2018; Sharma et al., 2020). Modification in the phylotypes of C. acnes could be a chief target in treating acne. Variations in treating the inflammation due to C. acnes with the help of monoclonal antibodies in a proposed future application, which targets the Christie, Atkins, Munch-Peterson (CAMP) factor 2 through injections in the form of the vaccine directly inside the lesions, were observed in ex vivo experiments. Phage therapy is recommended as future therapeutics that targets only acnegenic phylotypes of C. acnes which are present as C. acnes bacteriophages in the pilosebaceous unit (Dessinioti and Dreno, 2020). P. acnes are directly suppressed by antibacterial proteins produced by probiotics such as Enterococcus faecalis and Streptococcus salivarius; it was demonstrated in in vitro conditions. The bacteriocin-like inhibitory substance (BLIS) is an antibacterial protein that can limit the growth of P. acnes (Mottin and Suyenaga, 2018). S. epidermidis inhibits P. acnes-forming metabolites by fermenting glycerol and increases its use as a probiotic for better results, as it is a natural skin defense against acne (Wang et al., 2014; Bowe et al., n.d.; Kober and Bowe, 2015). Bacterium Lactococcus sp. HY 499 declines favorable bacteria as well as harmful bacteria. It diminishes the flourishing of S. epidermidis, P. acnes, S. aureus, and Streptococcus pyogenes (Oh et al., 2006). Besides it, Lactobacillus paracasei (L. paracasei) CNCM I-2116 was found to play a role in relieving skin irritation. The release of substance P from acne results in the difference in edema, TNF-alpha production, mast cell degranulation, vasodilation, edema, and other things (Gueniche et al., 2010). Enterococcus faecalis SL-101 bacteria are known for their function and were introduced in the study for having anti-P. acnes properties, which are used in a lotion with 1% extract. This formulation is not effective; hence the use of Lactobacillus plantarum with 5.5% extract concludes in curing light acne lesions and highlights the dependency on doses (Kang et al., 2009).

3.1.4. Rosacea

Rosacea is a dreadful inflammatory skin condition pronounced by frequent bouts present on faces such as pustules, erythema, and telangiectasia. It may cause itching and fiery sensations all over the skin, and it can be without stinging and burning also. It causes changes in the skin conditions such as rough and dry skin, phymatous changes, edema, and ocular involvement (Daou et al., 2021). Rosacea is mainly of four types: areocular, erythematotelangiectatic, phymatous, and papulopustular rosacea (F. Y. Wang and Chi, 2021). The rosacea's pathophysiological conditions involve abnormal or dysfunctioning of the immune system both innate and adaptive (Jabbehdari et al., 2021), genetic factors, neurovascular responses, environmental factors, and absence of good bacteria, and the growth of harmful bacteria leads to the repeated inflammation of this infectious disease (Daou et al., 2021). Knowledge is absent regarding this specific process, but it is thought that it may be linked to various comorbidities, which include metabolic disorders, gastrointestinal disorders, and neurologic and psychiatric diseases (F. Y. Wang and Chi, 2021). Most frequently reported comorbidities include various gastrointestinal diseases such as Crohn's disease, irritable bowel syndrome, Helicobacter pylori infection, ulcerative colitis, celiac disease, gastroesophageal reflux disease (GERD), and abundance of microbes in the small intestine (Wang and Chi, 2021). The pathogenesis of bacteria involves not only prior mentioned factors but also the presence of pathogenic microbes such as Bacillus olenorium, H. pylori, pneumonia, Chlamydia (Musthaq et al., 2018), β-hemolytic S. epidermidis (highly virulent than nonhemolytic S. epidermidis) (Ellis et al., 2019), and Demodex folliculorum (Demodex) mite. Demodex is present in the sebaceous glands; its existence is found on the skin of afflicted people during various investigations. Immune dysfunction is marked by the high levels of TLR 2 in their epidermis; due to this reason, there are increased inflammatory reactions. Overexpression of TLR 2 results in the aberrant formation of antimicrobial peptides such as cathelicidin and serine protease kallikrein. Both these proteins are the hallmark of the disease rosacea. Overexpression of cathelicidin, kallikrein 5, TLR-2, and various MMPs (MMP-2, MMP-9) are interconnected and work in a cascade manner, like KLK 5 converts inactive forms of cathelicidin to the active form by cleaving the peptide and results in the formation of LL-37. TLR 2 overexpression further initiates the expression of KLK 5; in this, MMP-9 synergizes the effect of TLR 2 into the formation of more KLK 5 activity, which further initiates the formation of LL-37 (Kim, 2020). Substitution of microbes (like some are thriving and some are dwindling) changes the composition of microbes, which may be involved in the overexpression or is the reason for overexpression (Musthaq et al., 2018). When the rosacea improves, the density of D. folliculorum on the face may decrease. Mites were also observed in people who are devoid of the formation of papules and pustules in the case of telangiectasias and erythema. Demodex mites are a distinct therapeutic target in all clinical variants (Cribier, 2021). Demodex is known to cure papules and pustules. Antibiotics used to treat rosacea, such as tetracyclines, may affect the bacteria D. folliculorum in the hosts. Topical administration of an antiparasitic medication is the most common treatment for lowering Demodex density. The success rate of 1% ivermectin in treating rosacea is quite good when compared with placebo and other medicines that increase the quality of life. Permethrin, benzyl benzoate, and crotamiton have been used off-label and shown to decrease the D. folliculorum populations (Cribier, 2021). Intestinal-borne dermatoses such as PPR, seborrheic dermatitis, and acne can be treated by the oral administration of Escherichia coli (Manzhalii et al., 2016). Their main goal was to change the microbe diversity to promote bacterial colonization that was less violent, hence reducing immune system overstimulation. E. coli inhibits the prosperity of anaerobic gram-negative bacteria because it has siderophores and antimicrobial compounds, which trap iron and hinder the formation of some pathogenic bacterium strains (Manzhalii et al., 2016). Fortuna et al. have used the probiotic therapy in combination with doxycycline for 8 weeks, two times a day to treat conjunctivitis, blepharitis, and PPR (Fortuna et al., n.d.). After this therapy regimen, the patient's cutaneous and visual manifestations were significantly improved. The use of doxycycline was discouraged; however, the use of probiotics on a long-term basis was recommended. The patient had not experienced a relapse. Oral topical probiotics and prebiotics are used to cure rosacea, but to trust their efficiency, their exact method of execution should be explored.

