Recent Advances and Future Perspectives of Microbial Metabolites: Applications in Biomedicine

Recent Advances and Future Perspectives of Microbial Metabolites: Applications in Biomedicine sheds new light on various applications of microbial metabolites in the biomedical sector. The purpose of this book is to integrate the latest research advancements on the application of microbial metabolites in the medical industry into a single platform.

In 10 chapters, the significance of biomedical applications and future therapeutic applications of microbial metabolites in human health are highlighted. Several chapters are dedicated to the role of microbial metabolites in precision medicine like the impact of the activities of microbial metabolites in antitumor and antidiabetic agents and immunosuppressive activities. It also provides a roadmap for drugs discovery based on antimicrobial products and the effect of microbial metabolites on humans’ health and the immune system. The book finalizes with a chapter on the use of microbial metabolites in OMICS technology.

Recent Advances and Future Perspectives of Microbial Metabolites: Applications in Biomedicine targets researchers from both academia and industry, professors, and graduate students from microbiology, molecular biology, biotechnology, and immunology.

• Highlights various microbial metabolites and their application in the biomedical sector
• Illustrates the application of microbial metabolites as potential therapeutic agents
• Convenient for buyers and readers to understand the basics with advanced information of microbial metabolites

• Language: English
• Publisher: Academic Press
• Release date: Oct 23, 2022
• ISBN: 9780323901147

Book preview

Front Cover for Recent Advances and Future Perspectives of Microbial Metabolites - Applications in Biomedicine - 1st edition - by Surajit De Mandal, Xiaoxia Xu, Fengliang Jin, Amrita Kumari Panda, Kalibulla Syed Ibrahim

Recent Advances and Future Perspectives of Microbial Metabolites

Applications in Biomedicine

Edited by

Surajit De Mandal

College of Plant Protection, South China Agricultural University, Guangzhou, P.R. China

Xiaoxia Xu

College of Plant Protection, South China Agricultural University, Guangzhou, P.R. China

Fengliang Jin

College of Plant Protection, South China Agricultural University, Guangzhou, P.R. China

Amrita Kumari Panda

Department of Biotechnology, Sant Gahira Guru University, Ambikapur, Chhattisgarh, India

Kalibulla Syed Ibrahim

PG & Research Department of Botany, PSG College of Arts & Science, Coimbatore, Tamil Nadu, India

Table of Contents

Cover image

Title page

Copyright

List of contributors

About the editors

Chapter one. The therapeutic role of microbial metabolites in human health and diseases

Abstract

1.1 Background

1.2 Mode of action of microbial metabolites

1.3 Therapeutical effects of microbial metabolites in human health and diseases

1.4 Conclusion

References

Chapter two. Peptides with therapeutic applications from microbial origin

Abstract

2.1 Introduction

2.2 Substrates for peptide production

2.3 Methods in peptide production

2.4 Hydrolysis by enzyme

2.5 Microbial fermentation

2.6 Computational approach

2.7 Hybrid approach

2.8 Pharmacological properties of microbial peptides

2.9 Pharmacological properties of bacterial peptides

2.10 Pharmacological properties of fungal peptides

2.11 Pharmacological properties of yeast peptides

2.12 Challenges

2.13 Conclusion and future perspectives of bioactive peptides

References

Chapter three. Current status of microbial lectins in biomedical research

Abstract

3.1 Introduction

3.2 Types of microbial lectins

3.3 Characterization of lectins

3.4 Application of lectins in biomedical research

3.5 Conclusion

Reference

Chapter four. Current trends and future perspectives of probiotics on human health: an overview

Abstract

4.1 Introduction

4.2 History and development of probiotics

4.3 Beneficial activities of probiotics

4.4 Next-generation probiotics

4.5 Conclusion

References

Chapter five. Bacteriocin and its biomedical application with special reference to Lactobacillus

Abstract

5.1 Introduction

5.2 Types of bacteriocin produced by lactic acid bacteria

5.3 Mode of action of lactic acid bacteria-bacteriocins

5.4 Biomedical applications

5.5 Conclusion

References

Chapter six. Microbial biosurfactants: current trends and applications in biomedical industries

Abstract

6.1 Introduction

6.2 Types of biosurfactant

6.3 Glycolipids

6.4 Rhamnolipids

6.5 Trehalolipids

6.6 Sophorolipids

6.7 Xylolipids

6.8 Cellobiolipids

6.9 Lipopeptides

6.10 Phospholipids

6.11 Fatty acid biosurfactants

6.12 Polymeric biosurfactant

6.13 Production of biosurfactants

6.14 Applications of biosurfactants

6.15 Antimicrobial activity

6.16 Biosurfactants as antibiofilm molecules

6.17 Disruptor molecules made of lipopeptide biosurfactant

6.18 Lipopeptides that is similar to fengycin

6.19 Biosurfactants as drug delivery agents

6.20 Biosurfactants in drug delivery applications: challenges, selection guidelines, and future prospects

6.21 Biosurfactants: strengthening of immune system

6.22 Antiviral applications

6.23 Vaccine development and immunomodulation

6.24 Nanomaterial for diagnosis

6.25 Conclusions and future perspectives

References

Chapter seven. Microbes used as anticancer agents and their potential application in biomedicine

