Sage Journals: Discover world-class research

Abstract

The gut microbiota plays a crucial role in various physiological functions, such as the production of microbial compounds and maintaining homeostatic equilibrium by complex host-microbial interactions. However, any shift in the constitution and diversity of the microbiota or abnormal interaction with the host can prompt the development of dysbiosis. This review thus illustrates that microbial metabolites, notably short-chain fatty acids, tryptophan metabolites, bile acids, and polyamines, exert significant regulatory effects on innate and adaptive immunological processes, immune response and intestinal barrier integrity through specific receptor activation, involving TLRs, NODs, GPCRs, nuclear receptors, and Wnt/β-catenin. It further explores the disruption of host signalling pathways, caused by dysbiosis, promoting the transcription of specific genes and activating pro-inflammatory pathways. Consequently, this suggests that microbiota acts beyond general health, eventually contributing to gastrointestinal, metabolic, and neurological disorders. Lastly, this review highlights therapeutic approaches required to restore balance and uphold physiological balance.

Keywords

Microbiome dysbiosis host-signaling pathway microbial metabolites therapeutic modulations

Introduction

Trillions of microbes in mammalian hosts contribute significantly to developing the immune system and regulating host metabolism, affecting numerous aspects of host physiology. The microbiome refers to microorganisms, their collective genetic elements, and their environmental interactions within a specific environment.¹ The human microbiome is a complex ecosystem of bacteria, viruses, fungi, and archaea that reside in and on the human body and play a pivotal role in maintaining health and regulating diseases.¹ Alterations to the normal microbiome called dysbiosis are associated with the onset and progression of several metabolic and inflammatory conditions, including obesity, insulin resistance, diabetes, inflammatory bowel disease, cancer, and infections.¹ Disruption of microbial balance can lead to widespread systemic effects, influencing distant organs and overall physiology.² Moreover, disparity of microbial communities in individuals is influenced by diet, lifestyle, genetics, and environmental exposures, which regulate disease susceptibility and therapeutic efficacy.³ Hence, the microbiome has emerged as a leading edge for tailored healthcare and biomedical research.³ Host cell signaling pathways, such as MAPK, NF-κB, PI3 K/Akt/mTOR, Wnt/β-catenin, and Notch, and GPCR-mediated cascades, regulate essential cellular functions, such as inflammation, immune responses, proliferation, and metabolism.⁴ These pathways, predominantly controlled by endogenous signals, are increasingly acknowledged as targets for microbial-derived molecules such as short-chain fatty acids (SCFAs), lipopolysaccharides (LPS), and peptidoglycans.⁵ This dynamic interaction underscores the role of the microbiome as an active modulator of host signaling, rather than a passive inhabitant.⁶ Recent research underscores the impact of microbial metabolites and structural elements on host signaling networks, affecting metabolic, immune, and neurological outcomes.⁷ Due to a lack of longitudinal studies and methodological challenges, an in-depth understanding of the mechanisms involved is limited.⁸ Influencing host signaling pathways mediated by the microbiome provides potential therapeutic opportunities. Strategies such as fecal microbiota transplantation (FMT), probiotics, and microbiome engineering are being investigated to reestablish microbial equilibrium and target disease-specific signaling pathways.⁹ Progress in multiomics and systems biology is aiding the creation of precision medicine approaches by pinpointing and altering microbial pathways that are functionally associated with disease conditions.¹⁰

However, safety issues, individual microbiome variability, and ecosystem complexity must be addressed for successful clinical implementation.⁷ This review explores the current understanding of how the microbiome modulates host cell signaling and its implications for therapeutic discovery. It defines the microbiome and its relevance to human health and provides an overview of host signaling systems and the influence of microbes. In addition to discussing potential treatments, current obstacles, and future directions in this quickly developing field, this review preferentially examines how dysbiosis interferes with host signaling pathways to trigger pro-inflammatory reactions that lead to neurological and metabolic disorders.^5,6

Microbiome composition and functional diversity

A comparative overview of microbial communities across major human body sites, highlighting dominant taxa, metabolites, and associated host functions, is presented in Table 1.

Table 1.

Comparative overview of microbiomes by body site – taxa, dominant metabolites, and associated host functions.

Body Site	Dominant Taxa (Phyla & Genera)	Key Microbial Metabolites	Associated Host Functions	Reference
Gut	Phyla: Firmicutes, Bacteroidetes Genera: Bacteroides, Faecalibacterium, Lactobacillus, Bifidobacterium	Short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate	Responsible for smooth digestion and maintaining gut integrity	¹¹
Skin	Phyla: Actinobacteria, Firmicutes Genera: Propionibacterium, Corynebacterium, Staphylococcus	SCFAs, amino acid metabolites, and antimicrobial peptides.	Acidify the skin, modulate body odor, and inhibit pathogens like can	^21–23
Oral	Phyla: Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria Genera: Streptococcus, Neisseria, Prevotella	Lactic acid, propionate, NH3, acetate, among other things	Lactic acid demineralizes the enamel, and NH3 buffers the acidic pH.	^24,25
Vagina	Lactobacillus	Lactic acid	This gives the vagina its acidic pH, which helps inhibit pathogen growth. It also prevents bacterial infections.	¹⁴

Microbial taxa across body sites

The human microbiome contains a variety of microbial communities, with different body sites carrying unique assortments of microbes that serve specific functions. For instance, the gut microbiota is primarily dominated by two phyla, Firmicutes and Bacteroidetes. Among these dominant phyla, several genera like Bacteroides, Faecalibacterium, Lactobacillus, and Bifidobacterium are noticeable, and their functions are to maintain smooth digestion, modulate the immune system, and maintain gut health and barrier.¹¹ The skin microbiota primarily comprises Actinobacteria such as Propionibacterium and Corynebacterium, and Firmicutes such as Staphylococcus. They ensure the skin is healthy and can protect against pathogens.¹² The oral microbiota is highly diverse, with the most common phyla being Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. The most predominant genera are Streptococcus, Neisseria, and Prevotella, which ensure good oral health and can fight diseases.¹³ The acidic pH of the vagina is due to the most abundant bacterial species found in the vagina, which is Lactobacillus. The importance of the acidic pH is significant because it helps protect against infections and diseases, like bacterial vaginosis, which can occur when the acidic condition is hampered.¹⁴

Functional roles: metabolism, immune regulation, and barrier integrity

Microbes play several roles in ensuring a good host physiology. They help metabolize dietary fibers into short-chain fatty acids (SCFA), such as acetate, propionate, and butyrate, which are used as energy sources for the host.¹⁵ Microbes communicate with the host immune system, producing immune cells and modulating the inflammatory response. For example, SCFAs cause the differentiation of regulatory T cells, resulting in immune homeostasis.¹⁶ Microbes also increase mucus and antimicrobial peptide production, and thus they strengthen epithelial barriers so that pathogens cannot move to a different location.¹⁷

Tools for profiling microbiomes

Recently, sequencing and technological advancements have characterized microbes more precisely. For instance, by 16S rRNA Gene Sequencing, we can identify and classify bacteria. Despite being a cost-effective procedure, it only provides us with limited information about the various functions of a specific bacterium.¹⁸ Metagenomics is a technique that sequences all microbial DNA and analyzes the genes and their potential functions.¹⁹ Another analysis technique, metabolomics, analyzes all microbial metabolites, determines their functions, and analyzes their effects on the host.²⁰

Overview of key host cell signaling pathways

Microbial components and metabolites significantly influence host cellular functions by modulating diverse types of intracellular signaling pathways. The major host signaling pathways influenced by TLR/NOD, Wnt, GPCR, nuclear receptor, and Akt pathways are illustrated schematically in Figure 1.

Figure 1.

Schematic diagram of various host signaling pathways. (a) Activation of TLR and NOD receptors occurs upon binding to MAMPs/PAMPs, initiating downstream signaling cascades. TLR activation leads to the phosphorylation of Raf (MAPKKK), subsequently activating MAPK. The activated MAPK translocates to the nucleus, promoting transcription of pro-inflammatory genes. NOD receptor activation similarly triggers phosphorylation of the NF-κB, IκBα, IκBβ, and IκBε complex, resulting in IκBα, IκBβ, and IκBε degradation and release of active NF-κB, which then enters the nucleus to initiate pro-inflammatory gene expression. (b) The Wnt ligand binds to the Frizzled receptor and LRP5 in the Wnt signaling pathway, activating Disheveled and inhibiting the destruction complex (APC, Axin, GSK3β, CK1). This prevents β-catenin degradation, allowing its accumulation and nuclear translocation, where it binds to TCF/LEF transcription factors to activate Wnt target genes. (c) Microbial metabolites such as short-chain fatty acids (SCFAs) activate G protein-coupled receptors (GPCRs), leading to adenylate cyclase activation, increased cAMP production, and subsequent activation of PKA, which translocates to the nucleus to regulate gene transcription. (d) Ligands like fatty acids activate nuclear receptors such as LXR and PPAR. They translocate to the nucleus upon activation and modulate gene expression by binding to specific DNA response elements. (e) In the Akt signaling pathway, ligand binding activates receptor tyrosine kinases (RTKs), leading to Ras activation and phosphorylation of IRS. This recruits PI3 K, which converts PIP2 to PIP3. The PIP3 facilitates PDK1 and Akt activation, resulting in mTORC1 and mTORC2 signaling pathways.

