Dysbiosis leads to structural and functional changes in the gut microbiome. If dysbiosis contributes to chronic inflammation by increased abundance of pathogenic flora it is termed as a gain of function dysbiosis. Loss of beneficial microbes promotes the development of chronic diseases such as irritable bowel disease (IBD), obesity, and others; this is known as loss of function dysbiosis. Moreover, increased abundance of pathogenic flora and decreased abundance of beneficial flora can occur simultaneously and lead to the onset of various diseases. ¹ The altered profile of gut microbiota is correlated with intestinal diseases such as coeliac diseases, IBD, and extraintestinal diseases including asthma, allergy, cardiovascular disease, chronic kidney disease, obesity, colorectal cancer, and metabolic syndrome ( Figure 1). Dysbiosis might interfere with the gut-brain cross-talk, leading to the development of mental illnesses and neuro-disorders, including Alzheimer’s disease, Parkinson’s disease, anxiety, and depression. ¹ Commensal bacteria may affect brain functioning through γ-aminobutyric acid (GABA), directly influencing both immune and neural receptors within the enteric nervous system (ENS) and central nervous system (CNS). Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression. ^{2 , 3} Additionally, recent studies confirm that gut microbiota dysbiosis may contribute to mood swing disorders as well. ⁴ Dysbiosis in neonates is a predisposition to energy and immune imbalance and metabolic syndrome. ⁵ Dysbiosis also leads to increased production of pro-inflammatory cytokines. Inflammation-induced microenvironmental changes drive oxidative stress, generation of ROS and DNA damage, thereby leading to mutation and cancer. Gut microbiota imbalance, therefore, seems to be a root cause of chronic illnesses. However, understanding how gut microbial modulation causes various diseases is still in its infancy. This review is an effort to holistically review multiple aspects of dysbiosis and its role in disease initiation and progression.

Dysbiosis is the change in the composition of the microflora of the gut leading to an increase in the abundance of pathogenic bacteria and a decrease in the abundance of beneficial micro-organisms. Therefore, the loss of commensals, bloom of pathobionts, and loss of diversity are characteristics of dysbiosis. ⁶ Dysbiosis leads to changes in taxonomical composition as well as the metagenomic functions of the microbial communities. For example, the transformation of short-chain fatty acids (SCFA)-producing microbiota to toxic metabolite-producing microbiota disrupts microbial homeostasis and hampers the crosstalk between gut and brain, eventually leading to the development of various chronic diseases.

Gut microbiota is composed of various functional groups of microorganisms that conduct metabolic functions. These groups contain SCFA-producing bacteria (acrogens), sulfate-producing bacteria (methanogens), lactate-utilizing and producing bacteria, vitamin-producing bacteria and amino acid-, bile acid-using bacteria. ⁷ The quantitative and/or qualitative change in the composition of these groups is known as taxonomic dysbiosis, whereas a change in metabolic profile is known as functional dysbiosis. Taxonomic dysbiosis has previously been studied through conventional microbiological techniques and recently using metagenomics. ^{8 , 9} Mass spectrometry methods are used to study functional metabolomics. Both aspects of dysbiosis are discussed briefly in the following sections.

Controlling the interaction with the microbiota accounts for a significant portion of the intrinsic function of the immune system. As a result, gastrointestinal (GI) tract colonized by the most beneficial microorganisms serves as the interface with the highest number of immune cells. In response, we see a dominant effect of the healthy microbiota on the immune system that further reinforce barrier immunity and hence their containment to defend their ecological niche. ⁶⁵ Minimizing contact between microorganisms and the epithelial cell surface, decreasing tissue inflammation, and microbial translocation is a key approach the host uses to preserve its homeostatic connection with the microbiota. The combined activity of mucus, epithelial cells, immunoglobulin A (IgA), immune cells, and antimicrobial peptides in the gastrointestinal system, which has the highest density of commensals, achieves this segregation. ⁶⁶ Pattern recognition receptors (PRR) regulate microbial colonization. ⁶⁷ Dysbiosis affects levels of zonula occludens toxin, which in turn increases the intestinal permeability by disengagement of a tight junction protein complex which increases the entry of bacteria or bacterial components into lamina propria. ⁶⁸ This compromised intestinal barrier paves the way for bacterial cell wall parts such as lipopolysaccharide (LPS) endotoxin or whole microbes to enter the systemic circulation, which triggers the release of inflammatory cytokines from immune cells through T-cell receptor (TLR) activation. Humans can develop an inflammatory, immunological response to even minor increases in blood LPS levels (0.5–1.0 ng/kg). ⁶⁹ Thereby, dysbiosis leads to chronic, low-grade inflammation. Dysbiosis-induced gut permeability and inflammation are risk factors in various diseases such as IBD, advanced liver disease, CKD, diabetes, and CRC. On the other hand, through bacteria-derived metabolites, dysbiotic microbiota hijacks the host’s immune system and alters inflammasome signaling, modulates TLR signaling, and degrades secretory IgA (sIgA). ⁷⁰ In addition, some bacterial species such as segmented filamentous bacteria (SFB), Bacteroides fragilis, Clostridia spp, and Mucispirillum spp . directly control the development and differentiation of the immune system. SFB induces IgA production and activates Th17 cells through interleukin (IL)-23, IL-22, and serum amyloid A protein by direct attachment to the intestinal epithelium. ^{71 , 72} On the other hand, most other bacteria use SCFAs, tryptophan metabolites, as communication mediators between microbiota and immune cells. These metabolites regulate regulatory T cells (Treg) homeostasis. A decrease in the abundance of SCFA-producing bacteria in dysbiosis creates imbalanced Treg production and inflamed mucosa. ⁷³ B. fragilis regulates the development of Treg cells through polysaccharide A. ⁷⁴