Abstract

7.1 Introduction

7.2 Mechanism of cancer suppression by microbes

7.3 Microbial bioengineering for cancer therapy

7.4 Different classes of microbial agents with anticancer potential

7.5 Microbes underwent clinical trials for cancer therapy over the past 5 years

7.6 Challenges associated with microbes used in anticancer therapy

7.7 Conclusion

References

Chapter eight. Revealing the hidden heights of microbial metabolites on reproductive physiology

Abstract

8.1 Background

8.2 Microbial contributions to the enhancement of male reproductive physiology

8.3 Microbial contributions in the enhancement of female reproductive physiology

8.4 Conclusion

References

Chapter nine. Secondary metabolites from extremophiles with therapeutic benefits

Abstract

9.1 Introduction

9.2 Brief history

9.3 Metabolites from terrestrial extremophiles

9.4 Metabolites from marine extremophiles

9.5 Conclusion

References

Chapter ten. Microbial metabolomics: recent advancements and applications in infectious diseases and drug discovery

Abstract

10.1 Introduction

10.2 Metabolomics approaches

10.3 Metabolomics technologies

10.4 Microbial metabolomics

10.5 Recent applications

10.6 Drug development

10.7 Precision medicine

10.8 Conclusion

References

Index

Copyright

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List of contributors

Saira Abbas,     Department of Zoology, University of Science and Technology, Bannu, Pakistan

Padmini Sateesha Acharya,     Department of Anatomy, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India

Sharjeel Ahmad,     National Microbial Culture Collection of Pakistan (NCCP), Bio-Resources Conservation Institute (BCI), National Agricultural Research Center (NARC), Islamabad, Pakistan

Iftikhar Ahmed,     National Microbial Culture Collection of Pakistan (NCCP), Bio-Resources Conservation Institute (BCI), National Agricultural Research Center (NARC), Islamabad, Pakistan

Madhavankutty Aishwarya,     Department of Biochemistry, PSG College of Arts & Science, Coimbatore, Tamil Nadu, India

Ahmad Ali,     National Microbial Culture Collection of Pakistan (NCCP), Bio-Resources Conservation Institute (BCI), National Agricultural Research Center (NARC), Islamabad, Pakistan

Snigdha Bhardwaj,     I.T.S College of Pharmacy, Ghaziabad, Uttar Pradesh, India

Sonam Bhatia,     Medical Affairs Division, Vytals Wellbeing India Private Limited, New Delhi, India

Satpal Singh Bisht,     Department of Zoology, D.S.B. Campus, Kumaun University, Nainital, Uttarakhand, India

Surajit De Mandal,     College of Plant Protection, South China Agricultural University, Guangzhou, P.R. China

Seeta Dewali,     Department of Zoology, D.S.B. Campus, Kumaun University, Nainital, Uttarakhand, India

Nandhakumar Divyaa,     Department of Biotechnology, PSG College of Arts & Science, Coimbatore, Tamil Nadu, India

Babu Gajendran

Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, P.R. China

The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, P.R. China

Sathya Narayanan Govindarajulu,     Department of Physiology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India

Kalibulla Syed Ibrahim,     PG & Research Department of Botany, PSG College of Arts & Science, Coimbatore, Tamil Nadu, India

Dheepthi Jayamurali,     Department of Physiology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India

Ramasamy Palanisamy Bharathi Kannan,     Department of Biochemistry, PSG College of Arts & Science, Coimbatore, Tamil Nadu, India

Rangasamy Karthika,     Department of Biotechnology, PSG College of Arts & Science, Coimbatore, Tamil Nadu, India

Ankit Kumar,     Department of Pharmaceutical Sciences, Sir J.C. Bose Technical Campus, Bhimtal, Kumaun University, Nainital, Uttarakhand, India

Kulbhushan Kumar,     Department of Zoology, D.S.B. Campus, Kumaun University, Nainital, Uttarakhand, India

Narayan Chandra Mandal,     Mycology and Plant Pathology Laboratory, Department of Botany, Visva-Bharati, Santiniketan, West Bengal, India

Sucheta Mandal

Mycology and Plant Pathology Laboratory, Department of Botany, Visva-Bharati, Santiniketan, West Bengal, India

Department of Botany, Banwarilal Bhalotia College, Asansol, West Bengal, India

Nivedita Manoharan,     Department of Physiology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India

Rashi Miglani,     Department of Zoology, D.S.B. Campus, Kumaun University, Nainital, Uttarakhand, India

Rojita Mishra,     Department of Botany, Polasara Science College, Ganjam, Odisha, India

Jayasekar Moniusha,     Department of Biotechnology, PSG College of Arts & Science, Coimbatore, Tamil Nadu, India

Amina Mughal,     National Microbial Culture Collection of Pakistan (NCCP), Bio-Resources Conservation Institute (BCI), National Agricultural Research Center (NARC), Islamabad, Pakistan