Toll-like receptor (TLR) and NOD-like receptor (NLR) signaling

The strong interplay between the gut microbiota and immune responses can maintain and regulate the internal environment of the gut. The cells of the gut can discriminate between pathogens via pattern recognition receptors (PRRs), which include families of toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD) like receptors (NLRs), among others. TLRs are mainly located on the membrane of immune and epithelial cells and consist of eleven transmembrane proteins.²⁶ Whether the TLR family activates the immune system or induces tolerance depends on its ability to recognize pathogen-associated molecular patterns (PAMPs) produced by microbial invaders or microbe-associated molecular patterns (MAMPs) from commensal microbes.²⁶ Upon recognizing PAMPs, TLRs trigger the innate immune system by detecting pathogens from both Gram-negative and Gram-positive bacteria, activating several intracellular signalling cascades, leading to the production of cytokines, chemokines, and transcription factors, and dimerization of TLR2 with other TLR members to stimulate the NF-κB proinflammatory pathway to maintain gut homeostasis.²⁶ NODs, such as NOD1 and NOD2, are present in the cytoplasm of enteric cells and, like TLRs, can recognize PAMPs and MAMPs and also induce the innate immune system by the activation of NF-κB, MAPK, type I interferon, cytokines, and chemokines, as illustrated in Figure 1(a).²⁷

MAPK and Nf-κb pathways

Mitogen-activated protein kinases (MAPKs) are a highly conserved signalling pathway that regulates various cellular processes such as cell proliferation and differentiation. They also play a crucial role in angiogenesis and tumour metastasis. The path comprises three kinases: MAP kinase kinase kinase (MKKK), MAP kinase kinase (MKK), and MAPK, where MAPK is the most critical signalling for the survival and development of tumour cells.²⁸ MAPK in the cytoplasm can translocate to the nucleus and mediate the phosphorylation of both cytoplasmic and nuclear proteins, contributing to metastasis, resistance towards apoptosis, and abnormal cell growth.²⁹ Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a transcription factor family of five subunits forming distinct protein complexes, which regulates cellular processes by binding to promoter regions at DNA sequences. In an inactive state, NF-κB, found in the cytoplasm, is bound to three inhibitory factors (IκBα, IκBβ, and IκBε).³⁰ However, its activation depends on a series of phosphorylation events resulting in free NF-κB dimers.³⁰ This results in NF-κB dimers translocating from the cytoplasm to the nucleus, regulating gene transcription and inducing protein conformational changes, promoting cell proliferation, angiogenesis, suppressing apoptosis, and facilitating metastasis.³¹

Wnt/β-catenin and notch pathways

Wnt is a family of 19 glycoproteins that modulates embryonic development, adult tissue homeostasis, and tissue regeneration. Activation of this signalling pathway induces the activation of both the canonical Wnt and non-canonical Wnt pathways of β-Catenin.³² However, accumulation of β-Catenin in the cytoplasm can lead to the migration from cytoplasm to nucleus, binding to LEF-1/TCF4, promoting increased transcription of c-Myc and CyclinD-1. The induction of oncogenes thus facilitates the tumour progression as shown in Figure 1(b).³³ Another signalling network, the Notch pathway, regulates the development and homeostasis of multiple organs and modulates cell proliferation, differentiation, and apoptosis.³⁴ ligand binding causes NOTCH receptors to undergo three cleavages, releasing the Notch intracellular domain (NICD). This results in translocation into the nucleus to regulate transcriptional complexes containing the DNA-binding protein.^34,35 However, aberrant activation can result in cancerous disease by disrupting homeostasis and immune responses.³⁵

GPCR and nuclear receptor pathways

G protein-coupled receptors (GPCR) are versatile and vital proteins of seven α-helical transmembrane proteins. They can facilitate various regulations and responses, including immune response, hormone regulation, and neurotransmission. Binding to ligands (microbial metabolites such as short-chain fatty acids) causes GPCRs to transduce extracellular signals and regulate intracellular second messengers by activating the downstream effectors of GPCR pathways, such as adenylate cyclase (AC), cyclic adenosine 3′,5′-monophosphate (cAMP), and protein kinase A (PKA), which regulate many physiological processes. Hence, this signalling pathway can influence the immune response as demonstrated in Figure 1(c).³⁶ The nuclear receptor gets activated when bound to hydrophobic ligands, including fatty acids, hormones, microbial-derived bile acids, and oxysterols. Examples of atomic receptors include proinflammatory-activated receptors (PPARs) and liver X receptors (LXRs), which, when stimulated, modulate cell differentiation, proliferation, and metabolism, contributing to cardiovascular diseases, cancer, and inflammation. The signalling cascade is represented in Figure 1(d).^37–39

PI3K/Akt/mTOR pathway

The phosphatidylinositol-3 kinase (PI3 K), a signal transduction pathway, modulates cell survival, growth, and metabolism.⁴⁰ Its activation occurs when the activated receptor tyrosine kinase activates IRS, which stimulates PI3 K and catalyzes the conversion of PIP2 to PIP3. The events follow with the binding of PKB/Akt to PIP3, allowing PDK1 to phosphorylate, resulting in partial PKB/Akt activation.⁴¹ This alteration activates mTORC1 and mTORC2. mTORC1 promotes protein synthesis and cell growth, while mTORC2 regulates cytoskeletal organization and cell survival.⁴⁰ Hence, any disruptions in this pathway can result in carcinogenesis. Figure 1(e) depicts the pathway.⁴⁰

Mechanisms of microbiome-mediated modulation of host signaling

Microbial communities influence host physiology by producing specific molecular signals that directly interacting with host receptors and signaling pathways. Table 2 summarizes major microbial-derived molecules and their targets within host signaling pathways. Figure 2 schematically illustrates the principal mechanisms through which microbial metabolites, molecular patterns, extracellular vesicles, and enzymes influence host signaling pathways by highlighting their roles in immune regulation, inflammation, and homeostasis.

Figure 2.

Mechanisms of microbiome-mediated modulation of host signaling. (a) Microbial metabolites like SCFAs, tryptophan, and polyamines bind to host GPCRs and regulate epigenetic changes, immune responses, and barrier function. (b) MAMPs such as LPS, peptidoglycan, and flagellin are recognized by host PRRs (e.g., TLR2, TLR4, NODs, etc.), activating NF-κB and MAPK pathways, leading to inflammatory cytokine release, immune defense, and pyroptosis. (c) Bacterial extracellular vesicles (BEVs) carry bioactive molecules influencing gut-brain communication and activating TLR2/TLR4 on epithelial cells. This changes host gene expression and triggers IL-10 production by CD4⁺ T cells, helping maintain homeostasis. (d) Microbial enzymes (proteases, glycosidases) and effectors modulate host immune signaling, inflammation, and cell survival.

Table 2.

Key microbial molecules and their known targets in host signaling pathways.

Microbial Molecules	Targets in the Host Signaling Pathway	Biological Effects	References
Lipopolysaccharide (LPS)	TLR4–MD2 complex via LPS binding receptor and CD14	NF-κB activation results in inflammatory cytokine production	⁵⁸
Peptidoglycans	TLR2 with TLR1/6 outside the cell and NOD1, NOD2 inside the cell	NF-κB & MAPK activation resulting in cytokines & antimicrobial peptides production	⁵⁹
Flagellin	TLR5 outside the cell and NAIP5/6 with NLRC4 complex inside the cell	-NF-κB activation resulting in cytokine production(intracellular) and release of matured interleukins leading to Pyroptosis (extracellular)	^60,61
Proteases	PARs (Protease-activated receptors)	Altered motility & permeability in the host	⁶²
Glycosidases	Specific sugar linkages in specific Glycans	Glycan degradation	⁶³
Secreted effectors	Specific proteins in the NF-κB and MAPK pathways	Inflammatory responses are weakened	⁶⁴
BEVs	TLRs and NODs	Signaling pathways are modulated, and systemic physiology is altered	⁶⁶

Microbial metabolites

The gut microbiota communicates with the host signalling pathways using microbial metabolites, like short-chain fatty acids (SCFAs), tryptophan metabolites, bile acids, and polyamines.⁴²

Short-chain fatty acids (SCFAs)

The gut microbiota metabolizes dietary fibers to metabolites such as short-chain fatty acids, acetate, butyrate, and propionate.⁴³ These metabolites can dictate the host's health through various mechanisms, including epigenetic regulation, immune modulation, and barrier integrity. Epigenetic regulation means altering the expression of genes without changing the DNA sequence. Metabolites such as butyrate and propionate are involved in the tryptophan metabolism of histone deacetylases. As a result, histone acetyltransferases can add acetyl groups to the histones to a greater extent, leading to an increased modulation of gene expression.⁴⁴ They also promote the differentiation of regulatory T cells.⁴⁴ SCFAs also regulate immune cell functions and inflammatory responses by activating G-protein coupled receptors like GPR41, GPR43, etc.⁴⁵ SCFAs can also increase the number of tight junction proteins and enhance mucin production. A study that aimed to determine the protective effects of SCFAs on intestinal barrier function used the immunoblotting technique to analyze the expression of ZO-1, a tight junction protein. Furthermore, it was revealed that after the treatment of the CACO 2 monolayer with SCFAs like acetate, propionate, and butyrate, the expression of ZO-1 increased.⁴⁶ Due to this, intestinal barrier function improves, leading to a well-balanced gut homeostasis (Figure 2(a)).⁴⁷

Tryptophan metabolites

The gut microbiota metabolizes tryptophan into compounds like indole derivatives, kynurenine, and serotonin.⁴⁸ These compounds influence host signaling in multiple ways. For instance, indole derivatives bind to aryl hydrocarbon receptor (AhR), a ligand-activated receptor, and then it moves to the DNA inside the nucleus and alters gene expression. This can lead to the modulation of immune responses and barrier function.⁴⁹ Not just this, tryptophan metabolism also triggers the synthesis and production of serotonin, a neurotransmitter, which influences gut motility and mood regulation.⁵⁰ The gut microbiota modifies the primary bile acids synthesized by the liver into secondary bile acids, which regulate host signaling in various ways.⁵¹ Secondary bile acids trigger lipid metabolism, glucose homeostasis, and inflammatory responses by activating the farnesoid X receptor (FXR), a nuclear receptor, and G-protein coupled bile acid receptor (TGR5).⁵² The antimicrobial properties of bile acids Gram-negative bacteria's outer membrane, which is LPS, directly influence host health.⁵³

Polyamines

Unlike other metabolites, polyamines such as putrescine, spermidine, and spermine are secreted by the host and the gut microbiota. They carry out multiple cellular functions. Polyamines play a role in maintaining intestinal mucosal integrity. They do this by triggering the proliferation and differentiation of epithelial cells.⁵⁴ An alteration in the levels of polyamines, which is associated with the onset of certain metabolic disorders like obesity and type 2 diabetes; hence, polyamines could be deemed as potential therapeutic targets of these metabolic disorders.⁵⁵ These metabolites explain the association of the gut microbiota with the host pathways, further demonstrating their potential as drug therapies.

