Adaptive immune responses mainly depend on CD4+ T helper cell differentiation into subsets (such as Tfhs, Th1s, Th2s, Th17s, Tregs, and other subtypes) with a variety of effector activities especially for the defense of host against pathogens (Saravia et al., 2019; Li et al., 2022b). Various studies highlight the influence of the gut microbiota on CD4+ T cells differentiation. Some species of Klebsiella genera, including K. pneumoniae and K. aeromobilis, cause Th1 cell responses in the gastrointestinal tract. Klebsiella colonization increases Th1 cell proliferation in the intestines of germ-free mice, thereby increasing the number of these cells (Atarashi et al., 2017) (Figure 4). Probiotic bacteria, especially Lactobacillus strains like L. salivarius (Ren et al., 2019) and L. plantarum (Matsusaki et al., 2016; Takeda et al., 2011), increase the Th1 cytokines [interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα)] production, while, inflammatory immune responses by Th1 cells were inhibited and antigen-specific oral tolerance was enhanced in arthritic mice treated with L. casei (So et al., 2008).

A research indicated that germfree mice exhibits a preference for Th2 cell responses; however, the introduction of polysaccharide A (PSA) derived from Bacteroides fragilis corrects this imbalance by favoring Th1 cell responses (Mazmanian et al., 2005). PSA via the toll-like receptor (TLR2) interacts with DCs to stimulate the release of IL-12. IL-12 causes STAT 4 activation, which results in differentiation of CD4+ T cell into Th1 cells that produce IFN-γ (Wang et al., 2006). In healthy conditions, the differentiation of Th1 cells specific to Klebsiella can be controlled without causing severe inflammation in the gut. In contrast, during dysbiosis, Klebsiella dominance may induce severe gut inflammation through the induction of Th1 cell differentiation, as evidenced by more prevalence of Klebsiella species in fecal samples taken from IBD patients in comparison to healthy individuals (Lloyd-Price et al., 2019). Thus, the Th1/Th2 response can be balanced by the introduction of engineered B. fragilis strains that could overproduce polysaccharide A (PSA) and therefore, prevent Klebsiella-induced Th1 cell differentiation and severe gut inflammation in IBD patients.

Th2 cells generate antibodies to combat infections, proliferate and develop into plasma cells, and also stimulate B cells (Chen et al., 2021a). Certain types of bacteria, like A4 bacteria in the Lachnospiraceae family, prevent Th2 cells from differentiating and being active by making DCs based TGF-β (Wu et al., 2016). It has been determined that B. fragilis and lactobacillus strains inhibit Th2 activity, thereby enhancing Th1 activity (Mazmanian et al., 2005; Takeda et al., 2011; Won et al., 2011). Bamias et al. reported that the Th2 response was induced by commensal bacteria in the chronic phase of Crohn's disease (CD)-like ileitis in SAMP1/YitFc mouse models, and symptoms were also deteriorated (Bamias et al., 2007). A symbiotic combination of A4 bacteria, B. fragilis and Lactobacillus strains can be administered to Crohn’s disease patients, that may inhibit Th2 cell differentiation and activity, hence lowering chronic inflammation and enhancing symptom management.

Th17 cells stimulate neutrophils, produce and secrete a variety of inflammatory cytokines, including IL-17 and IL-22, and infiltrate lesions to increase the inflammation. Retinoic acid-related orphan receptor (RORγt), an important transcription factor, facilitates Th17 cell development and Th17 cytokine production (Nalbant and Eskier, 2016; Chen and Tang, 2021). Interestingly, Th17 cells are not present in germfree mice, rather, they are induced when bacteria colonize the mice (Lee and Kim, 2017). Certain bacteria, like gram-positive bacteria and SFB, have been found to be inducers of Th17 cell proliferation. Serum amyloid A (SAA), elevates when SFB typically penetrates the mucus layer and adheres to epithelial cells. SAA markedly enhances the Naive CD4+ T cell differentiation into Th17 cells (Atarashi et al., 2015; Li et al., 2022b).

