Inflammatory bowel disease (IBD)

IBD, which includes CD and UC, exemplifies a chronic inflammatory condition with complex etiology involving genetic, environmental, and microbial factors. Among the various influences, metabolites derived from gut microbiota, such as SCFAs, hydrogen sulfide (H₂S), and BAs, are crucial in the disease’s pathogenesis and management, primarily through their roles in modulating immune responses and maintaining intestinal integrity [46].

SCFAs are essential for maintaining the epithelial barrier’s integrity, which is vital for overall intestinal health. In conditions of dysbiosis, a significant decrease in SCFA levels contributes to barrier weakening, thereby facilitating increased bacterial translocation that perpetuates the inflammatory cycles central to IBD development [47]. Furthermore, SCFAs enhance the development of B and Tregs, mitigating the pro-inflammatory states frequently observed in dysbiosis [48, 49]. However, the microbiomes of IBD patients often show a diminished presence of SCFA-producing bacteria, leading to elevated levels of pro-inflammatory cytokines as macrophages adopt a more inflammatory phenotype [49, 50].

Similarly, H₂S, a gaseous metabolite produced from cysteine and sulfate by numerous bacterial species including cystein catabolic bacteria (e.g., Fusobacterium) and sulfate-reducing bacteria (e.g., Desulfovibrio), exhibits a dual role in gut health. Under physiological conditions, H₂S contributes to intestinal homeostasis by enhancing the mucus barrier, stabilizing microbial biofilms, and regulating immune responses to limit pro-inflammatory cytokine activity such as tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) [51]. However, recent evidence suggests that both excessive and insufficient levels of H₂S can compromise epithelial integrity, promote oxidative stress, and aggravate inflammation [52, 53]. In IBD, dysbiosis often leads to an overgrowth of sulfate-reducing bacteria and reduced activity of H₂S-detoxifying enzymes, exacerbating inflammation and epithelial damage [54]. Although H₂S’s precise role in IBD pathogenesis remains an active area of research, current evidence highlights its significance in disease progression.

The role of the microbiome extends to the modulation of immune responses through BAs as well. Produced by the liver, BAs are modified by the gut microbiome, impacting immune regulation by affecting T cell activity to either promote or reduce inflammation [49]. Significantly, IBD patients often exhibit reduced levels of these modified BAs, suggesting an important mechanism by which dysbiosis may influence the regulation of the intestinal immune system [55].

Given the association between dysbiosis and intestinal inflammation, strategies to modulate the microbiome represent promising therapeutic avenues for altering the course of IBD. Probiotics, which confer health benefits, have been associated with improved outcomes in IBD, helping reduce disease recurrence and promote remission in both CD and UC patients [56]. Additionally, fecal microbiota transplantation (FMT) has gained traction as a treatment, for recurrent Clostridium difficile infection and IBD, which has been linked to improved remission rates. The success of FMT, however, may depend on various factors, including the donor’s microbial composition, the frequency of transplantation, and the timing relative to the disease course [56].

Irritable bowel syndrome (IBS)

IBS is a functional GI disorder characterized by symptoms such as abdominal pain, bloating, and altered bowel habits that significantly impact patients’ lives. Although the precise etiology of IBS is not well understood, recent evidence has emphasized the substantial role of the gut microbiome in its pathogenesis [57]. The brain-gut axis (BGA), a bidirectional pathway connecting the nervous system with the GI tract, plays a crucial role in this context [58]. It encompasses pathways involved in immune system regulation, hormonal balance, and the autonomic nervous system [59]. Gut dysbiosis can disrupt the BGA, leading to altered intestinal motility and visceral hypersensitivity, common in IBS [60].

Patients with IBS often show a microbial profile characterized by a decrease in beneficial bacteria such as Bifidobacterium and Faecalibacterium prausnitzii, and an increase in potentially harmful bacteria like Enterobacteriaceae and Ruminococcus gnavus [61, 62]. This shift is associated with a decreased production of microbial metabolites, including SCFAs, which are crucial for maintaining intestinal barrier function and modulating immune responses [63]. The reduction in SCFAs may impair these protective mechanisms, contributing to the pathophysiology of IBS [47] (Figure 2).

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Figure 2. 