Microbe-Associated molecular patterns (MAMPs)

The pattern recognition receptor (PRRs) recognize specific microbial structures called the Microbe-Associated Molecular Patterns (MAMPs), such as lipopolysaccharide (LPS), peptidoglycan, and flagellin, to generate an immune response and act as the host's first line of defense.^56,57

Lipopolysaccharide (LPS)

A crucial component of the Gram-negative bacteria's outer membrane is LPS, composed of an oligosaccharide, lipid A, and an O-antigen. Lipid A activates the endotoxic activity of LPS. When released, LPS binds to the LPS binding receptor in the serum, which is then sent to CD14. CD14 presents this to the TLR4-MD2 complex on immune cells. This association triggers a downward signaling cascade, including NF-κB activation, resulting in the release of inflammatory cytokines like TNF-α and IL-6.⁵⁸

Peptidoglycans

Peptidoglycans comprise cross-linkages between peptides and glycans, and they are the structural components of the bacterial cell walls. Both intracellular and extracellular PRRs recognize these peptidoglycans. Peptidoglycan fragments are usually identified by the TLR2-TLR1 or TLR2-TLR6 complex on the cell surface, causing the production of pro-inflammatory cytokines. Intracellular receptors like NOD1 and NOD2 recognize specific peptidoglycan fragments, activating NF-κB and MAPK pathways, eventually producing cytokines and antimicrobial peptides.⁵⁹

Flagellin

The major bacterial flagella protein, Flagellin, is a MAMP recognized by extracellular and intracellular PRRs. TLR5, present on epithelial cells, recognizes extracellular flagellin, which triggers the activation of NF-κB; hence, various cytokines are produced.⁶⁰ Intracellular flagellin is detected by NAIP5/6 and the NLRC4 inflammasome complex, releasing mature interleukins. This initiates pyroptosis, a process by which inflammatory cells die, as demonstrated in Figure 2(b).⁶¹

Microbial enzymes and effectors

Enzymes and effectors secreted from microbes provide ways to modulate host cell signalling pathways, which then lead to changes in the various physiological and pathological processes, such as immune responses, cell survival, and tissue homeostasis.

Proteases

Specific bacterial proteases, such as gingipains secreted from Porphyromonas gingivalis, can degrade host cytokines, including proinflammatory cytokines and immunoglobulins, which weakens the defense mechanisms of the host's immune system and also results in persistent inflammation.⁶² Conversely, bacterial proteases like LasB from Pseudomonas aeruginosa and GelE from Enterococcus faecalis alter the host's inflammatory responses by activating protease-activated receptors on host cells. It also results in altered gut motility and permeability.⁶²

Glycosidases

Some microbes can get the nutrients necessary for survival by expressing glycosidases that break down the host glycan molecules. For instance, Bacteroides thetaiotaomicron produces glycosidases that break down host mucin glycans, compromising the mucosal barrier and resulting in immune responses.⁶³ The microbes express glycosidases based on the amount of glycans in the lipid bilayers, endowing microbes in different host environments.⁶³

Secreted effectors

Pathogenic bacteria use their inbuilt secretion systems to secrete effectors into the host cells, and these effectors then hijack the host's signaling pathways. Escherichia coli (EPEC) employs a type III secretion system to deliver effectors like NleE, NleC, and NleD into the host. These effectors manipulate and interfere with NF-κB and MAPK signaling pathways, which are central regulators of the inflammatory responses. As a result, the inflammatory responses are weakened, as mentioned in Figure 2(d).⁶⁴ Conversely, Legionella pneumophila secretes effectors to inhibit host protein synthesis, demonstrating that the NF-κB pathway is not activated. This results in prolonged NF-κB activation and modified cytokine production, which may lead to the pathogenesis of various diseases.⁶⁴

Extracellular vesicles and nanoparticles

Bacterial extracellular vesicles (BEV) are nanosized particles secreted by the bacteria. They comprise lipid bilayers enclosing various molecules like proteins, lipids, nucleic acids, and metabolites. They can manipulate host physiological processes remotely, one of the many pivotal roles in inter-kingdom communication.⁶⁵

Role in inter-kingdom communication

The gut microbiota can interact with the host in many ways, one of which is by BEVs. Various microbial components can be sent to host cells through BEVs, leading to the modulation of multiple signaling pathways and altered systemic physiology. For instance, a study revealed that Akkermansia muciniphila secretes BEVs that can trigger serotonin release in the colon and hippocampus, meaning that the gut and the brain can communicate through BEVs.⁶⁶ According to a study, BEVs can reach distal organs like the liver and adipose tissues, where they unload their cargo and trigger some specific signaling cascades, leading to insulin resistance and glucose intolerance.⁶⁶ BEVs can also alter host immune responses. They can interact with various receptors on host cells, like Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors, which will eventually lead to either activation or suppression of immune signaling pathways. For instance, BEVs from Bacteroides fragilis interact with TLR2 and TLR4 and modulate their expression in epithelial cells, leading to the secretion of the anti-inflammatory cytokine IL-10 by CD4+ T cells.⁶⁷

Effects on immune and epithelial signaling

As mentioned before, BEVs play a role in influencing host immune response, but besides that, they can also influence epithelial cell signaling. They also achieve this action by activating or inhibiting signaling pathways. For example, BEVs from Escherichia coli Nissle 1917 upregulate tight junction proteins like zonula occludens-1 (ZO-1) and claudin-14, and downregulate claudin-2, which is a leaky protein, thus maintaining intestinal homeostasis (Figure 2(c)).⁶⁷ In the context of immune signaling, BEVs can exert both inflammatory and anti-inflammatory effects in separate cases. They carry out an inflammatory response by activating nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways that eventually produce pro-inflammatory cytokines. They employ an anti-inflammatory response approach, T cells, and suppress allergic responses; for example, BEVs secreted from Bifidobacterium bifidum exert anti-inflammatory effects in this way.⁶⁷

Host signaling responses to microbiome interactions

The human microbiome profoundly affects host physiology by regulating immune responses, cellular balance, barrier function, and neuroimmune signaling. Understanding these interactions is key to developing microbiome-based therapies.⁶⁸ Figure 3 illustrates key host responses to microbiome-derived signals, including immune modulation via PRRs, systemic effects of circulating metabolites on the brain, epigenetic regulation of gene expression, and epithelial barrier restoration through AHR signaling.

Figure 3.

Host signaling responses to microbiome interactions. (a) Interaction of commensal bacteria with pattern recognition receptors (PRRs), such as Toll-like receptors, activates NF-κB and MAPK pathways, producing pro-inflammatory cytokines, IL-10, and T-regulatory cells to maintain immune balance. (b) Bacterial metabolites such as short-chain fatty acids (SCFAs) enter the circulation system, cross the Blood-Brain Barrier (BBB) and the Central Nervous System (CNS), and modulate neurotransmitter production. Moreover, LPS binds with TLR to activate the NF-κB/MAPK pathway in immune cells, resulting in neurodegenerative diseases. (c) Microbial metabolites like butyrate are natural inhibitors of histone deacetylases (HDAC), which contribute to altered gene expression, resulting in the proliferation of epithelial cells or apoptosis of cancer cells. Additionally, butyrate can induce the proliferation of epithelial cells. (d) Incorporation of microbial metabolites on aryl hydrocarbon receptor (AHR) induces AHR signalling, resulting in Keratinocyte differentiation for barrier restoration.

Inflammation and immune modulation

The microbiota is essential in shaping the host immune system. Commensal microbes engage pattern recognition receptors (PRRs) like TLRs and NOD-like receptors, triggering signaling pathways such as NF-κB and MAPKs.²⁶ Signaling pathways that release pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 play an essential function in immune defense; however, an imbalance can cause chronic inflammation. In response, short-chain fatty acids (SCFAs) produced by microbial factors activate regulatory T cells (Tregs) and IL-10 synthesis to induce an anti-inflammatory response and maintain immune equilibrium, as depicted in Figure 3(a).⁶⁹

Cell proliferation, apoptosis, and differentiation

Microbial interactions affect host cell proliferation and apoptosis, which are vital for tissue maintenance and repair. For example, butyrate, a SCFA from dietary fiber fermentation, fuels colonocytes and modulates gene expression by inhibiting histone deacetylases (HDACs).⁷⁰ This modulation initiates a butyrate paradox process, which promotes healthy epithelial cell proliferation while inducing apoptosis in colorectal cancer cells.⁷¹ Furthermore, signaling networks that influence cellular growth and differentiation, such as the TGF-β pathway, are activated, enhancing immune evasion and metastasis (Figure 3(c)).⁷²

Barrier function and epithelial repair

Epithelial barrier integrity, especially in the gut, is vital for blocking pathogens and maintaining immune tolerance. Commensal microbes support this by boosting tight junction proteins, mucins, and antimicrobial peptides. Disrupted microbiota can weaken the barrier, causing increased permeability, inflammation, and disease.⁷³ Microbial metabolites activate aryl hydrocarbon receptor (AHR), facilitating keratinocyte differentiation and enhancing barrier integrity, thus contributing to skin barrier repair as outlined in Figure 3(d).⁷⁴

Neuroimmune and gut-brain axis signaling

The gut-brain axis allows the interaction between the gut microbiota and the central nervous system, influencing neurodevelopment, behavioral processes, and the progression of neurological disorders. Microbial metabolites like SCFAs can cross the blood-brain barrier, influencing neuroinflammation and neurotransmitter activity.⁷⁵ SCFAs have been shown to influence serotonin production, affecting mood and gastrointestinal motility.⁷⁶ Additionally, microbial components such as lipopolysaccharides (LPS) can activate Toll-like receptors, inducing the release of pro-inflammatory cytokines, contributing to pathogenesis in neuroinflammatory disorders, including Alzheimer's and Parkinson's (Figure 3(b)).⁷⁷

Case studies: disease contexts

Inflammatory bowel disease (IBD)

Inflammatory bowel disease (IBD) encompasses essentially two main disease subtypes: Ulcerative colitis (UC) and Crohn's disease (CD) and is characterized by chronic inflammation of the gastrointestinal tract.⁷⁸ Emerging theoretical perspectives suggest that one potential contributor to IBD is the gut microbiome dysbiosis, often induced by diet, lifestyle, medications, or infections. This imbalance causes commensal bacteria to transition into pathobionts, compromising the mucosal barrier. Consequently, a heightened activation of the host's immune and metabolic responses occurs to restore balance between the gut and microbiome.⁷⁹ IBD is specified by a series of symptoms such as diarrhoea, abdominal pain, gastrointestinal bleeding, weight loss and fatigue, caused due to the narrowing of the gastrointestinal tract, inflammation and ulceration.