Furthermore, the function of SFB such as Candidatus Arthromitus, and Prevotella has been reported in fostering strong Th17 cell proliferation along with the release of IL-17 and IL-22 (Atarashi et al., 2015; Farkas et al., 2015; Ivanov et al., 2009; Schnupf et al., 2015). In a study, P. gingivalis was introduced into a collagen-induced arthritis (CIA) mice model, found elevation in joint disease severity which was linked to systemic proinflammatory cytokine profiles that indicated Th17 pathway activation (Moen et al., 2006). A study reported a secondary bile acid produced by microbe to have a negative effect on Th17 cell differentiation. Th17 transcription factor RORγt (retinoic acid-related orphan receptor gamma t) was blocked by 3-oxolithocholic acid along with one of thirty diverse primary and secondary types of bile acids and the decrease in the differentiation of Th17 cells was observed in SPF mice (Hang et al., 2019). The exact mechanism by which certain bacteria induce intestinal Th17 differentiation is still unknown, thus, research must go into modifying gut microbiota to regulate the differentiation of Th17 cells and create innovative remedies for AIDs. Another promising therapeutic approach is to look into the interactions of bile acids with Th17 cells differentiation.

Treg cells are essential for the prevention of AIDs because they preserve immune homeostasis, control immune responses and promote tolerance to harmless antigens (Dominguez-Villar and Hafler, 2018). B. fragilis is able to trigger to generate large populations of Treg cells by producing PSA, which in turn causes Foxp3+ Treg cells to develop and produce IL-10 (Round and Mazmanian, 2010) as shown in Figure 4. Furthermore, adenosine and inosine, two bacterial metabolites, can bind with the adenosine A2A receptor (A2AR) on T cells, increasing the activity of Treg cell and suppressing the inflammatory responses of Th1 and Th17 (Liu et al., 2018; Wang et al., 2024). In a recent study Wang et al. found, Megamonas, Monoglobus, and Prevotella relative abundances were favorably connected with cytokine levels and CD4+ T cell counts; on the other hand, the T helper (Th17)/Treg ratio and the relative abundance of regulatory T cells (Tregs) were correlated negatively with RA disease activity (Wang et al., 2022b). Sun et al. reported the change in the composition of gut microbiota's by Bifidobacterium colonization. This improved the suppressive Treg cells function by encouraging their mitochondrial activity (Sun et al., 2020). Certain Lactobacillus strains, like Lacticaseibacillus casei, affect the differentiation and activity of T cells, resulting in the development of Treg cells and the release of IL-10 (Smits et al., 2005). L. acidophilus strain L-92 demonstrated related outcomes in BALB/c mice. L-92, when administered orally, led to a rise in the expression of Foxp3, TGF-β and IL-10 in mice under conditions of allergic contact dermatitis (ACD). This established the concept that L-92 mitigates ACD by increasing the proliferation of Treg cells, and Th1 and Th2 responses (Shah et al., 2012). A study conducted on in BALB/c mice, demonstrated that L. reuteri reduces allergic airway reactions (Forsythe et al., 2007) thereby, increases Foxp3 expression (Karimi et al., 2009), which positively affects the proliferation of Treg cell and reduces the intensity of AIDs. It has been shown that a different Lactobacillus strain, L. murinus regulates the small intestine's RORγt+ Treg cells, which reduces pulmonary inflammation caused by Mycobacterium tuberculosis infection (Bernard-Raichon et al., 2021).

Zhang et al. demonstrated that antibiotic-induced dysbiosis such as ampicillin, decreases Treg cell production and interferes with Th1 responses to infection caused by bacteria (Zhang and Bevan, 2011). Treg cell production and activities can also be affected by modifications in the microbiota, which can be caused by a variety of factors as Figure 4 illustrates, clostridium species are thought to have an effect on Treg cells, whose dysregulation can result in autoimmunity. These studies highlight, certain bacteria, such as B. fragilis and specific strains of Bifidobacterium and Lactobacillus, increase the production and activity of Treg cells, in result, reduce inflammatory responses and disease severity. Furthermore, antibiotics-induced dysbiosis can disrupt the production of Treg cells, that highlights the role healthy microbiota play in immune regulation.