Therapeutic pathways for irritable bowel syndrome. SCFA: short-chain fatty acid; FOS: fructooligosaccharides; GOS: galactooligosaccharides

The link between the microbiome and IBS has advanced our understanding of the disorder and opened new therapeutic avenues. Probiotics have been shown to alleviate IBS symptoms effectively. Studies indicate that specific strains such as Bifidobacterium spp. and Lactobacillus spp. can significantly improve GI as well as psychological symptoms, suggesting that these probiotics positively impact the BGA [64]. Additionally, prebiotics—non-digestible fibers that promote the growth of beneficial microbes—have proven effective. Compounds like inulin, fructooligosaccharides (FOS), and galactooligosaccharides (GOS) have been shown to enhance levels of beneficial bacteria and reduce IBS symptoms [65, 66].

While considerable progress has been made in leveraging the microbiome for managing IBS, further research is necessary. More detailed characterization of the IBS-associated microbiome could lead to targeted probiotic therapies that specifically address disruptions in the BGA, potentially improving both GI and psychological symptoms. Continued efforts to elucidate the complex interactions between the microbiome and IBS are crucial for developing more effective and specific therapeutic interventions for patients with this disorder.

Obesity/Metabolic syndrome

Obesity/Metabolic syndrome reflects systemic disorders characterized by impaired metabolic regulation, closely linked to insulin resistance, chronic inflammation, and dysregulated lipid metabolism. The role of gut microbiota-derived metabolites, particularly BCAAs, SCFAs, and tryptophan metabolites, has emerged as a critical factor in these conditions. Recent research highlights these metabolites’ profound influence on metabolic pathways, revealing their central role in modulating insulin sensitivity, inflammatory responses, and overall energy balance.

BCAAs have been found to regulate lipid metabolism and insulin sensitivity [67]. There is a dynamic, circular relationship between BCAAs and the gut microbiota. Studies in mice have shown that supplemented diet rich in BCAAs promotes a healthier microbial balance, with increases in beneficial bacteria like Bifidobacterium and Akkermansia and reductions in Enterobacteriaceae [68]. However, elevated BCAAs levels are also associated with insulin resistance and obesity [69]. In genetically obese mice, excessive BCAAs accumulation can directly induce insulin resistance [70]. Moreover, the gut microbiota further influences BCAA metabolism by producing and utilizing these amino acids. For instance, Bacteroides vulgatus and Prevotella copri are associated with BCAAs production, which correlates with obesity and insulin resistance. Conversely, lower amounts of bacteria able to use BCAAs, such as Butyrivibrio crossotus and Eubacterium siraeum, are seen in individuals with insulin resistance as BCAA levels are elevated [71].

Tryptophan, an amino acid found in foods such as oats, milk, cheese, poultry, and fish, plays a crucial role in protein synthesis and serves as a precursor for essential metabolites. Tryptophan follows three primary metabolic pathways: serotonin, kynurenine, and a third pathway involving gut microbiota, which metabolizes tryptophan into indoles and their derivatives [72, 73]. These indole metabolites act as ligands for the AhR, triggering the transcription of key pathways that regulate lipid metabolism and glucose homeostasis [74]. Gut microbial dysbiosis, characterized by impaired AhR ligand production, is a critical factor in the development of metabolic syndrome [75]. Impaired activation of the AhR pathway leads to decreased production of GLP-1 and interleukin-22 (IL-22), increasing intestinal permeability and enhancing gram-negative bacteria LPS translocation. This mechanism contributes to the systemic elevated inflammation commonly observed in individuals with obesity and metabolic syndrome [76].

Diabetes mellitus

Diabetes mellitus is primarily driven by a combination of genetic, environmental, and lifestyle factors that disrupt glucose metabolism. In type 2 diabetes mellitus (T2DM), this disruption is characterized by insulin resistance, where the body’s cells become less responsive to insulin, coupled with inadequate insulin production by the pancreas. Gut microbial metabolites play a role in the progression and potential mitigation of T2DM through various mechanisms, including the regulation of insulin sensitivity, inflammation, and glucose homeostasis.

Research into gut microbial metabolism has revealed that resistant starch (RS) metabolites improve glucose homeostasis by regulating the secretion of gut hormones. The production of SCFAs through microbial metabolism of RS can stimulate the release of GLP-1 and peptide YY (PYY) by binding to GPRs on intestinal enteroendocrine cells (EECs) [77]. This activation of ECCs promotes their differentiation and triggers the release of GLP-1 and PYY through Gα signaling pathways [78]. GLP-1 stimulates insulin secretion, inhibits glucagon release, slows gastric emptying, and reduces appetite—all of which improve glucose regulation and thwart the development or progression of insulin resistance [79]. Similarly, PYY contributes to appetite regulation, slows gastric emptying, and supports glucose homeostasis [80].