The quantitative or qualitative change in the composition of the gut microbiome is one of the most important factors regulating the intestinal immune system; it thus may influence the development and course of IBD.⁸⁰ A study examining the gut microbiome in IBD patients revealed the decreased representation of specific beneficial bacterium species, with an increase in detrimental bacteria, such as Bacteroides and Enterobacteriaceae species.⁸¹ Another study analyzing the efficacy of fecal microbiota from UC patients and healthy groups observed heightened levels of cytokines and immune-related markers such as IL-6, TNF-α, IL-10, IL-12, CD-80, and CD-86 in UC patients, indicating a stronger inflammatory response compared to healthy groups.⁸² Accumulating studies have concluded that IBD is associated with a generalized reduction in microbiota diversity and diminished microbiota composition, significantly increasing the host's immune responses."^83,84 By understanding the functional properties of the intestinal microbiome, it is possible to restore health to a diseased microbiome through diet, prebiotics, probiotics, antibiotics, and/or FMT. Probiotics are live microorganisms that can provide health benefits by suppressing pathogen growth and T-cell proliferation, and include organisms such as Bifidobacteria, Lactobacilli, and Enterococci, among others.⁸⁵ One of the first probiotics that was administered to UC patients was Escherichia coli Nissle 1917, which exhibited beneficial effects.⁸⁶ Prebiotics are non-digestible dietary compounds such as lactulose, lactosucrose, oligofructose, and inulin, providing food for specific host microbiota, facilitating growth and enhancing gut function.⁸⁷ FMT influences multiple stages of the immune system, such as increasing regulatory T cells, while reducing TH17 cells and proinflammatory pathways.^88,89 A study analysed the uses of rifaximin, metronidazole, clarithromycin, and ciprofloxacin antibiotics in Crohn's disease and observed improved patient clinical outcomes.⁹⁰

Cancer

Microbial metabolites produced during the metabolic process of microorganisms can influence host tumorigenesis and tumour progression by several mechanisms, including modulation of the immune system, cancer or immune-related signaling pathways, epigenetic modification of proteins, and DNA damage. For instance, a Methylobacterium causes a decrease in the production of TGF-β and CD8⁺ tissue-resident memory T-cells, leading to gastric cancer.⁹¹ Candida albicans releases IL-22 by activating the aryl hydrocarbon receptor (AHR) and STAT3, resulting in cell metastasis and the formation of intratumoral blood vessels.⁹¹ Moreover, tumor and microenvironment cells respond to signals from microbiota, regulating multiple host pathways related to carcinogenic processes. One such example is presented by Escherichia coli or Fusobacterium nucleatum, which induces DNA damage via the pks gene and genetic mutations in epithelial cells and modulation of the tumor microenvironment, leading to colorectal carcinogenesis.⁹² There is a strong correlation between a patient's gut microbiota and their response to immunotherapy; however, whether this correlation is positive or negative depends on the abundance and range of organisms in the gut microbiota.

Treatment targeting synergistic inhibitory molecules that suppress the immune response, such as CTLA-4, PD-1, and PD-L1, is applied to reduce tumor progression. The presence of B. polymorpha, B. fragilis, and Burkholderia cepacia in one research has been associated favourably with the efficacy of CTLA-4-targeting therapy.⁹³

In another study, examining the effect of anti-PD-L1 treatment in melanoma patients showed an abundance of Faecalibacterium in responders. At the same time, an increase in Bacteroides thetaiotaomicron, Escherichia coli, and Anaerotruncus was observed in patients with poor clinical outcomes.⁹⁴ An analysis of the effect of anti-PD-1 efficacy in metastatic melanoma patients revealed a significantly improved response in patients with higher abundances of bacterial species such as Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium.⁹⁵ In contrast, patients with hepatocellular carcinoma responded poorly to anti-PD-1 treatment due to increased Proteobacteria and decreased Akkermansia muciniphila and Ruminococcaceae spp.⁹⁶ The studies strongly suggest that manipulating the profile and concentration of gut microbiota may modulate cancer immunotherapy.

Metabolic diseases

Several metabolic diseases, such as type 2 diabetes mellitus, non-alcoholic fatty liver disease, and atherosclerosis, have been implicated in dysbiosis. The gut microbiota triggers activation against bacterial components and metabolic production from dietary compounds to regulate metabolic health; thus, disruptions in the pathway cause low-grade inflammation and altered metabolic processes.⁹⁷

Impact on insulin signaling

Gut dysbiosis reduces the production of short-chain fatty acids (SCFA), with increased absorption of lipopolysaccharide (LPS) resulting in the activation of Toll-like receptor and LPS receptor CD14, leading to the induction of inflammatory cytokines, NF-κB, and MAPK pathways. With these activations, an impairment of the insulin signaling is observed with the increased serine phosphorylation of IRS by protein kinases such as c-Jun N-terminal kinase (JNK) and inhibitory κB kinase (IKK)-β, and decreased tyrosine phosphorylation of the insulin receptor, insulin receptor substrate (IRS), and Akt. Additionally, the plasma concentration of IL-6 is inversely proportional to insulin sensitivity. Other cytokines, IL-17 and IFN-γ, and tumor necrosis factor (TNF)-α can also affect insulin signalling. Thus, low-grade inflammation plays a key role in the mechanisms of insulin resistance.^98,99

Impact on lipid metabolism

The gut microbiota regulates dietary lipid composition, digestion, and absorption, potentially altering intestinal lipoprotein formation. The lipid and lipoprotein metabolism can be affected by gut microbiota via bile acid receptors FXR and TGR5, short-chain fatty acids (SCFAs), branched-chain fatty acids (BCFAs), bile salt hydrolase (BSH), and lipopolysaccharides (LPS). Prevalent SCFAs, including acetate, propionate, and butyrate, are involved in cholesterol synthesis and lipid metabolism and have been observed in decreased amounts in patients affected by dysbiosis. Consequently, an increased proportion of lipopolysaccharide (LPS)-containing microbiota in the gut has been linked to increased glycemia and insulinemia by transporting lipids in lipoproteins. The findings suggest that influencing SCFA, LPS production, and cholesterol-metabolism-related gene expression can alter lipid metabolism.^100,101 Bioactive compounds such as polyphenols, prebiotics, and FMT can reduce the effect on metabolic pathways.¹⁰²

Neurological disorders

Five separate studies established the communication process between the commensal microbiota, highlighting the onset of neurological disorders due to any disruptions in this pathway.¹⁰³

Microbiota-Gut-Brain axis

A strong interplay between gut microbiota and the brain via the microbiota-gut-brain axis(MGB) involves bidirectional communication, responsible for maintaining mood, cognition, and neurodevelopment by modulating immune, endocrine, neural, and metabolic pathways.¹⁰⁴ The gut microbiota produces crucial neurotransmitters such as GABA, dopamine, and glutamate, with approximately 90% of serotonin being synthesized in the gut. They also make short-chain fatty acids (SCFAs) like butyrate and propionate, which modulate the microglial activity in the brain, modify the blood-brain barrier, and impact neuroinflammation.^104,105 Additionally, MGB affects the hypothalamic-pituitary-adrenal (HPA) axis, which maintains the stress response.¹⁰⁶ lastly, they can modulate host physiological processes through microbial constituents such as lipopolysaccharides or substrate metabolism, including bile acids.¹⁰⁶

Neuroinflammation and neurological disorders

Association between neurological disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis due to dysbiosis has been demonstrated in recent findings.¹⁰⁷ In Alzheimer's disease (AD), dysbiosis can accumulate amino acids like phenylalanine and isoleucine, inducing neuroinflammation by activating TH1 cells, cell differentiation, and microglial activation.^108,109 In Parkinson's disease (PD), dysbiosis causes inflammation and oxidative stress, transmission of α-synuclein protein, which causes dopaminergic neuron death in the substantia nigra, leading to motor symptoms of PD.¹¹⁰ Multiple sclerosis (MS) is characterized by the composition and range of gut bacteria, marked by elevated production of Methanobrevibacter, Akkermansia, and Bacteroidetes. At the same time, a reduced population of Bifidobacteria, Roseburia, Coprococcus, and Prevotella is observed in MS patients. Noticeably, short-chain fatty acids are produced by the present bacteria, contributing to chronic inflammation in MS.^111,112 SCFA supplementation, probiotics, prebiotics, and FMT have been explored among the therapies.¹¹³

Table 3 summarizes key microbiome–host signaling interactions across various disease contexts and highlights emerging therapeutic strategies aimed at modulating these pathways.

Table 3.

Summary of microbiome-host signaling interactions across diseases and potential therapeutic interventions.

Disease	Interactions between Microbiome and Host	Signalling Pathways	Effect	Therapeutic Modulation	Reference
Inflammatory Bowel Disease (IBD)	Increased proportion of cytokines and immune-related markers causing chronic inflammation	NF-κB, TLR, signaling	Reduced Bifidobacterium species and increased Bacteroides and Enterobacteriaceae species.	FMT, prebiotics, probiotics	⁸²
Cancer	Inducing DNA damage via the pks gene	Aryl hydrocarbon receptor (AHR) and STAT3	Increased release of cytokine factors, and decreased production of TGF-β, and CD8⁺	Targeting CTLA-4, PD-1, and PD-L1 synergistic molecules	⁹¹
Metabolic Disease	Reduced SCFA production and elevated LPS expression, inducing inflammatory pathways	NF-κB, TLR, MAPK signaling	Low-grade inflammation, insulin resistance	FMT Bioactive compounds: polyphenols, prebiotics, probiotics	^98–101
Neurological Disorders	Influencing Microbiota-Gut-Brain Axis	Production of short-chain fatty acids (SCFA), affecting the blood-brain barrier, hypothalamic- pituitary-adrenal (HPA) axis	Activation of TH1 cells, microglia, and increased expression of Bacteroidetes with decreased production of Prevotella	SCFA supplementation, prebiotics, probiotics	^108,109

Therapeutic opportunities and strategies

Probiotics, prebiotics, and postbiotics

Microbiome-targeted therapies like probiotics, prebiotics, and postbiotics modulate host signaling pathways to restore balance and treat diseases, with specific strains or metabolites targeting distinct pathways. Probiotics modulate host pathways like NF-κB and TLR, reducing inflammation and improving barrier function strains such as Lactobacillus rhamnosus and Bifidobacterium longum lower pro-inflammatory cytokines.^114,115 Tailored microbial consortia enhance this effect, restoring microbial balance and immunity. Anaerobe consortia, for instance, promote regulatory T cells via SCFAs for gut anti-inflammatory responses.^116,117 Prebiotics, non-digestible fibers, and oligosaccharides, selectively promote beneficial microbiota that produce metabolites modulating host pathways.¹¹⁸ Insulin-type fructans increase SCFA production, activating GPR41/43 and inhibiting histone deacetylases, enhancing GLP-1 secretion and insulin signaling.¹¹⁹ They also regulate TLR-mediated immune responses, fostering an anti-inflammatory state. Postbiotics modulate host signaling without live microbes, including microbial metabolites and secreted factors. SCFAs, bacteriocins, and exopolysaccharides regulate NF-κB, MAPK, and PI3 K/Akt pathways to reduce inflammation, strengthen epithelial barriers, and influence metabolism.¹²⁰ Butyrate, for instance, promotes regulatory T cell differentiation by inhibiting histone deacetylases, affecting gene expression for immune tolerance. Postbiotics offer a stable, well-defined alternative to probiotics, bypassing viability and colonization issues.¹²¹ Multi-omics and systems biology will facilitate the accurate identification of microorganisms and metabolites that influence host signaling, hence aiding the creation of personalized, disease-specific microbiome therapies.