The human GI tract is essentially sterile in utero, so exposure to microbes during delivery and in the environment immediately following birth is key to the establishment of the microbiota. Colonization in the intestine starts right after birth, which depends on the mode of delivery and evolves as we grow. Cesarean section (C-section)-delivered infants are colonized with environmental and skin microbes ( Staphylococcus, Streptococcus, Veillonella, Propionibacterium, E. coli, Salmonella, Klebsiella pneumoniae), whereas infants delivered through the vagina contain maternal vaginal and urogenital tract microbiota ( Lactobacillus, Bacteroides, Prevotella, Bifidobacterium). ⁷⁵ Although this difference in microbial composition decreases with time, C-section birth is linked to a delay in the colonization of some taxa. ⁷⁶ The microbial abundance increases up to six-fold in the first few weeks after birth and continues to evolve in the first few years. The postnatal factors in microbiota development include consumption of antibiotics, breastfeeding, host genetics, and environment. The infant to adult microbiome transition starts when solid food is introduced into the diet, which stabilizes after approximately three years of life. Microbial communities that colonize in the initial stages shape our immune system and drive adaptive immunity development. ⁷⁷ Infant gut dysbiosis is characterized by a significant imbalance between beneficial and potentially pathogenic bacteria in the GI tracts of newborn babies. A recent study conducted a metagenomics survey and showed that 90% of US infants have signatures of dysbiosis, high levels of bacteria associated with gut inflammation, and antibiotic resistance genes. Overall, 93% of the microbiome belonged to 10 bacterial families and most of them are pathogenic bacteria ( Enterobacteriaceae, Streptococcaceae, Clostridiaceae, and Staphylococcaceae). ⁷⁸ Pre-term infants have more microbiome instability, immature gut epithelium, and severe dysbiosis (higher proportion of Gammaproteobacterial than in-term infants). ⁷⁹ With the advancement in high-throughput sequencing technology, researchers have started studying the microbiome of the mother before birth. They proposed that colonization in mothers happens long before birth, with the mothers actively passing on to the offspring. Therefore, it is imperative to make the mother’s gut microbiome healthier with beneficial commensals rather than waiting until birth. ⁸⁰

The gut microbiome and the brain communicate bidirectionally, each one potentially influencing the functioning of the other. This communication bridge is known as the gut-brain axis (GBA). The efficient functioning of the microbiota-gut-brain axis includes coordination among the CNS, autonomic nervous system (ANS) including sympathetic and parasympathetic branches, ENS, the immune system, metabolic signaling, and endocrine system ⁹³ ( Figure 2). In vitro, in vivo, and human studies confirm a positive correlation between gut microbiome dysbiosis and functional changes in the brain. ⁹⁴ The microbiota can affect the CNS directly or indirectly through the modulation of neurotransmitters and neuroactive microbial metabolites such as short-chain fatty acids.

Despite the fact that several types of bacterial phyla dominate the human GI tract, such as Firmicutes, Actinobacteria, and Bacteroidetes, the overall composition of the human gut microbiota is highly variable, which gives rise to inter-individual variation in drug therapy responses. ¹¹⁰ The effect of gut microbiota variations on pharmacodynamics and pharmacokinetics is known as pharmacomicrobiomics which deals with the interactions between the gut microbiome and xenobiotics. ¹¹¹ Gut microbiota affects drug efficacy by activating or inactivating pharmacological properties of drugs, or by producing drug-metabolizing enzymes involved in drug activation, inactivation or deconjugation. ¹¹² As a matter of fact, the gut microbiota can execute a variety of metabolic responses on medicines, drug metabolites, and other xenobiotics. ¹¹³ Gut microbiota regulates drug-metabolizing genes. Claus et al. discovered that germ-free mice had lower levels of Cyp2c29, Cyp3a11, and Cyp8b1, necessary for drug metabolism. The expression level of these enzymes was normalized after 20 days of bacterial colonization. ¹¹⁴