Amer Mumtaz,     Food Sciences Research Institute (FSRI), National Agricultural Research Center (NARC), Islamabad, Pakistan

Amrita Kumari Panda,     Department of Biotechnology, Sant Gahira Guru University, Ambikapur, Chhattisgarh, India

Rajeshwari Parasuraman,     Department of Physiology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India

Nagma Parveen,     Department of Zoology, D.S.B. Campus, Kumaun University, Nainital, Uttarakhand, India

Rajkumar Praveen,     Department of Biotechnology, PSG College of Arts & Science, Coimbatore, Tamil Nadu, India

Mahendra Rana,     Department of Pharmaceutical Sciences, Bhimtal Campus, Kumaun University, Nainital, Uttarakhand, India

Gaurav Rawat,     Department of Zoology, D.S.B. Campus, Kumaun University, Nainital, Uttarakhand, India

Gowsalya Saminathan,     Department of Microbiology, CSIR-Central Leather Research Institute, Chennai, Tamil Nadu, India

Krishnapriya M. Varier,     School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, Guizhou, P.R. China

About the editors

Dr. Surajit De Mandal is a postdoctoral researcher at the College of Plant Protection, South China Agricultural University, Guangzhou, P.R. China. He completed his Ph.D. in the Department of Biotechnology, Mizoram University, India. He has several years of research experience in the field of molecular microbiology and microbial diversity and published several research articles in international journals. Dr. De Mandal also acts as an editorial board member/reviewer for various international journals. His research interest interests focus on metagenomics and microbial diversity.

Dr. Xiaoxia Xu is presently working as an associate professor at the College of Plant Protection, South China Agricultural University, Guangzhou, P.R. China. She has 5 years of postdoctoral experience (2 years in SCAU and 3 years in UMKC). Her major research interest is insect immunity, application of entomopathogenic bacteria and fungi in agriculture, and isolation and characterization of novel microbial metabolites. She has served as a principal investigator in several projects and published many research and review articles in international journals. She has several patents and is presently serving as a reviewer in many international journals.

Dr. Fengliang Jin is presently working as a professor at the College of Plant Protection, South China Agricultural University, Guangzhou, P.R. China. His major research interest is on the role of noncoding RNAs in the regulation of insect immune signal transduction, exploring the interaction mechanism of insects to entomopathogens using next-generation sequencing and bioinformatic analysis and RNAi-based functional analysis of immune-related genes and their role in the regulation of antimicrobial peptides of insects. Prof. Jin served as a principle investigator for several research projects related to the development of biopesticide from various agencies. He has several patents and scientific articles and is presently serving as a reviewer and editor in many international journals.

Dr. Amrita Kumari Panda, Ph.D., is currently working as an assistant professor of biotechnology at the Department of Biotechnology, Sant Gahira Guru Vishwavidyalaya Sarguja, Chhattisgarh, India. She obtained her doctoral degree in biotechnology from Berhampur University, Odisha, India. Dr. Panda received fast track postdoctoral fellowship from Science and Engineering Research Board, Govt. of India, New Delhi. She has more than 8 years of research experience in the field of molecular microbiology and microbial diversity and published several research papers and review articles in national and international peer-reviewed journals. She received Federation of European Microbiological Society (FEMS) Meeting grant award in the year 2014. Her research interest includes metagenomics and microbial diversity.

Dr. Kalibulla Syed Ibrahim received his B.Sc. and M.Sc. from Bharathidasan University and Ph.D. degree from Alagappa University, Tamil Nadu, India. He started his career as a postdoctoral fellow at Mizoram Central University, Mizoram, India, in 2011; he received the prestigious DST-SERB Young Scientist award in 2015 for working in human microbiome of gastric cancer patients and then moved to PSG College of Arts and Science, Coimbatore, India, in 2019, as a full-time assistant professor. His research interests focus on enzyme purification, characterization, molecular cloning, metagenomics, and drug target interactions.

Chapter one

The therapeutic role of microbial metabolites in human health and diseases

Nivedita Manoharan*, Rajeshwari Parasuraman*, Dheepthi Jayamurali* and Sathya Narayanan Govindarajulu,    Department of Physiology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India

Abstract

Microorganisms were known to be the first life on earth, marking their existence as early as 3.5 billion years ago. Microorganisms are the basic foundation of the biosphere. The gut microbiota and the associated metabolites play an inexorable role in human health and disease. The microbial metabolites are of two forms, one is primary metabolites like nucleotides, amino acids, and fermented end products and secondary metabolites are the organic compounds formed at the end of stationary phase. The primary metabolites exert their functional effects on the host through the integration of receptor-mediated metabolite signaling and activation of host intracellular metabolic pathways, whereas the secondary metabolite has no role in the functioning or development of humans. In a healthy individual, beneficial microbiota population is high, when this homeostasis gets altered due to stress, unhealthy food habit, antibiotics, pollution, drugs, infections, or xenobiotics, it may lead to dysbiosis which results in the development of various disorders such as atherosclerosis, diabetes, metabolic syndrome, inflammatory bowel disease, neurological disorder, and colorectal cancer. Microbial dysbiosis leads to alteration in the levels of various metabolites like short-chain fatty acids, bile acids, branched-chain amino acids, trimethylamine N-oxide, phenyl acetyl glutamine, and increase in proinflammatory bacteria. This proinflammatory bacterium carries immunoreactive lipopolysaccharide which can destroy the tight junctions between the host intestinal epithelial cells and forms leaky gut which induces inflammation. Besides their impact on the development of disease, there are some of the microbial metabolites that have therapeutic significance too. Recent researches have proved the therapeutic efficacy of various metabolites in preventing inflammation, apoptosis, hyperresponsiveness of platelets, development of cancerous cell, and regulation of glucose metabolism.