Microbiome-Derived metabolites as drug leads

Metabolites produced from the microbiome are increasingly acknowledged as possible therapeutic possibilities because they alter host signalling and maintain homeostasis. These substances offer potential treatments for metabolic, neurological, and inflammatory diseases and their synthetic derivatives. Notably, through GPR41/43 activation and HDAC inhibition, short-chain fatty acids like acetate, propionate, and butyrate control immune activity, metabolism, and epithelial integrity.¹²² To improve stability, mimetics like tributyrin reduce inflammation and aid repair in models.¹²³ Synthetic HDAC inhibitors also show promise in modulating immune tolerance and metabolism.¹²⁴

Bile acids, converted by gut microbes, regulate metabolism and immunity via FXR and TGR5.⁵³ Obeticholic acid, an FXR agonist, treats biliary cholangitis and is under study for NASH.¹²⁵ TGR5-targeting analogs may improve metabolism by enhancing energy use and insulin sensitivity.¹²⁶ Microbiome metabolites like tryptophan catabolites modulate AhR and immune checkpoints, serving as drug leads.¹²⁷ Synthetic indole derivatives targeting AhR treat autoimmune diseases by modulating mucosal immunity.¹²⁸ Challenges in stability and bioavailability remain, but advances in chemistry and delivery will improve these therapies.

Engineered microbes and synthetic biology

Synthetic biology and microbial engineering enable precise delivery of bioactive molecules by programming microbes to sense host cues and produce therapeutics, allowing targeted modulation of host signaling for treating complex diseases.¹²⁹ Genetically modified microbes deliver cytokines, enzymes, or peptides to modulate immune and metabolic signaling. Lactococcus lactis secreting IL-10 reduced colitis inflammation by inhibiting NF-κB.¹³⁰ Synthetic biology enables microbes to sense biomarkers and release therapeutics conditionally, enhancing safety and restoring signaling balance.¹³¹ Engineered microbes can deliver enzymes to metabolize pro-inflammatory compounds or correct metabolic issues. E. coli Nissle 1917 expressing bile salt hydrolase modulates FXR and TGR5 signaling, affecting metabolism and immunity.¹³² Bacteria secreting antimicrobial peptides shape microbiota and host immunity, though challenges like stability, immunogenicity, and regulation remain.¹³³ Genome editing, biocontainment, and synthetic circuits enhance engineered microbes’ robustness and control, advancing clinical translation.¹³⁴

Fecal Microbiota transplantation

FMT restores microbial diversity, enhancing immunity, barrier integrity, and metabolism.¹³⁵ It is highly effective in recurrent C. difficile infection, with cure rates over 85%, surpassing antibiotics by restoring colonization resistance and reducing inflammation.^136,137 Beyond rCDI, FMT may modulate host signaling in IBD, metabolic syndrome, and neuropsychiatric disorders.¹³⁸ In ulcerative colitis, it promotes regulatory T cells and reduces NF-κB inflammation.¹³⁹ However, efficacy varies due to donor differences, lack of protocols, and unclear mechanisms limiting optimization.¹⁴⁰ Safety concerns over pathogen transmission require strict donor screening and quality control.¹⁴¹ The incomplete understanding of the long-term effects of FMT highlights the significance of long-term research. Efforts are being made to create synthetic microbiota and defined microbial consortia that can alter host signalling pathways to get beyond the current constraints.¹⁴² Furthermore, it is anticipated that combining systems biology and multi-omics techniques would make it easier to identify critical microbial effectors, promoting the creation of individualised treatment plans.

Current challenges and future directions

Individual variability and personalized microbiome medicine

The microbiome's composition differs among individuals due to variations in genetic factors, diet, environment, and lifestyle, which complicates the creation of universal microbial biomarkers.¹⁴³

Causality versus correlation in microbiome studies

Distinguishing causation from correlation in microbiome-disease links is challenging.¹⁴³ Functional studies using germ-free animals and synthetic communities help infer causality, but applying these findings to humans is restricted by complexity and ethical considerations.¹⁴⁴

Need for integrated multi-omics and computational modeling

A precise understanding of microbiome-host interactions necessitates the integration of multi-omics data.¹⁴⁵ While computational tools can make predictions, there is still a need for standardized methods and large, validated cohorts.¹⁴⁶

Regulatory and ethical considerations

Microbiome therapies face regulatory challenges due to the complexity and variability of live microbial products.¹⁴⁷ Quality control, long-term safety, and risk mitigation, including horizontal gene transfer, must be prioritized in regulatory frameworks. Donor permission, safeguarding the privacy of microbiome data, and guaranteeing equitable access to customised treatments are all ethical considerations.¹⁴⁸ Individuals from different sectors, such as Physicians, Microbiologists, Bioinformaticians, and regulatory agencies, should affiliate to address these pressing concerns. Advances in single-cell technology, synthetic biology, and longitudinal studies may enhance treatment precision and understanding of causality. Realizing the full clinical potential of microbiome-based therapies requires integrating mechanistic understanding with robust ethical and regulatory frameworks.

Table 4 outlines the key obstacles in this field and summarizes proposed solutions aimed at advancing microbiome-focused therapeutic research

Table 4.

Challenges and proposed solutions in microbiome-based therapeutic research.

Challenge	Description	Proposed Solutions	References
Individual Variability	High inter-individual differences in microbiome composition and function	Personalized microbiome profiling; stratified clinical trial designs	^149,150
Causality vs Correlation	Difficulty distinguishing causal relationships from associations	Use of germ-free and gnotobiotic models; longitudinal multi-omics studies	^151,152
Complexity of Microbiome-Host Interactions	Multifactorial signaling networks complicate mechanistic understanding	Integrated multi-omics and computational modeling; systems biology approaches	^152,153
Limited Standardization	Lack of standardized protocols for sample collection, sequencing, and analysis	Development of consensus guidelines; use of standardized reference materials	^154,155
Regulatory and Ethical Challenges	Regulatory frameworks lag behind technological advances, and ethical concerns over manipulation.	Early engagement with regulators, ethical frameworks for clinical translation	^156,157
Stability and Delivery of Therapeutics	Maintaining the viability and activity of live microbes or bioactives during delivery	Advances in formulation technologies; targeted delivery systems	^158,159
Safety Concerns	Potential for unintended consequences such as pathogen transmission or dysbiosis	Rigorous preclinical safety testing; monitoring in clinical trials	^160,161

Conclusion

The delicate balance between the human microbiome and host cell signaling is essential in determining health and disease. The review highlights that microbial communities’ metabolites and structural components alter major host signaling systems such as NF-κB, MAPK, PI3 K/Akt, Wnt/β-catenin, and GPCR pathways. These interactions affect the immune responses, metabolism, neuroinflammation, epithelial integrity, and cancer progression. Notably, microbial products like short-chain fatty acids, bile acids, and tryptophan degradation products have therapeutic potential by acting on the inflammatory, metabolic, and neuroimmune routes. Treatments that promise to rectify dysregulated host signaling and reinstate microbial balance include probiotics, prebiotics, postbiotics, microbiome-derived metabolites, engineered microbes, and microbiota transplantation, including FMT. The indications of the successful use of these interventions include a wide range of diseases: inflammatory bowel disease and metabolic disorders, neurological disorders, and oncological disorders. However, these can be limited by the cross-individual microbiome biodiversity, incomplete mechanistic knowledge, safety issues, and a deficit of regulatory standardization. The ultimate outcomes of microbiome-based therapeutics should be to provide precision, patient-specific treatments and exploit a favorable microbiome-host interaction associated with minimal risks. The development of more of these personalized treatments is likely to be boosted by improving the state of multi-omics, synthetic biology, and computational modeling. Although these approaches have much potential, they must address shortcomings, including stability, delivery, and differentiating causality and correlation in microbiome research.

In summary, host signaling regulated by the microbiome is a paradigm shift in therapeutic discovery. The strengths are numerous, with specific modulation, low invasiveness, and overall systemic effects. However, the method has to deal with a complicated regulatory and biological environment. Future studies of microbial effectors, host responses, and delivery platforms will be instrumental in achieving the potential of microbiome-integrated medicine.

Footnotes

Acknowledgements

The author(s) would like to thank the Department of Biochemistry & Microbiology, School of Health & Life Sciences at North South University, Dhaka, Bangladesh, for providing the resources and support necessary for this work.

ORCID iDs

Mahjabin Sanam

Chowdhury Fatema Tuz Zohra Hossain

Tahmida Binte Hyder

Reasat Tarannum

Jahin Fairuj Oishi

Md. Fakruddin

Author contributions

M.S. led the literature search, citation management, introduction writing/editing, figure/table preparation, final formatting, and review. C.F.T.Z.H. handled the abstract, signaling overview, disease case studies, and final review. T.B.H. wrote the host response, therapy, and future direction sections. R.T. contributed microbiome and mechanism sections and assisted with formatting. J.F.O. finalized the conclusion, figures, and legends. K.M.M.R., S.M.B.U.I., N.B., J.S.J., MAS.S., and A.S. reviewed and revised the draft. M.D.F. conceptualized the manuscript. All authors approved the final version.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

MOLECULAR BIOLOGY | Microbiome. In: Encyclopedia of Food Microbiology. Elsevier, pp. 788–792.

Nazir

Hussain

FHN

Nadeem Hussain

, et al. Therapeutic targeting of the host-microbiota-immune axis: implications for precision health. Front Immunol Epub ahead of print 29 April 2025; 16. DOI: 10.3389/fimmu.2025.1570233

Zakria

Raouf

Ahmad

, et al. MICROBIOME-HOST INTERACTION AND THEIR IMPACT ON HUMAN HEALTH. J Med Health Sci Rev Epub ahead of print 3 March 2025; 2. DOI: 10.62019/5xpj3015

Juarez

Montalbine

Singh

. Microbiome as an immune regulator in health, disease, and therapeutics. Adv Drug Deliv Rev 2022; 188: 114400.