3.2. Gastrointestinal and Liver diseases associated with microbial dysbiosis

Gut dysbiosis not only affects skin but also stomach, liver, and intestine. Lack/absence of good gut bacteria results in the growth of unwanted species, which causes the inflammation of the stomach lining and intestine and affects the liver. All these inflammations result in various diseases associated with various organs.

3.2.1. Irritable bowel syndrome

It is a physiological ailment known as irritable bowel syndrome (IBS). Condition is characterized by flatulence, altered bowel habits, and abdominal pain. Many factors are involved to play a role in the development of disease, such as stress, anxiety, diet, and the bacteria of the gastrointestinal tract. Acute gastroenteritis is an uncertain factor in the progression of IBS (Porter et al., 2011). Gastrointestinal infection and psychological issues lead to postinfection IBS and chronic fatigue (Ford et al., 2020). Symptoms of the illness can also arise as a result of increased fermentation, high concentrations of SCFAs (Gomaa, 2020), and gas production. To make sure the patient is suffering from IBS, the main detection method is the presence of antivinculin and anti-Cdt (cytolethal distending toxin) antibodies, and these antibodies test positive only in IBS patients and not in celiac disease or any other intestinal disorders (Kumar et al., 2017; Pimentel et al., 2015). In IBS patients, the Streptococcus levels were greater in the stool, and Proteobacteria levels were higher in the mucosa than in healthy controls (Schupack et al., 2022). Shigella, Campylobacter jejuni, Salmonella, C. difficile, and E. coli (Klem et al., 2017) are the causes of IBS. All these groups of bacteria share a common factor that is difficult to identify. One of the common factors is Cdt. Genetically altered C. jejuni is deprived of Cdt B due to which patients infected with this bacteria show fewer indications (change in bowel routine) and minor inflammation (rectal lymphocytes) (Spiller et al., n.d.), which was more in the case of the wild-type strain of C. jejuni (Pokkunuri et al., 2012). Intestinal diseases have a connection to the gut–brain axis, which ties the gut and the brain together. Intestinal Toll-like receptors (TLRs), TLR 4 and TLR 5, are overexpressed in IBS patients. TLR 4 recognizes the lipopolysaccharide membrane of bacteria, and TLR 5 recognizes the presence of flagellin protein. These are the essential mediators of the intestinal immune response to gut microbes (Ford et al., 2020; Chauhan et al., 2017). B. infantis 35624 reduces stomach discomfort, bowel movements, and bloating. All these results were seen in the double-blind, random experiment, which was held in IBS patients where placebo is used as control. Another experiment was conducted on 50 IBS-D patients where probiotics combining three strains of Lactobacilli, Streptococcus thermophiles, and Bifidobacteria were used for 8 weeks in the treatment. A high percentage of patients found relief from IBS (Ford et al., 2020; Chauhan, 2017). A recent study has introduced the concept of a low FODMAP (defined as fermentable oligo-, di-, and monosaccharides and polyols) diet, which can diminish the unhealthy microbiome diversity because it resists the person to consume the food that praises the fermentation of microbes in the gut. Long-term use of the low FODMAP diet poses a hurdle, and it is a challenge that requires further study (Pimentel and Lembo, 2020). Fecal transplantation has proven a promising therapeutic area, with the greatest effect reported in patients with recurrent C. difficile colitis. According to the Norwegian study on transplantation of healthy people's stool to IBS-D, patients during colonoscopy result in an improvement in symptoms in 3 months (Pimentel and Lembo, 2020).

3.2.2. Inflammatory bowel disease

A variety of severe inflammatory illnesses, which were initiated by the immune system and disturb the digestive system, make up IBD (Gomaa, 2020; Yadav et al., 2018). IBD is caused by a combination of environmental and genetic variables (sleep habits, stress, antibiotics, cleanliness, smoking, and nutrition) and gut dysbiosis. There are two types of IBD: Crohn's disease (CD) and ulcerative colitis (UC) (Schirmer et al., 2018; Kumar et al., 2011). CD can affect any part of the GI tract from mouth