Dysbiosis has been linked to decreased efficacy of medicines along with increased chemotherapy toxicity. ¹¹⁵ A paradox also emerges, in that chemotherapeutics may aggravate rather than alleviate any dysbiotic state, potentially resulting in serious drug toxicity. ¹¹⁶ But there is a paucity of data on the effect of dysbiosis on drug efficacy. Some studies report that dysbiosis negatively affects the effectiveness of drugs used in chemotherapy. Yuan et al. showed that antibiotic-induced dysbiosis significantly reduced the efficacy of 5-Fluorouracil, a drug used for the treatment of CRC. Antibiotics reduced microbiota biodiversity and altered microbiota community. The pathogenic bacteria including Escherichia, Shigella, and Enterobacter significantly increased, while other commensal bacteria decreased. ¹¹⁷ Cyclophosphamide is another cancer drug that stimulates antitumor immune responses. This drug induces the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs. Such bacteria stimulate a subset of "pathogenic" Th17 (pTh17) cells to be produced, as well as memory Th1 immune response. Tumors were resistant to cyclophosphamide in antibiotic-treated animals without Gram-positive bacteria, and pTh17 responses were reduced. ¹¹⁸ Therefore, the gut microbiota plays a crucial role in maintaining intestinal homeostasis, drug metabolism, and co-metabolism. However, depending on the microbiota composition, this impact may be beneficial or deleterious to the host. ¹¹⁹

The contribution of the gut microbiota to drug metabolism and toxicity is astonishingly recognized but remains largely less studied due to the highly complex relationship between the gut flora and the host. Understanding the underlying mechanism of the gut microbiota in drug metabolism is necessary before any practical advances can be made in drug development or personalized medicine. Innovation in analytical methods is urgently needed to enhance the ability to recognize microbial functions, including metagenomics, metabolomics, and interdisciplinary knowledge integration. Studies of the effects of gut microbiota on drug metabolism and toxicity will provide new evidence for personalized medicine by manipulating the gut microbiota.

The field of microbiome research has evolved rapidly in the last decade and has become a topic of great scientific and public interest. Nonetheless, this extremely fast-growing discipline faces a variety of challenges such as data standardization, better coordination, and collaboration across the field of microbiome. Last but not least is finding the underlying mechanistic details.

In human studies, confounding factors like geographic location, race, diet, culture, health status,variation in the microbiome, and drug use lead to inconsistency in identifying microbiota associated with various diseases. ^{27 , 28} Microbes are rarely annotated at the species or strain level using current sequencing and analytical methods. This leads to difficulty in the identification of disease-associated microorganisms because functional capacity differs amongst strains of the same species. The transcriptome and proteome are less studied in the majority of dysbiosis studies. The use of multi-omics technology in microbiome research could improve accuracy. Variation in the microbiome of animals that are otherwise genetically identical and incompatibility of gnotobiotic advanced technologies with omics technologies pose challenges in animal studies examining the dysbiotic microbiome. To validate predictions made in human studies and explore processes of host-microbiota interactions in dysbiosis-related metabolic disorders, the scientific community must overcome these technical difficulties and develop robust and standardized experimental systems.

The emergence of metagenome-wide association studies in the microbiome area over the last two decades has demonstrated that human biology is a holobiont biology. In other words, human biology is dependent on coexisting microbes, the majority of which live in the digestive system and generate bioactive chemicals, or activate host reactions that affect numerous physiological functions such as immunity, neurobiology, as well as metabolism. ¹²⁰ One popular theory proposes that the lack of diversity in our microbiome increases the risk of diseases. ¹ This study demonstrates that dysbiosis is a complex problem of the intestinal microbiota that is thought to play a role in the pathogenesis of IBD, as well as other diseases such as CRC and allergy disorders, although more research is needed to corroborate this theory. The involvement of numerous bacteria such as Fusobacterium nucleatum, ETBF, E. coli, and Klebsiella spp in the development of various health conditions has been reported using metagenomics of stool samples. In neonates, dysbiosis can lead to fatal infections such as NEC and developmental problems. Emerging novel biomarkers promise precise phylum and species discrimination, confirming evidence of microbial involvement in type 2 diabetes, obesity, metabolic disorders, IBD, and even cancer. ¹²¹

Most research provides a snapshot of the microbiome at one or two time points, although, it is highly variable over time; therefore, more data on the short- and long-term patterns of the intestinal microbiome is needed. Most studies have utilized fecal samples for microbiota analysis since the collection of materials from the human intestine is difficult. The stool microbiota profile does not entirely reflect the gut microbiome as feces do not include all the microbes in the gut. ¹²² As a result, non-invasive methods for collecting microbiota samples from various places along the intestinal system are required, as feces only represents a small portion of the gut microbiota. Metabolomics is used to investigate the metabolic characteristics of the functional microbiota. Dysbiosis causes metabolite concentrations to change, which can lead to crucial organ damage. TMAO is one such metabolite that has been linked to several diseases and is therefore a metabolite of concern. Researchers have used metabolomics to go beyond finding biomarkers to deciphering the mechanisms that underpin phenotypes. ¹²³

Future researchers must be aware of the multiple factors that influence the development of gut dysbiosis, including genetics, food, and environmental factors. Future researchers should be able to get closer to address dysbiosis and its related disorders. The ongoing effort of identifying the gut microbiota present in humans will provide a better understanding of the role of dysbiosis in health and disease. ¹²⁴

When it comes to the translational implications of microbiome research, it was recently discovered that, in addition to their well-known impacts on clinical variables, most medications influence the microbial, metatranscriptomic, and metabolomic profiles.

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