Keywords

Microbiota; dysbiosis; metabolic syndrome; inflammation

1.1 Background

The existence of microorganisms was reported 3.5 billion years ago. Their development in the biosynthetic pathway is anonymous (Baltz, 2010). The microorganisms are well-known to be flourished from the abyssal region to the stratosphere and also, they have been reported to withstand extreme temperatures as in freezing ice to the hot volcano (Imshenetsky, Lysenko, & Kazakov, 1978; Wainwright, Alharbi, & Wickramasinghe, 2006). Microorganisms also have massive significance in the biome which is the prime source of nutrients and recyclers in the environment (Bisen, Debnath, & Prasad, 2012). The human body is considered a well-suitable niche for a diverse range of microorganisms (Knight et al., 2017). Even though humans are colonized by an abundance of microbiota, their metabolic variety narrows them to a great level of biosynthetic firing between the species (Dorrestein, Mazmanian, & Knight, 2014). The human gut exhibits complex associations with trillions of microorganisms of around 1×10¹³ to 1×10¹⁴, biomass >1 kg. This microbiota along with their microbiome has many functions like the maintenance of homeostasis through a taut stability of cell-to-cell signaling and release of peptides. This gut microbiota is considered the microbial organ of the body (Neish, 2009; Nicholson, Holmes, & Wilson, 2005).

The composition of microbiota is stable in different locations and they are undeniably high from 10²–³ in the proximal ileum and jejunum to 10⁷–⁸ in the distal ileum (Neish, 2009; Zoetendal, Vaughan, & de Vos, 2006). The gut microbiota is considered the prime source of small biomolecules and some bioactive compounds that can prompt both immune and metabolic pathways (Martinez, Leone, & Chang, 2017). The gut microbiota plays a vital role in human health and disease. The beneficial outcome of the microbiota was predominantly provided by means of the intrinsic parts of gut microbiota and the microbiota-associated metabolites (Cani, 2019; Postler & Ghosh, 2017; Rooks & Garrett, 2016). An imbalance in the microbiota composition is referred to as dysbiosis and this was presented with evidence in intestinal diseases like colorectal cancer (CRC) (Arthur et al., 2012), irritable bowel disease (Liu et al., 2017), inflammatory bowel syndrome (Takahashi et al., 2016) and nonintestinal diseases like cardiovascular disease (CVD) (Zamparelli et al., 2016), neuro-psychiatric diseases (Mu, Yang, & Zhu, 2016), obesity (Schwiertz et al., 2010), fatty liver (Zamparelli et al., 2016), and asthma (Arrieta et al., 2015).

The gut microbiota and their metabolites through their biotransformation have been related with interindividual change that was detected in response to dietary supplementation and drugs (Coryell, McAlpine, Pinkham, Mc Dermott, & Walk, 2018; Rekdal, Bess, Bisanz, Turnbaugh, & Balskus, 2019; Rothhammer et al., 2018). The gut microbiota produced significant interindividual changes in dietary intervention as like antiseizure effect of ketogenic diet (Bashiardes, Zilberman-Schapira, & Elinav, 2016; Flint, Duncan, Scott, & Louis, 2014; Olson et al., 2018; Requena, Martinez-Cuesta, & Pelaez, 2018; Rioscoviá et al., 2016). The microbial population differs from individual to individual due to the factors like environmental, host-extrinsic, and host-intrinsic (Tsb, Raes, & Bork, 2018). The understanding of dietary mediations and their metabolites which are commencing from microbiota are complicated (Wang et al., 2019). The progression of understanding the host-microbiota was through a novel technology called 16S rRNA sequencing revealed the previous unknown microbial populations. The functional features of this sequencing were through metagenomic sequencing which includes metatranscriptomics, metaproteomics, and metabolomics (Martinez et al., 2017). Metagenomics associates the contribution of microbiome with disease in human and animal models. These 16S rRNA sequences have given a wide knowledge about microbial diversity and their phylogenetic community (Langille et al., 2013). The limiting factor 16S rRNA serves as a marker gene sequence in the reference gene database (Sharpton, 2014). Massive shotgun sequencing tools are significant in exploring the microbiome gene function arena and also it can avoid bias in amplicon sequencing. These metagenomics are used as assembly programs and novel interfaces (Crusoe et al., 2015; Eren et al., 2015). The gene content and functional capacity of microbiome can be identified through shotgun metagenomics. The combination of both metatranscriptomic shotgun and metagenomics shotgun can help to identify microbial genomes of different disease states. Although it provides basic characteristics and activity of the whole microbial genome, the tool has its own limitations (Bashiardes et al., 2016).