Cruz

Abernathy

Dichosa

AEK

, et al. The Age of Next-Generation Therapeutic-Microbe Discovery: Exploiting Microbe-Microbe and Host-Microbe Interactions for Disease Prevention. Infect Immun Epub ahead of print 19 May 2022; 90. DOI: 10.1128/iai.00589-21

Olteanu

Ciucă-Pană

M-A

Busnatu Ștefan

, et al. Unraveling the microbiome–human body axis: a comprehensive examination of therapeutic strategies, interactions and implications. Int J Mol Sci 2024; 25: 5561.

Microbiome-based therapeutics: Opportunity and challenges. In: Progress in Molecular Biology and Translational Science. Elsevier, pp. 229–262.

Holmes

Kinross

Gibson

, et al. Therapeutic Modulation of Microbiota-Host Metabolic Interactions. Sci Transl Med Epub ahead of print 6 June 2012; 4. DOI: 10.1126/scitranslmed.3004244

Athar

Rasool

Muzaffar

, et al. The human microbiome: a critical player in health and disease. World J Biol Biotechnol 2023; 8: 31.

10.

Aggarwal

Kitano

Puah

GRY

, et al. Microbiome and human health: current understanding, engineering, and enabling technologies. Chem Rev 2023; 123: 31–72.

11.

Paul

Azmal

Haque

ASNB

, et al. Unlocking the secrets of the human gut microbiota: Comprehensive review on its role in different diseases. World J Gastroenterol Epub ahead of print 7 February 2025; 31. DOI: 10.3748/wjg.v31.i5.99913

12.

Zhu

Cheng

. Human skin bacterial microbiota homeostasis: a delicate balance between health and disease. mLife 2023; 2: 107–120.

13.

Rajasekaran

Krishnamurthy

Bosco

, et al. Oral microbiome: a review of its impact on oral and systemic health. Microorganisms 2024; 12: 1797.

14.

Chee

WJY

Chew

Than

LTL

. Vaginal microbiota and the potential of Lactobacillus derivatives in maintaining vaginal health. Microb Cell Factories Epub ahead of print December 2020; 19. DOI: 10.1186/s12934-020-01464-4

15.

Den Besten

Van Eunen

Groen

, et al. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res 2013; 54: 2325–2340.

16.

Haase

Haghikia

Wilck

, et al. Impacts of microbiome metabolites on immune regulation and autoimmunity. Immunology 2018; 154: 230–238.

17.

Ubeda

Djukovic

Isaac

. Roles of the intestinal microbiota in pathogen protection. Clin Transl Immunol Epub ahead of print February 2017; 6. DOI: 10.1038/cti.2017.2

18.

Janda

Abbott

. 16S rRNA gene sequencing for bacterial identification in the diagnostic laboratory: pluses, perils, and pitfalls. J Clin Microbiol 2007; 45: 2761–2764.

19.

Sharpton

. An introduction to the analysis of shotgun metagenomic data. Front Plant Sci Epub ahead of print 16 June 2014; 5. DOI: 10.3389/fpls.2014.00209

20.

Zhang

Butcher

, et al. Advancing functional and translational microbiome research using meta-omics approaches. Microbiome Epub ahead of print December 2019; 7. DOI: 10.1186/s40168-019-0767-6

21.

Grice

Segre

. The skin microbiome. Nat Rev Microbiol 2011; 9: 244–253.

22.

Troccaz

Gaïa

Beccucci

, et al. Mapping axillary microbiota responsible for body odours using a culture-independent approach. Microbiome Epub ahead of print December 2015; 3. DOI: 10.1186/s40168-014-0064-3

23.

Song

Bai

Rudramurthy

, et al. Staphylococcus saprophyticus prevents skin damage by inhibiting Staphylococcus aureus quorum sensing. Sci Rep Epub ahead of print 16 April 2025; 15. DOI: 10.1038/s41598-025-97044-w

24.

Bowen

. Dental caries – not just holes in teeth! A perspective. Mol Oral Microbiol 2016; 31: 228–233.

25.

Bailey

Tokheim

Porta-Pardo

, et al. Comprehensive characterization of cancer driver genes and mutations. Cell 2018; 173: 371–385. .e18.

26.

Valentini

Piermattei

Di Sante

, et al. Immunomodulation by gut Microbiota: role of toll-like receptor expressed by T cells. J Immunol Res 2014; 2014: 1–8.

27.

Ting

JPY

Duncan

Lei

. How the noninflammasome NLRs function in the innate immune system. Science 2010; 327: 286–290.

28.

MAPK Signaling - an overview | ScienceDirect Topics, https://www.sciencedirect.com/topics/neuroscience/mapk-signaling/ (accessed 12 July 2025).

29.

Guo

Pan

Liu

, et al. ERK/MAPK signalling pathway and tumorigenesis (Review). Exp Ther Med 2020; 19(3): 1997–2007.

30.

Xia

Tan

Zhou

, et al. Role of the NFκB-signaling pathway in cancer. OncoTargets Ther 2018; 11: 2063–2073.

31.

Xia

Shen

Verma

. NF-κB, an active player in human cancers. Cancer Immunol Res 2014; 2: 823–830.

32.

Maurice

Angers

. Mechanistic insights into wnt–β-catenin pathway activation and signal transduction. Nat Rev Mol Cell Biol 2025; 26: 371–388.

33.

Shang

Hua

Z-W

. The regulation of β-catenin activity and function in cancer: therapeutic opportunities. Oncotarget 2017; 8: 33972–33989.

34.

Xing

Anbarchian

Tsai

, et al. Wnt/β-catenin signaling regulates ependymal cell development and adult homeostasis. Proc Natl Acad Sci Epub ahead of print 26 June 2018; 115. DOI: 10.1073/pnas.1803297115

35.

Kopan

. Notch signaling. Cold Spring Harb Perspect Biol 2012; 4: a011213–a011213.

36.

Liu

Wang

, et al. G-Protein coupled receptors (GPCRs): signaling pathways, characterization, and functions in insect physiology and toxicology. Int J Mol Sci 2021; 22: 5260.

37.

Oxysterol - an overview | ScienceDirect Topics, https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/oxysterol (accessed 12 July 2025).

38.

Bile Acid - an overview | ScienceDirect Topics, https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/bile-acid (accessed 12 July 2025).

39.

Nuclear Receptor - an overview | ScienceDirect Topics, https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/nuclear-receptor (accessed 12 July 2025).

40.

Hemmings

Restuccia

. PI3K-PKB/Akt Pathway. Cold Spring Harb Perspect Biol 2012; 4: a011189–a011189.

41.

Glaviano

Foo

ASC

Lam

, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer Epub ahead of print 18 August 2023; 22. DOI: 10.1186/s12943-023-01827-6

42.

Debnath

Kumar

, et al. Gut-microbiota derived bioactive metabolites and their functions in host physiology. Biotechnol Genet Eng Rev 2021; 37: 105–153.

43.

Ferenc

Sokal-Dembowska

Helma

, et al. Modulation of the gut Microbiota by nutrition and its relationship to epigenetics. Int J Mol Sci 2024; 25: 1228.

44.

Luo

Leach

Barres

, et al. The Microbiota and Epigenetic Regulation of T Helper 17/Regulatory T Cells: In Search of a Balanced Immune System. Front Immunol Epub ahead of print 10 April 2017; 8. DOI: 10.3389/fimmu.2017.00417

45.

Zhang

Shen

, et al. Short-Chain fatty acids and their association with signalling pathways in inflammation, glucose and lipid metabolism. Int J Mol Sci 2020; 21: 6356.

46.

Feng

Wang

, et al. Short-Chain fatty acids manifest stimulative and protective effects on intestinal barrier function through the inhibition of NLRP3 inflammasome and autophagy. Cell Physiol Biochem 2018; 49: 190–205.

47.

Ghosh

Whitley

Haribabu

, et al. Regulation of intestinal barrier function by microbial metabolites. Cell Mol Gastroenterol Hepatol 2021; 11: 1463–1482.

48.

Agus

Planchais

Sokol

. Gut Microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 2018; 23: 716–724.

49.

Anjum

, et al. Dual Role of Indoles Derived From Intestinal Microbiota on Human Health. Front Immunol Epub ahead of print 17 June 2022; 13. DOI: 10.3389/fimmu.2022.903526

50.

Roth

Zadeh

Vekariya

, et al. Tryptophan metabolism and gut-brain homeostasis. Int J Mol Sci 2021; 22: 2973.

51.

Guzior

Quinn

. Review: microbial transformations of human bile acids. Microbiome Epub ahead of print 14 June 2021; 9. DOI: 10.1186/s40168-021-01101-1

52.

Baars

Oosting

Knol

, et al. The gut Microbiota as a therapeutic target in IBD and metabolic disease: a role for the bile acid receptors FXR and TGR5. Microorganisms 2015; 3: 641–666.

53.

Larabi

Masson

HLP

Bäumler

. Bile acids as modulators of gut microbiota composition and function. Gut Microbes Epub ahead of print 31 December 2023; 15. DOI: 10.1080/19490976.2023.2172671

54.

Zhang

Zhen

Weng

, et al. Research progress on the microbial metabolism and transport of polyamines and their roles in animal gut homeostasis. J Anim Sci Biotechnol Epub ahead of print 15 April 2025; 16. DOI: 10.1186/s40104-025-01193-x

55.

Ramos-Molina

Queipo-Ortuño

Lambertos

, et al. Dietary and Gut Microbiota Polyamines in Obesity- and Age-Related Diseases. Front Nutr Epub ahead of print 14 March 2019; 6. DOI: 10.3389/fnut.2019.00024

56.

Zhang

Liang

. Innate recognition of microbial-derived signals in immunity and inflammation. Sci China Life Sci 2016; 59: 1210–1217.

57.

Rolland

Douard

Lapaque

. Role of pattern recognition receptors and microbiota-derived ligands in obesity. Front Microbiomes Epub ahead of print 8 March 2024; 3. DOI: 10.3389/frmbi.2024.1324476

58.

Mazgaeen

Gurung

. Recent advances in lipopolysaccharide recognition systems. Int J Mol Sci 2020; 21: 379.

59.

. Pattern recognition receptors in health and diseases. Signal Transduct Target Ther Epub ahead of print 4 August 2021; 6. DOI: 10.1038/s41392-021-00687-0

60.

Hajam

Dar

Shahnawaz

, et al. Bacterial flagellin—a potent immunomodulatory agent. Exp Mol Med 2017; 49: e373–e373.

61.

Lage

Longo

Branco

, et al. Emerging Concepts about NAIP/NLRC4 Inflammasomes. Front Immunol Epub ahead of print 2 July 2014; 5. DOI: 10.3389/fimmu.2014.00309

62.