Beyond hormone regulation, butyrate modulates glucose homeostasis via epigenetic mechanisms, notably by inhibiting of histone deacetylase (HDAC) [81]. By inhibiting HDAC, butyrate influences gene expression linked to glucose metabolism [82]. Studies in mice have shown that HDAC activation reduces glucose uptake in skeletal muscle and liver cells by suppressing the expression of glucose transporter type 4 (GLUT4) and promoting gluconeogenesis in the liver via the hepatocyte nuclear factor 4 alpha (HNF4A) pathway [83]. A reduction in butyrate levels has been associated with increased HDAC activity in the colon, impairing glucose regulation [84]. Supplementation with butyrate via RS-rich foods to augment epigenetic regulation and improve glucose homeostasis could be a novel treatment strategy for T2DM.

Butyrate has also been shown to enhance pancreatic β-cell function. In vitro studies demonstrate that butyrate supports β-cell metabolism and viability by preventing inflammatory cytokine-induced dysfunction. This occurs through the downregulation of specific gene expressions linked to inflammation [85]. Further research has shown that butyrate suppresses nuclear factor kappa-B (NF-κB), thereby preventing IL-1β-induced inflammatory gene expression and preserving pancreatic β-cell function, crucial for maintaining proper glucose regulation [86].

However, not all gut microbial metabolites are beneficial. Some, such as LPS and trimethylamine-N-oxide (TMAO), have been implicated in promoting insulin resistance and T2DM. Increased intestinal permeability in T2DM patients allows LPS to enter the bloodstream, triggering TLR4, an inflammatory marker that disrupts insulin signaling and glucose homeostasis [87]. Similarly, elevated TMAO levels are associated with insulin resistance by activating inflammatory pathways that impair insulin signaling [88]. Additionally, BCAAs can interfere with the insulin receptor signaling cascade, further promoting insulin resistance [89].

Metabolic dysfunction-associated steatotic liver disease (MASLD)

MASLD is characterized by hepatic steatosis and is closely linked to metabolic disorders such as obesity and insulin resistance. As in other metabolic disorders, gut microbiota metabolites, namely those of vitamins, proteins, and BAs, act as critical regulators in the pathogenesis of this form of steatotic liver disease (Table 2).

Choline, an essential vitamin, undergoes microbial metabolism in the gut, producing trimethylamine (TMA), which is then oxidized in the liver to form TMAO. The gut microbiota composition significantly influences TMA production, and dysbiosis can lead to fluctuations in TMA levels [90]. Research has demonstrated that TMAO contributes to MASLD progression by increasing oxidative stress [91]. It also promotes the expression of proteins associated with the unfolded protein response, leading to dysregulated lipid metabolism in hepatocytes and further advancing the disease [92]. Lastly, TMAO suppresses key enzymes involved in BA synthesis—CYP27A1 and CYP7A1—thereby reducing BA production. BAs serve as signaling molecules that modulate lipid and glucose metabolism, and their dysregulation can lead to increased hepatic triglyceride levels, promoting the development of hepatic steatosis [93].

BCAAs are metabolized in the liver into branched-chain ketoacids (BCKAs), which enter the tricarboxylic acid (TCA) cycle and serve as signaling molecules in hepatocytes. Elevated BCAA levels have been linked to MASLD, likely due to their role in enhancing mitochondrial lipid β-oxidation [94]. Gut dysbiosis, often caused by high-calorie, high-fat diets, has been associated with increased absorption and circulation of BCAAs, exacerbating MASLD [95]. Contrary to BCAA, the metabolism of certain aromatic amino acid derivatives serves a beneficial role in hepatic function. For instance, tryptophan is metabolized by the gut microbiota into indole-3-acetic acid (IAA), which has demonstrated anti-inflammatory effects in the liver, potentially halting the progression of hepatic steatosis in animal models [96]. Indole supplementation in animals has been shown to reduce hepatic steatosis and inflammation by inhibiting the NF-κB signaling pathway. Importantly, Bifidobacterium bifidum plays a significant role in producing IAA from tryptophan, suggesting that promoting beneficial gut bacteria may help in MASLD treatment [97].