Metabolomics—the involvement of the microbes is gritty for the metabolism in host. One of the approaches was the comparison of tissues in germ-free mice which was developed in the absence of microbiome. This germ-free mouse was reported to develop anomalies like alterations in the anatomical features of the gut and changes in the physiological characteristics with metabolic variations and decreased cardiac output (Al-Asmakh & Zadjali, 2015; Coates, 1975; Nicklas, Keubler, & Bleich, 2015). Apart from the germ-free mice-related studies, the recent discovery of metabolites or the candidate small molecules has also extended our knowledge about the impact of microbes in the host (Donia & Fischbach, 2015). For the optimum growth of microbes, the primary metabolites like nucleotides, amino acids, and fermented end products are meticulously used (Sun et al., 2015). The secondary metabolites are the organic compounds which are formed at the end of stationary phase that are not involved in the development, growth and reproduction of microbes but only associated in healthcare activities like enzymatic inhibitors, immunosuppressive, antitumor, antimicrobial, and antiparasitic agents (Demain, 1999).

These microbiome-associated metabolites have functional effects on the host like integration of receptor-mediated metabolite signaling and activation of host intracellular metabolic pathways. In previous studies, these microbial metabolites act as endocrine sources (Plovier & Cani, 2017) and in the latter studies, the eukaryotic host cells were reported to directly recognize these microbial metabolites where they activate the receptor-mediated signaling and cell-specific transcriptional responses. These signaling metabolites include the indole derivatives, short-chain amino acids and niacin, etc. (Levy, BlacherE, & Elinav, 2017). These microbial metabolites not only integrate cellular metabolism but also act as the regulators of immune system and gut function (Levy, Kolodziejczyk, ThaissC, & Elinav, 2017). For a thorough understanding of microbial metabolites on host responses, receptor-related studies like pattern recognition receptors such as C-type lectin-like receptors, Toll-like receptors, nucleotide-binding oligomerization domain-like receptors (NLRs), retinoic acid-inducible gene-I and absent in melanoma 2 like receptor (ALRs) are significant (Agier, Pastwinska, & Brzezinska-Blaszczyk, 2018; Kurilshikov, Wijmenga, Fu, & Zhernakova, 2017). This article describes about the microbial metabolite’s therapeutic role in human health and diseases.

1.2 Mode of action of microbial metabolites

In recent decades, microbial metabolites have been recognized to play a diverse role in human health and disease. Researchers have investigated the mechanisms by which the commensal microbiome and its metabolites mediate their impact on human physiology (Descamps, Herrmann, Wiredu, & Thaiss, 2019). In a healthy individual, beneficial microbiota population is high, when this milieu intérieur gets altered, it may lead to various disorders such as atherosclerosis, diabetes, metabolic syndrome, inflammatory bowel disease, neurological disorder, and CRC (Appanna, 2018). There are many causes that may lead to dysbiosis (Fig. 1.1) and how this dysbiosis brings about various disorders will be discussed under separate disease conditions.

Figure 1.1 Causes and complications of dysbiosis.

1.2.1 Diabetes mellitus

Gut microbiota has been proposed to be a neglected endocrine organ because of its metabolic capacity to influence various functions in the host by producing several metabolites like vitamins, secondary bile acids (BAs), neurotransmitters, and gastrointestinal hormones, including ghrelin, leptin, and glucagon-like peptide-1 (GLP-1), peptide YY (PYY) (Clarke et al., 2014; Velmurugan, Dinakaran, Rajendhran, & Swaminathan, 2020). Microbial metabolites is shown to play a pivotal in controlling metabolic processes such as insulin sensitivity, glucose tolerance, fat storage, and appetite (Martin, Sun, Rogers, & Keating, 2019). Microbial dysbiosis leads to decreased short-chain fatty acids (SCFAs) and BAs levels, increased branched-chain amino acids (BCAAs), and trimethylamine N-oxide (TMAO) level which might decrease the insulin sensitivity. In diabetes mellitus, due to dysbiosis there is increase in proinflammatory bacteria which carry immunoreactive lipopolysaccharide (LPS)—on their cell walls and flagellin—a structural component of flagellum, these molecules can destroy the tight junctions between the host intestinal epithelial cells and forms leaky gut which induces inflammation through TRL2 and TRL4 signaling pathway. Presence of high concentration of BCAAs and TMAO in the blood may results in insulin resistance and inflammation (Leylabadlo, Sanaie, Heravi, Ahmadian, & Ghotaslou, 2020).