CD8+T cells also referred as cytotoxic T lymphocytes (CTLs), are essential components of the immune system because they specifically target and destroy malignant cells. Shimokawa et al. reported, Nematode-derived trehalose alters the gut microbiota and elevates the number of Ruminococcus species, which stimulates CD8+ T cells (Shimokawa et al., 2020). To enhance the effectiveness of immune-based therapies, there is need to understand how gut microbiota modulation, induced by dietary components like nematode-derived trehalose or probiotics, influences systemic immune responses like CD8+ T cell activation and infiltration of various tissues. A research discovered an association of commensal strains, predominantly Bacteroidetes, that might specifically produce CD8+ T cells unique to the microbiota having anticancer capabilities (Tanoue et al., 2019). Moreover, Bacteroidetes species produces integrase that contains a motif which raised the risk of systemic damage to the pancreas in Type 1 diabetes mellitus (T1DM) while simultaneously increasing CD8+ T cells in the gut (Nanjundappa et al., 2017). In a mice model with altered gut microbiota enriched in Fusobacteria expressed a magnesium transporter (Mgt), that accelerated the development of diabetes. An islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP)-mimicking peptide carried by this transporter stimulated the CD8+ T cells specific to IGRP and caused diabetes in vivo (Tai et al., 2016).

Studies have suggested that the major SCFAs, like acetate, butyrate and propionate, which are metabolites of microbes, are involved in the mediation of CD8+ T cell function. A study demonstrated increased acetate levels in MS patients' blood, which were associated with CD8+ T cells that produce IL-17 (Pérez-Pérez et al., 2020). It is worth noting, the diet high in acetate and lesser butyrate level in non-obese diabetic (NOD) mice model of T1DM decreased the frequency of autoreactive CD8+ T cells and increased the number of CD4+Foxp3+ Treg cells in the spleen and colon, but there was no change in the peripheral lymph nodes (Mariño et al., 2017). Following this diet plan might decrease the frequency of pathogenic autoreactive T cells in MS and T1DM by shifting the balance toward a more regulatory T cell profile, thereby potentially mitigating disease progression. Through APCs, butyrate and propionate regulate the activation of CD8+ T cell and IL-12 production (Nastasi et al., 2017). According to another study, butyrate directly boosts the activity of CD8+ T cell by enhancing the expression of granzyme B and IFNγ (Luu et al., 2018). Thus, microbiome-immune axis could reveal new adjuvants for the treatment of certain AIDs, tailored to individual microbiota profiles.

IFNγ based CD8+ T cell induction might be linked with particular metabolites produced by bacterial strains, such as dimethylglycine, mevalonate and SCFAs (Tanoue et al., 2019; Bachem et al., 2019), which enter the bloodstream and cause CD8+ T cell systemic activation. As a result, the microbiota can influence the effectiveness of immunotherapy and CD8+ T cell function. Butyrate from Lachnospiraceae species was found to inhibit CD8+ T cells that secreted IFNγ. Butyrate inhibited DCs based stimulation of the IFN gene (STING), that is linked to responses of CD8+ T cell and reduces the effectiveness of radiation therapy (Yang et al., 2021). Pentanoate produced by Megasphaera malasiliensis stimulates the activity of effector CD8+ T cells. Higher levels of TNFα and IFNγ were found in the presence of M. massiliensis, and this had a favorable impact on adoptive T cell therapy's effectiveness (Luu et al., 2021). Future studies should focus on enhancing the efficacy of adoptive T cell therapies for controlling CD8+ T cell responses that may be done by engineering microbes to produce beneficial metabolites, such as acetate, butyrate and pentanoate.

NKT cells, resembles conventional T cells and can be influenced by the microbiota and have a role in autoimmune diseases (Simoni et al., 2013). NKT cells can sense the surrounding lipid environment by engaging their TCR with CD1-expressing cells, as opposed to CD4+ T cells' ability to sense protein antigens (Cheng et al., 2024). According to studies, gram-negative bacteria like Sphingomonas act as NKT cell stimulators, and commensal microbiota regulate the homeostasis of NKT cells. As microbial antigens, the glycosphingolipids and glycosylceramides derived from Sphingomonas induce NKT cell activation and secretion of IFNγ (Kinjo et al., 2005; Mattner et al., 2005). Moreover, 40–70% of the membrane phospholipids in the Bacteroides genus contain sphingolipids, which CD1d may present to NKT cells, the bacteria of this genus may be essential for controlling the population of NKT cells. B. fragilis synthesize an isoform of αGalCer. In a CD1d-dependent manner, this sphingolipid has been demonstrated to activate and stimulate the production of IFN-γ in both human and mouse NKT cells (Brown et al., 2021; Brailey et al., 2020). This approach may improve pathogen clearance and immune surveillance in chronic infections like cancer, with dosage and glycosphingolipid combinations personalized based on individual microbiome profiles.