In addition to the metabolism of lipids, BA and their metabolites are intricately linked to liver function. Patients with MASLD show increased levels of BA-metabolizing bacteria such as Lactobacillus, Bifidobacteria, Enterobacter, and Clostridium, which produce a variety of BA derivatives. One metabolite, glycine, has been shown to improve steatosis and insulin resistance when supplemented in rats with diet-induced hepatic steatosis [98]. Similarly, taurine, which conjugates with BA, has demonstrated protective effects against MASLD by improving histological steatosis and reducing oxidative stress and fatty acid synthesis [99]. Disruptions in BA metabolism, therefore, play an important role in MASLD pathogenesis, and restoring balance through targeted interventions could be a potential therapeutic strategy [100].

Systemic lupus erythematosus (SLE)

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies against nuclear antigens, leading to widespread inflammation and tissue damage. The pathogenesis of SLE involves complex interactions between genetic, environmental, and immunological factors, with emerging evidence highlighting the role of the gut microbiota in disease progression [131].

In patients with SLE, dysbiosis is often observed, with a reduction in butyrate-producing bacteria such as Faecalibacterium prausnitzii and an increase in pathogenic bacteria such as Ruminococcus gnavus [132]. This imbalance contributes to the pro-inflammatory state, worsening disease symptoms. For example, the decrease in butyrate-producing bacteria disrupts immune regulation, reducing differentiation of Tregs and increased production of pro-inflammatory cytokines such as IL-6 and TNF-α [133].

Additionally, tryptophan metabolism by gut bacteria influences the immune response in SLE. The kynurenine pathway, a major route of tryptophan catabolism, generates metabolites such as kynurenine and quinolinic acid, which can modulate T-cell responses. Elevated levels of these metabolites have been associated with disease activity in SLE, suggesting a link between tryptophan metabolism and autoimmunity [134]. The combined effects of gut dysbiosis, altered immune responses, and disrupted tryptophan metabolism underscore the critical role of the gut-immune axis in SLE and highlight the need for further exploration of microbiota-targeted therapies to modulate disease progression.

Multiple sclerosis (MS)

Multiple sclerosis (MS) is an autoimmune disorder characterized by demyelination of neurons in the central nervous system (CNS), resulting in a variety of neurological symptoms. The gut-brain axis, a bidirectional communication network between the gut microbiota and the CNS, has been increasingly recognized for its significance in the development and progression of MS.

Gut microbiota-derived SCFAs, particularly propionate, have been shown to protect against CNS autoimmunity by promoting the differentiation of Tregs and enhancing the integrity of the blood-brain barrier (BBB) [135]. In patients with MS, dysbiosis is commonly observed, marked by a reduction in SCFA-producing bacteria and an increase in pro-inflammatory species such as Akkermansia muciniphila [136]. This imbalance may contribute to increased gut permeability and systemic inflammation, both of which are implicated in the pathogenesis of MS.

Furthermore, BA metabolism by the gut microbiota has been implicated in MS. BAs can modulate immune responses by activating of receptors such as FXR and the G protein-coupled bile acid receptor 1 (GPBAR1). Alterations in BA metabolism have been observed in MS patients, including reduced levels of anti-inflammatory BA like lithocholic acid, which may contribute to disease progression and severity [136, 137]. The disruption in both SCFA and BA metabolism highlights the importance of gut microbiota in influencing immune responses and CNS inflammation in MS.

Psoriasis

Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation of keratinocytes and infiltration of immune cells into the skin. While the exact cause of psoriasis is not fully understood, gut microbiota-derived metabolites are thought to play a role in modulating immune responses and skin inflammation.

In patients with psoriasis, dysbiosis is commonly observed, characterized by a reduction in butyrate-producing bacteria, which may contribute to the chronic inflammatory state that defines the disease [138]. Butyrate, a SCFA, plays a key role in immune regulation, and its deficiency disrupts immune homeostasis, potentially worsening inflammation. Altered tryptophan metabolism has been linked to psoriasis, with elevated levels of pro-inflammatory metabolites from the kynurenine pathway, such as 3-hydroxykynurenine, thought to drive the Th17-mediated immune responses that are characteristic of psoriasis [139]. Moreover, BAs also play a role in maintaining skin health by promoting skin barrier integrity and modulating immune function. In psoriasis, dysbiosis leads to changes in BA metabolism, resulting in increased levels of pro-inflammatory secondary BAs, which may further exacerbate skin inflammation. The intricate interplay between gut microbiota, tryptophan metabolism, and BA dysregulation highlights the critical role of the gut-skin axis in the pathogenesis of psoriasis, highlighting potential therapeutic targets in modulating these pathways to alleviate disease symptoms [140].