Increased concentration of SCFAs can promote the secretion of GLP-1 and PYY which prevents intestinal transit, insulin resistance and also stimulates the secretion of GLP-2 which leads to reduced intestinal barrier function, endotoxemia, and inflammation (Aoki et al., 2017). BAs can bind to the Takeda G-protein receptor-5 (TGR5) and activate intestinal cells to secrete GLP-1, which leads to increased insulin sensitivity and glucose uptake (Jahansouz et al., 2016). BCAAs and imidazole propionate (ImP) causes insulin resistance through hyperactivation of rapamycin complex 1 (mTORC1) which inhibits hepatic insulin receptors (Caesar, 2019; Herrema & Niess, 2020). Hyocholic acid (HCA) can effectively regulate the glucose level in the blood by activating TGR5 and inhibiting farnesoid X receptor (FXR) signaling. HCA promotes the secretion of GLP-1 by intestinal endocrine cells, thus controls blood glucose levels. Gut microbiota can also regulate blood glucose levels through intrinsic enteric-associated neurons which are functionally adapted to the region of intestine it belongs. A study by Muller et al. (2020), suggested the direct control on Cocain- and amphetamine-regulated transcript (CART) neurons by the microbes in order to control the blood glucose level independently.

1.2.2 Cardiovascular disease

Many investigations have proved the role of microbial metabolites such as TMAO, phenylalanine, and SCFAs in the development of various CVDs such as hypertension, atherosclerosis, and heart failure, which are the major cause of death worldwide. Most studies have proved the influence of microbial metabolites in the development and occurrence of CVD (Chen, Zhou, & Wang, 2021). Microbial metabolites like SCFAs have been proven to reduce the risk of CVD by regulating blood pressure, modulating inflammation, and enhancing cardiac repair (Murphy et al., 2017; Properzi et al., 2018). SCFAs have been presented with evidence to have antiinflammatory action through G-protein-coupled receptor (GPCR) signaling by binding to GPR43 and have a role in the modulation of blood pressure by binding to GPR41. Another important metabolite involved in the development of CVD is TMAO derived from choline, which is the precursor of acetylcholine in cholinergic neurons. Choline is present in large quantities in foods rich in fats and cholesterol like animal liver, egg yolk, and red meat. Choline is reported to protect the structural integrity of the cell membranes and maintains cholinergic nerve transmission (Tang, Hazen, 2014; Zeisel, Kerry-Ann, 2010). Dysbiosis may result in the production of trimethylamine (TMA) which is further oxidized to TMAO by flavin monooxygenase 3 secreted by the liver. Increased levels of TMAO make glucose tolerance worse, inhibits insulin signaling in the liver, promotes platelet hyperactivity and inflammation of adipose tissue (Romano, Vivas, Amador-Noguez, & Rey, 2015). Decreased dietary fiber decreases the SCFAs levels leading to dysbiosis and hence causes leaky gut which facilitates the passage of microbial toxins like LPS. Increased levels of LPS lead to inflammation and heart failure (Trøseid, Andersen, Broch, & Hov, 2020). Phenylacetylglutamine (PAGN)—a phenylalanine-derived metabolite is associated with a high risk of major CVD like heart attack, stroke, and death. High-protein intake leads to increased phenylalanine levels in the gut, when this phenyalanine reaches the large intestine, it is converted to phenylacetic acid in the presence of intestinal microbiota. Then this phenylacetic acid enters the circulation and reaches the liver, there it combines with glutamine and forms PAGN exerts its action by interacting with GPCRs, which include the α- and β-adrenergic receptors (Nemet et al., 2020; Xu X et al., 2021). Especially β-adrenergic receptors like β1 and β2 adrenergic receptors are highly expressed in cardiomyocytes. Activation of adrenergic receptors enhances the activity of platelet and leads to atherosclerosis, thrombosis, heart attack, and stroke (Wang, Gareri, & Rockman, 2018; Offermanns, 2006; Xu X et al., 2021).

1.2.3 Neurological disorder

The role of microbial metabolites in neurological disorders is carried out by a number of factors which includes decreased neurotransmitters, vagal stimulation, decreased SCFAs, decreased choline, and increased tryptophan derivatives. First, the neurotransmitters—the ruler of the nervous system is also synthesized in the gastrointestinal tract (GIT), either they are produced directly by gut microbiota or the gut microbiota produces neuroactive metabolites which acts on the central nervous system to indirectly produce these neurotransmitter molecules (Romano et al., 2015), they are collectively called as gut peptides. The absence of gut microbiota is associated with a significant decrease in intestinal levels of neurotransmitters like norepinephrine, 5-HT, and γ-aminobutyric acid (Asano et al., 2012). Especially the intestinal concentration of 5-HT is maintained by enterochromaffin cells by secreting an enzyme called tryptophan hydroxylase which converts dietary tryptophan to 5-HT (Yano et al., 2015). The important metabolite of neurological disorder is SCFAs which bind and activates the GPR43 and GPR41 as well as the less common CPR164 and GPR109a (Stilling et al., 2016). By binding to these receptors SCFAs exert antiinflammatory responses and maintain the integrity of blood–brain barrier. Antiinflammatory activity of SCFAs is exerted by butyrate by acting on microglial GPR109a receptors (Ma et al., 2019; Bourassa, Alim, Bultman, & Ratan, 2016), on the other hand, propionic acid was shown to activate microglia and promote immune cell recruitment (Trompette et al., 2014). Butyrate is a histone deacetylase (HDAC) inhibitor that causes histone acetylation in the hippocampus, reduces Iba1 marker and inhibits microglial activation (Misztak, Pańczyszyn-Trzewik, & Sowa-Kućma, 2018; Davie, 2018; Yamawaki et al., 2018). Activation of microglia is essential for maintaining the normal defense mechanism of the brain. Metabolic breakdown of tryptophan by host [tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) and bacterial enzymes tryptophanase] produces neuroactive molecules such as 5-HT, kynurenine, and indole. Kynurenine is further metabolized into kynurenic acid (KYNA) or quinolinic acids via the nicotinamide adenine dinucleotide pathway. Overstimulation of the kynurenine pathway leads to increased lipid peroxidation and neuroinflammation which is shown to cause neuronal cell death (Young, 2013; Nishizawa et al., 1997). Indole and its derivatives activate the aryl hydrocarbon receptor (AhR) thus inhibits neuroinflammation (Müller & Schwarz, 2008). Choline is one of the most important dietary components for the active functioning of the nervous system. But excessive choline metabolism by the gut microbiota reduces the choline levels, increases the TMAO levels in the hippocampus and basal ganglia thereby may lead to depressive-like behavior (Renshaw et al., 1997; Ende, Braus, Walter, Weber-Fahr, & Henn, 2000; Tian et al., 2016).