A study reported that the commensal bacteria decreases the accumulation of mucosal NKT cells. The frequency and quantity of colon NKT cells were found to be higher in germfree mice compared to SPF mice, indicating a possible link between allergic asthma morbidity and IBD (Olszak et al., 2012). In neonatal mice, sphingolipid generated by B. fragilis suppresses NKT cell proliferation, regulating homeostasis (An et al., 2014). Pneumolysoid and type-3-polysaccharide (T3P) produced by Streptococcus pneumoniae stimulate Tregs, which reduce airway hyperreactivity dependent on NKT cell (Thorburn et al., 2012). Microbial bile acids regulate the accumulation of hepatic NKT cell through mediating CXCL16 (CXC-motif ligand 16) expression. Liver sinusoidal endothelial cells express more CXCL16 when exposed to bile acids modified by Clostridium species. Additionally, hepatic NKT cell recruitment has demonstrated remarkable anti-tumor responses against tumors of EL4 lymphoma (Ma et al., 2018). Therefore, it will be crucial to look into whether changes in microbiome of AIDs patients influence the pathophysiology of the disease by regulating NKT cells.

γδ T cells are known to have semi-invariant TCRs consisting of γ and δ chains, and they are connected to many homeostatic functions such as wound healing and immunological monitoring (Ribot et al., 2021). In various disease models, γδ T cells play an important role as early responders, and frequently they produce the first cytokines like IFN-γ and IL-17 (Ribot et al., 2021; Chien et al., 2014). Although the amount of intestinal γδ intraepithelial lymphocytes (IELs) appears to be unaffected by the gut microbiota, some commensals can raise the frequency of γδ T cells that are positive for IL-17 and IL-1R1 by signaling via VAV1 (a guanine nucleotide exchange factor), which may provide protection against illness (Duan et al., 2010). Thus, there is need to investigate the type of commensals that increases IL-17 and IL-1R1-positive γδ T cells as it may result in the development of innovative probiotics for immune homeostasis. Moreover, the homeostasis of γδ T cells, which produce IL-17A, is also facilitated in the liver by the commensal microbiota. This disturbs the activation of these cells and their secretion of IL-17 cytokines, which in turn affects the advancement of NAFLD (Li et al., 2017a).

Li et al. (2017b) findings showed that via dose-dependent manner hepatic γδ T cell restoration was done by Escherichia coli. Additionally, immune surveillance was restored in mice treated with antibiotics when IL-17A and γδ T cells were added (Cheng et al., 2014). A study determined that microbial metabolite, propionate works as a major component in regulating γδ T cells based release of IL-17 (Dupraz et al., 2021). In the colon, Lactobacillus breves DM9218 expressed TLR2, which directly stimulated γδ T cells and had positive effects on colitis (Li et al., 2018). Certain beneficial bacteria, like Bacillus spp. and Bifidobacterium, increased TLR2 expression, which improved barrier functions via γδ T cells (Li et al., 2017b). Indeed, certain gut commensals can enhance IL-17 and IL-1R1-positive γδ T cells, that suggests using targeted probiotics might enhance immune defense. More specific insights related to these strains can lead to novel treatments for conditions like NAFLD and colitis by upregulating beneficial T cell activity. Table 2 presents the types of microbiota or metabolites involved in the manipulation of T cell subtypes functions and their effects.

RA is a type of chronic AID that destroys joints and impairs its function. Recently, certain genetic factors along with gut dysbiosis has been proposed as the pathogenesis of RA (Maeda et al., 2016; Jubair et al., 2018). Microbiome research on germfree mice highlights the importance of instability in gut microbiota composition for the etiology of arthritis (Scher et al., 2013). Patients having RA exhibit markedly altered compositions of gut microbiota, with a decrease in Faecalibacterium, a beneficial microbe, and an increase in Prevotella species such as Prevotella copri (Wells et al., 2020). In a mouse model of arthritis, oral exposure to Prevotella nigrescens and Porphyromonas gingivalis exacerbated the inflammation by inducing IL-17 production by the immune system and promoting a Th17 cell response (de Aquino et al., 2014). In addition, Collinsella has been linked to cause severe arthritis in mouse models by promoting the expression of IL-17A and thereby increasing gut permeability. Collinsella has been found to be elevated in RA patients (Chen et al., 2016a). In early stages of RA, the patients have a dominant gut microbiota that includes Collinsella (Koh et al., 2023) and Prevotella copri (Zhang et al., 2015), indicating their potential roles in the etiology of disease. P. gingivalis has been found in the serum of RA patients as well as those who are at verge of developing RA (Mikuls et al., 2012).