Caminero

Guzman

Libertucci

, et al. The emerging roles of bacterial proteases in intestinal diseases. Gut Microbes Epub ahead of print 31 December 2023; 15. DOI: 10.1080/19490976.2023.2181922

63.

Garbe

Collin

. Bacterial hydrolysis of host glycoproteins – powerful protein modification and efficient nutrient acquisition. J Innate Immun 2012; 4: 121–131.

64.

Fontana

Banga

Barry

, et al. Secreted bacterial effectors that inhibit host protein synthesis are critical for induction of the innate immune response to virulent Legionella pneumophila. PLoS Pathog 2011; 7: e1001289.

65.

Huang

Wang

, et al. Extracellular vesicles as a novel mediator of interkingdom communication. Cytokine Growth Factor Rev 2023; 73: 173–184.

66.

Sultan

Mottawea

Yeo

, et al. Gut Microbiota extracellular vesicles as signaling molecules mediating host-Microbiota communications. Int J Mol Sci 2021; 22: 13166.

67.

Wang

Luo

Xiang

, et al. Roles of bacterial extracellular vesicles in systemic diseases. Front Microbiol Epub ahead of print 28 September 2023; 14. DOI: 10.3389/fmicb.2023.1258860

68.

O’Riordan

Moloney

Keane

, et al. The gut microbiota-immune-brain axis: therapeutic implications. Cell Rep Med 2025; 6: 101982.

69.

Park

Kim

Kang

, et al. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR–S6 K pathway. Mucosal Immunol 2015; 8: 80–93.

70.

Liu

Xue

, et al. Role of short-chain fatty acids in host physiology. Anim Models Exp Med 2024; 7: 641–652.

71.

Ryu

Kaiko

Stappenbeck

. Cellular differentiation: potential insight into butyrate paradox? Mol Cell Oncol 2018; 5: e1212685.

72.

Baba

Rah

Bhat

, et al. Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within. Front Pharmacol Epub ahead of print 28 February 2022; 13. DOI: 10.3389/fphar.2022.791272

73.

Gieryńska

Szulc-Dąbrowska

Struzik

, et al. Integrity of the intestinal barrier: the involvement of epithelial cells and Microbiota—A mutual relationship. Animals (Basel) 2022; 12: 145.

74.

Uberoi

Bartow-McKenney

Zheng

, et al. Commensal microbiota regulates skin barrier function and repair via signaling through the aryl hydrocarbon receptor. Cell Host Microbe 2021; 29: 1235–1248. .e8.

75.

Ullah

Arbab

Tian

, et al. The gut microbiota–brain axis in neurological disorder. Front Neurosci Epub ahead of print 4 August 2023; 17. DOI: 10.3389/fnins.2023.1225875

76.

Buey

Forcén

Grasa

, et al. Gut Microbiota-derived short-chain fatty acids: novel regulators of intestinal serotonin transporter. Life 2023; 13: 1085.

77.

Dhakad

Mishra

. Toll-like receptor expression during inflammatory processes in human diseases. Rheumatol Autoimmun 2025; 5: 1–14.

78.

Ryma

Samer

Soufli

, et al. Role of probiotics and their metabolites in inflammatory bowel diseases (IBDs). Gastroenterol Insights 2021; 12: 56–66.

79.

Shan

Lee

Chang

. The gut microbiome and inflammatory bowel diseases. Annu Rev Med 2022; 73: 455–468.

80.

Hedin

Whelan

Lindsay

. Evidence for the use of probiotics and prebiotics in inflammatory bowel disease: a review of clinical trials. Proc Nutr Soc 2007; 66: 307–315.

81.

Gyriki

Nikolaidis

Stavropoulou

, et al. Exploring the gut microbiome’s role in inflammatory bowel disease: insights and interventions. J Pers Med 2024; 14: 507.

82.

Wang

Yao

Liu

. Fecal microbiome from patients with ulcerative colitis is potent to induce inflammatory responses. Int Immunopharmacol 2018; 59: 361–368.

83.

Basha

Hafez

Salem

, et al. Impact of gut microbiome alteration in ulcerative colitis patients on disease severity and outcome. Clin Exp Med 2022; 23: 1763–1772.

84.

Lane

Zisman

Suskind

. The microbiota in inflammatory bowel disease: current and therapeutic insights. J Inflamm Res 2017; 10: 63–73.

85.

Yang

Huang

, et al.

Probiotics for inflammatory bowel disease: is there sufficient evidence?

Open Life Sci 2024; 19: 20220821.

86.

Kruis

Schütz

Fric

, et al. Double-blind comparison of an oral Escherichia coli preparation and mesalazine in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther 1997; 11: 853–858.

87.

Roy

Dhaneshwar

. Role of prebiotics, probiotics, and synbiotics in management of inflammatory bowel disease: current perspectives. World J Gastroenterol 2023; 29: 2078–2100.

88.

Quraishi

Beggs

, et al. OP09 Immunomodulatory mechanisms of faecal microbiota transplantation are associated with clinical response in ulcerative colitis: early results from STOP-colitis. J Crohns Colitis 2020; 14: S010–S010.

89.

Wei

Y-L

Chen

Y-Q

Gong

, et al. Fecal Microbiota Transplantation Ameliorates Experimentally Induced Colitis in Mice by Upregulating AhR. Front Microbiol Epub ahead of print 24 August 2018; 9. DOI: 10.3389/fmicb.2018.01921

90.

Patterson

. EFFECTIVENESS OF ANTIBIOTICS AS A TREATMENT OPTION FOR PATIENTS WITH CROHN’S DISEASE: a META ANALYSIS. Gastroenterology 2021; 160: S9.

91.

Zhou

Han

Feng

, et al. Microbial metabolites affect tumor progression, immunity and therapy prediction by reshaping the tumor microenvironment (Review). Int J Oncol Epub ahead of print 6 June 2024; 65. DOI: 10.3892/ijo.2024.5661

92.

Hanus

Parada-Venegas

Landskron

, et al. Immune System, Microbiota, and Microbial Metabolites: The Unresolved Triad in Colorectal Cancer Microenvironment. Front Immunol Epub ahead of print 26 March 2021; 12. DOI: 10.3389/fimmu.2021.612826

93.

Chaput

Lepage

Coutzac

, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol 2017; 28: 1368–1379.

94.

Wang

Yang

H-R

Wang

D-J

, et al. Association between the gut microbiota and patient responses to cancer immune checkpoint inhibitors. Oncol Lett 2020; 20: 342.

95.

Matson

Fessler

Bao

, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018; 359: 104–108.

96.

Zheng

Wang

, et al. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. J Immunother Cancer Epub ahead of print December 2019; 7. DOI: 10.1186/s40425-019-0650-9

97.

Bandopadhyay

Ganguly

. Gut dysbiosis and metabolic diseases. Prog Mol Biol Transl Sci 2022; 191: 153–174.

98.

Sharma

Lal

, et al. Dysbiosis versus diabesity: pathological signaling and promising therapeutic strategies. Drug Discov Today 2023; 28: 103558.

99.

Caricilli

Saad

MJA

. The role of gut microbiota on insulin resistance. Nutrients 2013; 5: 829–851.

100.

Raka

Adeli

. The role of the gut Microbiota in lipid and lipoprotein metabolism. J Clin Med 2019; 8: 2227.

101.

Deng

Pan

Zhu

, et al. Effect of gut Microbiota on blood cholesterol: a review on mechanisms. Foods 2023; 12: 4308.

102.

Sharma

Jaiswal

Ravindra

. Modulation of gut microbiota by bioactive compounds for prevention and management of type 2 diabetes. Biomed Pharmacother 2022; 152: 113148.

103.

Cryan

O’Riordan

Cowan

CSM

, et al. The Microbiota-gut-brain axis. Physiol Rev 2019; 99: 1877–2013.

104.

Medical School Year 6, Central Asian University, Uzbekistan, Pulatova D . IMPACT OF GUT MICROBIOTA ON THE GUT-BRAIN AXIS IN NEUROLOGICAL DISORDERS AND THE ROLE OF ENDOCRINE AND METABOLIC MARKERS. Am J Med Sci Pharm Res 2024; 6: 70–79.

105.

Yassin

Nakhal

Alderei

, et al. Exploring the microbiota-gut-brain axis: impact on brain structure and function. Front Neuroanat Epub ahead of print 12 February 2025; 19. DOI: 10.3389/fnana.2025.1504065

106.

Rusch

Layden

Dugas

. Signalling cognition: the gut microbiota and hypothalamic-pituitary-adrenal axis. Front Endocrinol Epub ahead of print 19 June 2023; 14. DOI: 10.3389/fendo.2023.1130689

107.

De La Serre

. Gut Microbiome-Brain Communications Regulate Host Physiology and Behavior. J Nutr Health Food Sci Epub ahead of print 2015; 3. DOI: 10.15226/jnhfs.2015.00141

108.

Wang

Sun

Feng

, et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res 2019; 29: 787–803.

109.

Tarawneh

Penhos

. The gut microbiome and Alzheimer’s disease: complex and bidirectional interactions. Neurosci Biobehav Rev 2022; 141: 104814.

110.

Wang

Luo

Ray Chaudhuri

, et al. The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options. Brain 2021; 144: 2571–2593.

111.

Jangi

Gandhi

Cox

, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun Epub ahead of print 28 June 2016; 7. DOI: 10.1038/ncomms12015

112.

Feng

, et al. Emerging insights between gut microbiome dysbiosis and Parkinson’s disease: pathogenic and clinical relevance. Ageing Res Rev 2022; 82: 101759.

113.

Tiwari

Dwivedi

Bansal

, et al. Role of gut Microbiota in neurological disorders and its therapeutic significance. J Clin Med 2023; 12: 1650.

114.

Sanders

Merenstein

Reid

, et al. Probiotics and prebiotics in intestinal health and disease: from biology to the clinic. Nat Rev Gastroenterol Hepatol 2019; 16: 605–616.

115.

Chen

Y-W

Lee

M-L

Chiang

C-Y

, et al. Effects of systemic Bifidobacterium longum and Lactobacillus rhamnosus probiotics on the ligature-induced periodontitis in rat. J Dent Sci 2023; 18: 1477–1485.

116.

Belkaid

Hand

. Role of the Microbiota in immunity and inflammation. Cell 2014; 157: 121–141.

117.

Arpaia

Campbell

Fan

, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013; 504: 451–455.

118.