1.2.4 Gastrointestinal disorder

Microbial metabolites involved in the pathogenesis of gastrointestinal disorders like inflammatory bowel disorder (IBD) and ulcerative colitis (UC) include SCFAs, indole derivatives from tryptophan metabolites, and BAs. Most of the SCFAs are found in both small and large intestines, and butyrate is found only in the colon and ceacum (Koh, De Vadder, Kovatcheva-Datchary, & Backhed, 2016). Reduction in butyrate-producing bacteria in the intestine may lead to IBD and UC. SCFAs enhance the intestinal barrier thus prevent inflammation and they provide energy to the gut epithelial cells (Peng, Li, Green, Holzman, & Lin, 2009; Scheppach, 1994; Cox et al., 2009). Second, it has been suggested that tryptophan deficiency can cause the development of IBD or aggravate the disorder. Tryptophan is metabolized by three main pathways which include the kynurenine pathway, the serotonin pathway, and the indole pathway. This chapter focuses on the indole pathway, in which the tryptophan is metabolized into a range of indole metabolites, including indoleacetic acid, indole-3-acetaldehyde, indole-3-aldehyde, indole acrylic acid which can act as AhR ligands. AhR is an important transcription factor responsible for T-cell immunity and it exerts antiinflammatory effects in the gut through IL-22. It has been suggested that increase in tryptophan metabolism via the kynurenine pathway, reduced expression of AhR and dietary tryptophan deficiency is associated with the pathogenesis of IBD and also worsening of colitis by increasing inflammation, decreasing mucin production and tight junctions (Lavelle & Sokol, 2020). BAs are reabsorbed in the ileum in two forms—either as conjugated BA or as deconjugated BA through active and passive transport respectively. The conjugated BAs are actively reabsorbed in the ileum by binding with FXR leading to the production of fibroblast growth factor 19 (FGF 19). FGF 19 has been reported to inhibit BA production in the liver which might lead to liver disorder (Schaap, Trauner, & Jansen, 2013; Jahnel et al., 2014; Nyhlin, Merrick, & Eastwood, 1994). Primary BA is converted to secondary BA in the colon by the process of desulfation.

1.2.5 Colorectal cancer

Of all the SCFAs, butyrate is the major source of energy for colonic epithelial cells and they are rapidly absorbed after digestion. Butyrate is a crucial molecule that prevents CRC. Decreased butyrate level due to decreased butyrate-producing bacteria can cause carcinogenesis (Peng, Nie, Yu, & Wong, 2021). Butyrate prevents tumorigenesis by maintaining the gut barrier, providing energy to colon cells, inhibiting HDACs, and hence butyrate modulates the translation of tumor suppressor genes. Butyrate is described to exhibit anticancerous and antiinflammatory effects by activating GPCRs signaling pathway (McNabney & Henagan, 2017). Activation of GPR109A receptor causes downregulation of Bcl-2, Bcl-xL, cyclin D, causes inhibition of NK-κB signaling pathway and facilitates the differentiation of Treg cells (O’Keefe, 2016). Butyrate interacts with GPR43 and suppresses the Wnt/β-catenin signaling which can inhibit the development of intestinal cancer (Singh et al., 2014). BA is known to possess carcinogenic property because of the excessive production of secondary BAs. BAs are deconjugated and converted to secondary BAs via the action of gut microbiota in the colon (Chen et al., 2020). The primary BAs such as cholic acid (CA) and chenodeoxycholic acid (CDCA) are dehydroxylated and generate deoxycholic acid (DCA) and lithocholic acid (LCA), respectively by 7α-dehydroxylating bacteria. The increased levels of 7α-dehydroxylating bacteria and DCA are considered significant contributors in the development of CRC (Ticho, Malhotra, Dudeja, Gill, & Alrefai, 2019; Ocvirk et al., 2020). The microbiome has a vital role in estrogen metabolism (Cook, Kennaway, & Kennaway, 1940). Bacterial β-glucuronidases are responsible for the deconjugation of conjugated estrogens that enable the reuptake and increase in the serum estrogen levels. This can cause changes in the expression of mitochondrial genes which are the contributors of estrogen-induced carcinogenesis (Baker, Al-Nakkash, & Herbst-Kralovetz, 2017; Chen, Yager, 2004; Mikó et al., 2019). High-protein intake increases carcinogenic metabolites in the colon such as NOCs and H2S (Cheng, Ling, & Li, 2020). NOCs are reported to exert carcinogenic effects via DNA alkylation (Gill, Rowland, 2002; Loh et al., 2011). H2S is generated by sulfate-reducing bacteria by utilizing methionine and cysteine as substrates. H2S stimulates CRC progression by inhibiting butyrate oxidation, by inducing DNA damage via reactive oxygen species production, and by breaking down gut barrier integrity (Marquet, Duncan, Chassard, Bernalier-Donadille, & Flint, 2009).