The link between RA and SCFAs in the diet has been brought to light by many researches. Because of their function as histone deacetylase inhibitors, SCFAs especially butyrate, suppress the inflammation in RA (Chen et al., 2016b; Maslowski et al., 2009). Research has demonstrated that butyrate inhibits RA by suppressing the inflammatory cytokines secretion and by regulating Treg cells (Takahashi et al., 2020; Yang et al., 2024). By blocking histone deacetylase (HDAC)2 activity in osteoclasts and HDAC8 activity in T cells, butyrate decreased the inflammation in a CIA mice model, which in turn decreased the joint inflammation (Kim et al., 2018). In addition, in RA models, mice lacking SCFA receptors show increased inflammation (Maslowski et al., 2009). The influence of gut microbiota on RA is indicated by the presence of species such as Porphyromonas and the decrease in beneficial microbe like Faecalibacterium. Additionally, SCFAs such as butyrate have anti-inflammatory properties; this implies that dietary changes may help control RA by influencing immunological responses and gut health.

T1DM is a type of AIDs, caused when T lymphocytes attacks and destroys insulin-producing β-cells of pancreas. The link between T1DM and the gut microbiota is evident by the reduced numbers of intestinal Treg cells along with healthy microbiota in individuals suffering with T1DM (Anderson, 2023). Studies conducted on humans from a variety of ethnic backgrounds have consistently reported changes in gut microbiota in relation to T1DM (Kostic et al., 2015; Needell and Zipris, 2016; Mejía-León et al., 2014), marked by an increase in Bacteroides species and a decrease in the amount of bacteria that produce SCFA, namely F. prausnitzii (de Goffau et al., 2014; de Goffau et al., 2013; Chukhlovin et al., 2023). Children with T1DM, had lower levels of members of Clostridium clusters IV and XIVa (de Goffau et al., 2013). Moreover, the individuals with T1DM have been found to have decreased expression of intestinal FOXP3, an important transcription factor for the Treg cells activation (Badami et al., 2011). Additional data suggests that microbial diversity was lower (Kostic et al., 2015) and intestinal permeability was higher (Maffeis et al., 2016) prior to the T1DM diagnosis.

In a recent research, when LEfSe analysis was performed, 28 bacterial taxonomic clades showed statistically major alterations (13 elevated and 15 reduced) in T1DM patients in comparison to healthy controls. Porphyromonadaceae, a family of the Bacteroidetes phylum, was overrepresented in T1DM patients, but Paenibacillaceae, Veillonellaceae, Ruminococcaceae, and Phascolarctobacterium, all belonging to the Firmicutes, were most abundant in healthy individuals. Furthermore, the phylum Fusobacteria was differentially enriched in healthy participants (Abuqwider et al., 2023).

Studies on animals using NOD mouse models have clarified the SCFAs protective applications against T1DM. For instance, NOD mice of T1DM given specific diets that increased the amount of acetate and butyrate released by the bacteria which resulted in higher number of Treg cells and lower number of autoreactive T cells and protected them against the development of T1DM (Mariño et al., 2017). Furthermore, in a recent study conducted on T1DM model of NOD mice reported, decrease in the number of SCFAs (Wang et al., 2023b). Interestingly, gut permeability is shown to be a critical mediator between intestinal microbiota, inflammation, and the onset of T1DM, with implications for both human and animal models (Vaarala et al., 2008). Therefore, it is logical to hypothesize that SCFAs could preserve the integrity of the gut barrier by modifying the gut microbiota, encouraging tight junctions and thickening of the mucus layer, which would prevent the onset of T1DM.

The symptoms of T2DM include insufficient insulin secretion, increased insulin sensitivity and hepatic glucose production. According to recent studies, dysbiosis may have played a role in the development of T2DM (Arora et al., 2021). Numerous studies examining the gut microbiota of T2DM patients have discovered significant genus-level variations between the patients and healthy controls. These results suggest a connection between diabetes and modifications in the gut microbiota. Frequently reported results indicate that Ruminococcus, Fusobacterium, and Blautia have positive associations with T2DM, while the genera Akkermansia, Bacteroides, Bifidobacterium, Faecalibacterium and Roseburia have negative associations (Larsen et al., 2010; Gurung et al., 2020).