Gibson

Probert

Loo

, et al. Dietary modulation of the human colonic microbiota: updating the concept of prebiotics. Nutr Res Rev 2004; 17: 259–275.

119.

Sheng

Zhang

. Immunomodulatory effects of inulin and its intestinal metabolites. Front Immunol Epub ahead of print 10 August 2023; 14. DOI: 10.3389/fimmu.2023.1224092

120.

Vinolo

MAR

Rodrigues

Nachbar

, et al. Regulation of inflammation by short chain fatty acids. Nutrients 2011; 3: 858–876.

121.

Takahashi

Hoshina

Kabumoto

, et al. Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells. EBioMedicine 2020; 58: 102913.

122.

Deleu

Machiels

Raes

, et al.

Short chain fatty acids and its producing organisms: an overlooked therapy for IBD?

eBioMedicine 2021; 66: 103293.

123.

Pant

Venugopal

Lorenzo Pisarello

, et al. The role of gut microbiome-derived short-chain fatty acid butyrate in hepatobiliary diseases. Am J Pathol 2023; 193: 1455–1467.

124.

Zhang

S-Y

Zhang

L-Y

Wen

, et al. Histone deacetylases and their inhibitors in inflammatory diseases. Biomed Pharmacother 2024; 179: 117295.

125.

Zakim and Boyer’s Hepatology. Elsevier. Epub ahead of print 2018. DOI: 10.1016/c2013-0-19055-1.

126.

Lun

Yan

Guo

, et al. Mechanism of action of the bile acid receptor TGR5 in obesity. Acta Pharm Sin B 2024; 14: 468–491.

127.

Wang

, et al. Metabolic mediators: microbial-derived metabolites as key regulators of anti-tumor immunity, immunotherapy, and chemotherapy. Front Immunol Epub ahead of print 16 September 2024; 15. DOI: 10.3389/fimmu.2024.1456030

128.

Lamas

Natividad

Sokol

. Aryl hydrocarbon receptor and intestinal immunity. Mucosal Immunol 2018; 11: 1024–1038.

129.

Kim

Cho

Lee

D-H

. Synthetic biology-driven microbial therapeutics for disease treatment. J Microbiol Biotechnol 2024; 34: 1947–1958.

130.

Saito

Kakizaki

Okuno

, et al. . Lactococcus lactissubsp.cremorisC60 creates a type I regulatory T cell-dominant anti-inflammatory intestinal environment through functional modification of dendritic cells. Epub ahead of print 6 December 2024. DOI: 10.1101/2024.12.03.626564.

131.

Del Valle

Fulk

Kalvapalle

, et al. Translating New Synthetic Biology Advances for Biosensing Into the Earth and Environmental Sciences. Front Microbiol Epub ahead of print 4 February 2021; 11. DOI: 10.3389/fmicb.2020.618373

132.

Lynch

Goers

Lesser

. Emerging strategies for engineering Escherichia coli nissle 1917-based therapeutics. Trends Pharmacol Sci 2022; 43: 772–786.

133.

Ostaff

Stange

Wehkamp

. A ntimicrobial peptides and gut microbiota in homeostasis and pathology. EMBO Mol Med 2013; 5: 1465–1483.

134.

Kumar

Hasty

. Stability, robustness, and containment: preparing synthetic biology for real-world deployment. Curr Opin Biotechnol 2023; 79: 102880.

135.

Gupta

Allen-Vercoe

Petrof

. Fecal microbiota transplantation: in perspective. Ther Adv Gastroenterol 2016; 9: 229–239.

136.

Minkoff

Aslam

Medina

, et al. Fecal microbiota transplantation for the treatment of recurrent Clostridioides difficile (Clostridium difficile). Cochrane Database Syst Rev Epub ahead of print 25 April 2023; 2023. DOI: 10.1002/14651858.cd013871.pub2

137.

Yadegar

Pakpour

Ibrahim

, et al. Beneficial effects of fecal microbiota transplantation in recurrent clostridioides difficile infection. Cell Host Microbe 2023; 31: 695–711.

138.

M-Q

. Fecal microbiota transplantation broadening its application beyond intestinal disorders. World J Gastroenterol 2015; 21: 102.

139.

Yang

Chen

Cai

. Fecal microbiota transplantation: emerging applications in autoimmune diseases. J Autoimmun 2023; 141: 103038.

140.

Liu

Chen

, et al. Fecal microbiota transplantation: application scenarios, efficacy prediction, and factors impacting donor-recipient interplay. Front Microbiol Epub ahead of print 25 March 2025; 16. DOI: 10.3389/fmicb.2025.1556827

141.

Merrick

Allen

Masirah M Zain

, et al. Regulation, risk and safety of faecal Microbiota transplant. Infect Prev Pract 2020; 2: 100069.

142.

Sahle

Engidaye

Shenkute Gebreyes

, et al. Fecal microbiota transplantation and next-generation therapies: A review on targeting dysbiosis in metabolic disorders and beyond. SAGE Open Med Epub ahead of print January 2024; 12. DOI: 10.1177/20503121241257486

143.

Kashyap

Chia

Nelson

, et al. Microbiome at the frontier of personalized medicine. Mayo Clin Proc 2017; 92: 1855–1864.

144.

Gheorghe

Ritz

Martin

, et al. Investigating causality with fecal microbiota transplantation in rodents: applications, recommendations and pitfalls. Gut Microbes Epub ahead of print January 2021; 13. DOI: 10.1080/19490976.2021.1941711

145.

Chetty

Blekhman

. Multi-omic approaches for host-microbiome data integration. Gut Microbes Epub ahead of print 31 December 2024; 16. DOI: 10.1080/19490976.2023.2297860

146.

Kim

Maguire

Tsang

, et al. Machine Learning for Antimicrobial Resistance Prediction: Current Practice, Limitations, and Clinical Perspective. Clin Microbiol Rev Epub ahead of print 21 September 2022; 35. DOI: 10.1128/cmr.00179-21

147.

Mimee

Citorik

. Microbiome therapeutics — advances and challenges. Adv Drug Deliv Rev 2016; 105: 44–54.

148.

Pham

. Ethical and legal considerations in healthcare AI: innovation and policy for safe and fair use. R Soc Open Sci Epub ahead of print May 2025; 12. DOI: 10.1098/rsos.241873

149.

Chen

Zhernakova

Kurilshikov

, et al. Influence of the microbiome, diet and genetics on inter-individual variation in the human plasma metabolome. Nat Med 2022; 28: 2333–2343.

150.

Goldiș

Dragomir

Mercioni

, et al. Personalized microbiome modulation to improve clinical outcomes in pediatric inflammatory bowel disease: a multi-omics and interventional approach. Microorganisms 2025; 13: 1047.

151.

Walter

Armet

Finlay

, et al. Establishing or exaggerating causality for the gut microbiome: lessons from human Microbiota-associated rodents. Cell 2020; 180: 221–232.

152.

Koh

Bäckhed

. From association to causality: the role of the gut Microbiota and its functional products on host metabolism. Mol Cell 2020; 78: 584–596.

153.

Venafra

Sacco

Perfetto

. SignalingProfiler 2.0 a network-based approach to bridge multi-omics data to phenotypic hallmarks. Npj Syst Biol Appl Epub ahead of print 23 August 2024; 10. DOI: 10.1038/s41540-024-00417-6

154.

Roy

Coldren

Karunamurthy

, et al. Standards and guidelines for validating next-generation sequencing bioinformatics pipelines. J Mol Diagn 2018; 20: 4–27.

155.

Richards

Aziz

Bale

, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med 2015; 17: 405–424.

156.

Mennella

Maniscalco

De Pietro

, et al. Ethical and regulatory challenges of AI technologies in healthcare: a narrative review. Heliyon 2024; 10: e26297.

157.

Goktas

Grzybowski

. Shaping the future of healthcare: ethical clinical challenges and pathways to trustworthy AI. J Clin Med 2025; 14: 1605.

158.

Wang

Z-D

Zhang

Liang

T-X

. Advancements in oral delivery systems for probiotics based on polysaccharides. Polymers (Basel) 2025; 17: 144.

159.

Islam

Ahmed

MMS

Islam

, et al. Advances in nanoparticles in targeted drug delivery–A review. Results Surf Interfaces 2025; 19: 100529.

160.

Yadav

Chauhan

. Microbiome therapeutics: exploring the present scenario and challenges. Gastroenterol Rep Epub ahead of print 25 January 2022; 10. DOI: 10.1093/gastro/goab046

161.

Simon

Nnaji

Anumudu

, et al. Microbiome-Based interventions for food safety and environmental health. Appl Sci 2025; 15: 5219.

Bridging two worlds: Host Microbiota crosstalk in health and dysregulation

Abstract

Keywords

Introduction

Microbiome composition and functional diversity

Microbial taxa across body sites

Functional roles: metabolism, immune regulation, and barrier integrity

Tools for profiling microbiomes

Overview of key host cell signaling pathways

Toll-like receptor (TLR) and NOD-like receptor (NLR) signaling

MAPK and Nf-κb pathways

Wnt/β-catenin and notch pathways

GPCR and nuclear receptor pathways

PI3K/Akt/mTOR pathway

Mechanisms of microbiome-mediated modulation of host signaling

Microbial metabolites

Short-chain fatty acids (SCFAs)

Tryptophan metabolites

Polyamines

Microbe-Associated molecular patterns (MAMPs)

Lipopolysaccharide (LPS)

Peptidoglycans

Flagellin

Microbial enzymes and effectors

Proteases

Glycosidases

Secreted effectors

Extracellular vesicles and nanoparticles

Role in inter-kingdom communication

Effects on immune and epithelial signaling

Host signaling responses to microbiome interactions

Inflammation and immune modulation

Cell proliferation, apoptosis, and differentiation

Barrier function and epithelial repair

Neuroimmune and gut-brain axis signaling

Case studies: disease contexts

Inflammatory bowel disease (IBD)

Cancer

Metabolic diseases

Impact on insulin signaling

Impact on lipid metabolism

Neurological disorders

Microbiota-Gut-Brain axis

Neuroinflammation and neurological disorders

Therapeutic opportunities and strategies

Probiotics, prebiotics, and postbiotics

Microbiome-Derived metabolites as drug leads

Engineered microbes and synthetic biology

Fecal Microbiota transplantation

Current challenges and future directions

Individual variability and personalized microbiome medicine

Causality versus correlation in microbiome studies

Need for integrated multi-omics and computational modeling

Regulatory and ethical considerations

Conclusion

Footnotes

Acknowledgements

ORCID iDs

Author contributions

Funding

Declaration of conflicting interests

References