Rheumatoid arthritis (RA)

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation of the joints, leading to pain, swelling, and eventual destruction. The role of the gut microbiota in RA has garnered significant attention, with dysbiosis thought to play a key role in the initiation and progression of the disease.

In patients with RA, the reduced presence of SCFA-producing bacteria, such as those responsible for generating butyrate and propionate, significantly effects on immune regulation. This decline impacts the immune system by impairing the formation of Tregs and allowing for an increase in pro-inflammatory cytokines like IL-1β and TNF-α, both of which are key contributors to the inflammatory cascade in RA [22]. Tryptophan metabolism is also altered in RA, with higher levels of pro-inflammatory metabolites from the kynurenine pathway exacerbating the disease by influencing T cell activity [141]. Additionally, altered BA metabolism has been linked to disease activity, as changes in BA profiles further contribute to immune disruption and inflammation [142]. This complex interaction between SCFAs, tryptophan metabolites, and BA dysregulation highlights the significant role of the gut microbiota in driving RA pathology.

Asthma

Asthma is a chronic respiratory condition affecting more than 300 million people globally, with various clinical phenotypes, primarily categorized into Th2-high and Th2-low endotypes [143]. The most common form is driven by a Th2 immune response, which leads to the overproduction of pro-inflammatory cytokines such as IL-4, IL-5, and IL-13. Microbial metabolites, including SCFAs, tryptophan derivatives, polyamines, and p-cresol sulfate, have been shown to modulate immune responses by regulating T cells and dendritic cells, thereby contributing to the attenuation of asthma symptoms through anti-inflammatory mechanisms [144].

SCFAs play a protective role against allergic asthma. Studies have shown that SCFA levels in children are inversely correlated with asthma risk, and experimental models demonstrate that SCFAs can reduce airway inflammation [145]. Tryptophan metabolism also influences immune responses in asthma, with microbial derivatives such as D-tryptophan and kynurenine reducing airway hyperresponsiveness and downregulating Th2-mediated inflammation [146]. Moreover, polyamines and metabolites like p-cresol sulfate further emphasize the influence of microbial products on lung function and inflammation [18]. Spermidine, a polyamine, has been found to reduce the severity of asthma and prevent tissue damage. At the same, p-cresol sulfate, a product of L-tyrosine metabolism, limits dendritic cell recruitment in the lungs, thereby minimizing inflammation [147]. These interactions between the microbiome and the immune system suggest that modulating microbial metabolites could offer promising therapeutic strategies for managing asthma.

Atopic dermatitis (AD)

Atopic dermatitis (AD) is a chronic inflammatory skin disorder influenced by genetic, environmental, and immune factors. It is particularly prevalent in young children, making it one of the most common pediatric skin conditions globally. Recent data show an increasing prevalence of AD, now affecting roughly 20% of children and 10% of adults, underscoring its significance as a widespread and concerning dermatological issue [148, 149].

The skin’s microbial communities are critical in maintaining its protective barrier and immune balance. In healthy skin, commensal bacteria like Staphylococcus epidermidis and Staphylococcus hominis produce antimicrobial peptides that inhibit pathogens such as Staphylococcus aureus. However, in AD, an overgrowth of Staphylococcus aureus disrupts this balance, leading to decreased microbial diversity, which has been inversely correlated with the severity of the disease. This imbalance contributes to a compromised skin barrier, exacerbating inflammation and making the skin more susceptible to infections [150].

AD patients also exhibit reduced levels of anaerobic bacteria that produce SCFAs, such as Bifidobacterium and Faecalibacterium prausnitzii [151]. These SCFAs are essential for lowering skin pH and protecting against infection and inflammation [152]. The decrease in SCFA-producing bacteria leads to skin and gut microbiome disturbances, potentially contributing to the inflammatory processes in AD. Studies have linked lower SCFA levels in early childhood with an increased risk of developing AD and other allergic conditions [153].

Additionally, lower levels of tryptophan-derived metabolites have been observed in AD patients, further affecting skin barrier function. Microbial metabolites like indole-3-aldehyde (IAlD) can alleviate AD symptoms by binding to the AhR in skin cells, enhancing barrier integrity, and modulating immune responses [154]. These disruptions in the skin microbiota and the decline in protective microbial metabolites highlight the integral role of the gut-skin axis in the pathogenesis of AD.