1.3 Therapeutical effects of microbial metabolites in human health and diseases

The microbiomes can respond directly to the somatic interactions or via the molecules they secrete, they increase their access to the peripheral circulation thus affecting human health and cause diseases (Descamps et al., 2019). Besides the microbes, its structural components that is, microbial metabolites can also enter the circulation. Its impact has been broadly studied. These metabolite interferences are therapeutically eye-catching by all means—small molecules with high concentration, probably low toxicity with short half-life. These metabolite-based therapeutics or postbiotics aim at the downstream signaling pathways of microbiome and act through mitigating the adverse effects of an excess lack and the dysregulation of metabolites in the pathway (Wong & Levy, 2019). The following are some of the microbiome or microbial-derived metabolites that have prospective therapeutic significance.

1.3.1 Short-chain fatty acid

SCFAs are the most concentrated metabolites in the GIT (Descamps et al., 2019). They preserve the intestinal mucosa integrity, regulate energy expenditure, increase glucose and lipid metabolism, regulate the immune and inflammatory responses (Agus, Clément, & Sokol, 2021). Acetate, propionate and butyrate are produced from the fermented dietary fibers and starches (Koh et al., 2016). These metabolites are recognized by the seven transmembrane GPCR and the free fatty acid receptors (Priyadarshini, Kotlo, Dudeja, & Layden, 2018; Descamps et al., 2019). SCFAs are used in the treatment of a wide range of diseases, including metabolism, neurology, gut health and it can associate with diseases like IBD, diabetes, and obesity (De Vadder et al., 2014; Slingerland, Schwabkey, Wiesnoski, & Jenq, 2017). In human studies, colonic infusion of propionate enhances the release of PYY and GLP-1 which can reduce energy intake (Chambers et al., 2015). Acetate infusion in the distal colon elevates the fatty acid oxidation and improve the metabolic markers in obese men (Van der et al., 2016). On the other hand, oral intake of butyrate did not alter insulin sensitivity in individuals with metabolic syndrome (Bouter et al., 2018). In neurological disorders like Schizophrenia, Autism, Alzheimer’s, Huntington’s and Parkinson’s disease, butyrate ameliorated the adverse effects; by activating GPCR and acting as cellular energy source (Cuomo et al., 2018; Erny et al., 2015; Bourassa et al., 2016; Govindarajan, Agis-Balboa, Walter, Sananbenesi, & Fischer, 2011; Lopes-Borges et al., 2015). In a mice study, oral propionate from maternal microbiota crossed the placenta and converse resistance to obesity in fetus via SCFA-GPCR axis. This showed that SCFA modified the metabolism in pregnancy (Kimura et al., 2020). Although SCFAs are used as therapeutic agents in different diseases, there is also research which is interested in prebiotic study as the microbiota can generate SCFA (Burokas et al., 2017).

1.3.2 Bile acids

BAs are vital molecules that are synthesized in liver from cholesterol. The BA along with CDCA and CA are necessary for digestion and absorption of lipid/vitamins (Thomas, Pellicciari, Pruzanski, Auwerx, & Schoonjans, 2008; Urdaneta & Casadesus, 2017). They are reabsorbed in the small intestine and reprocessed in the liver via enterohepatic circulation. The primary BA is converted to secondary BA by the bacterial deconjugation, 7α-dihydroxylation, and epimerization. The CDCA could be converted to monohydroxy LCA and CA could be further converted to dihydroxy DCA. The gut microbiota can further metabolize DCA to tertiary BA—dihydroxy ursodeoxycholic acid (UDCA) (Urdaneta & Casadesus, 2017). BA regulates cholesterol homeostasis through FGF19/FGF15. It also regulates metabolism through TGR5 (Selwyn, Csanaky, Zhang, & Klaassen, 2015) and FXR which aid in energy expenditure, insulin secretion, glycogen synthesis, insulin sensitivity, thermogenesis, and facilitating satiety signals to brain (Ðanić et al., 2018).

In mice, short-term administration of antibiotics reduces—the hepatic secondary BA (regulator of metabolic homeostasis),