In comparison to healthy controls, the gut microbiota of individuals having T2DM from Northern China had lower levels of Akkermansia and Bifidobacteria species, but higher levels of Dorea (Li et al., 2020). In a metagenome-wide association study, adequate level of gut dysbiosis was found in patients having T2DM. Control samples had higher levels of Lactobacillus spp. and butyrate-producing bacteria, T2DM patients had higher levels of opportunistic pathogens like Clostridium spp. (Qin et al., 2012). Reduced levels of butyrate producing bacteria, which affect insulin sensitivity, are associated with T2DM (Vrieze et al., 2014). A diet that produces acetate and butyrate has been shown to improve gut integrity, stimulate Treg cells, secrete IL-21, and prevent T2DM (Puddu et al., 2014). Through particular G protein receptors (GPR41, GPR43), SCFAs cause intestinal L-cells to secrete GLP-1, which affects insulin release, pancreatic function, and central effects on appetite regulation (Fava, 2014).

In addition to SCFAs, gut microbiome alpha diversity has been linked to other serum metabolites. A microbiome-metabolite score that combined the levels of these metabolites in circulation showed stronger correlations with cardiometabolic traits. Significantly, this score was connected to the incidence and prevalence of T2DM, indicating that metabolites derived from the microbiome play a mechanistic role in the relationship between the composition of the microbiome and health (Menni et al., 2020). While considering the link between dysbiosis of the gut microbiota and T2DM, alteration of gut microbiota may prove to be a useful therapeutic approach. Insulin sensitivity and secretion may be improved by the development of personalized probiotic therapy to increase SCFA-producing bacteria. Moreover, a combined microbiome-metabolite score may also be utilized to mitigate the onset and progression of T2DM by enabling early diagnosis.

Reduced metabolic capacity and early-life dysbiosis of the gut microbiota can impair pulmonary and local immunity, making individuals more vulnerable to lung disorders like atopic asthma (Zhao et al., 2023). Microbes in the environment may have an impact on asthma risk even before birth. Numerous studies have demonstrated that exposure of mother to a farming environment protects her offspring from allergic reactions, such as asthma (Roduit et al., 2011; Loss et al., 2012; Ver Heul et al., 2019). Animal models used in experiments, especially newborn mice given antibiotics, showed reduced diversity of gut microbes, altered metabolite profiles, elevated response of immune cells and greater vulnerability to allergic inflammation of lungs (Russell et al., 2012; Cait et al., 2018). Moreover, the inflammation was reduced in these mice models when SCFAs were added in their diet. The mechanism for this improvement was linked to lower levels of circulating IgE and immune--modulating markers like T cells and IL-4-producing CD4+ T cells (Cait et al., 2018).

The relationship between the gut microbiota and asthma was investigated in a clinical research involving 58 patients having asthma and healthy controls. The findings showed a favorable relationship of the relative abundance of Bifidobacterium and Lachnospiraceae family with asthma. On the other hand, asthmatic participants had a decrease in the relative abundance of Bacteroides and Enterobacteriaceae family (Begley et al., 2018). Moreover, Proteobacteria was found to be the predominant phylum overrepresented in human observational studies (Wang et al., 2022a), which connected pro-inflammatory mechanisms to the pathogenesis and severity of asthma. Bifidobacterium administration has been demonstrated to increase IL-10–producing Treg cells, that aid in suppressing over reactive immune responses. Individuals with asthma who received a Bifidobacterium mixture in a randomized controlled experiment, reported better quality of life and clinical symptoms than those who received a placebo (Miraglia Del Giudice et al., 2017).

In human airway inflammation, SCFAs, known to be protective bacterial metabolites showed anti-inflammatory effects. The two most common bacterial phyla that produce SCFAs are Firmicutes and Bacteroidetes, and both are capable of producing acetate. In Firmicutes, (Coprococcus, Clostridium, and Ruminococcus) are the primary producers of butyrate. Bacteroidetes like Prevotella produce propionate (Zhao et al., 2023). Soluble fiber demonstrated anti-inflammatory properties through the binding of SCFAs to related G-protein-coupled receptors (GPCRs) (McLoughlin et al., 2019). Research also indicates the production of pro- and anti-inflammatory metabolites like histamine (Pugin et al., 2017) and oxylipins like 12,13-diHOME (Stewart, 2019) by gut bacteria, pointing a complex interaction between gut microbiota and asthma. Dietary fiber can be used by gut microbes to produce SCFAs, in order to control immunological response of the host (Silva and Bernardi, 2020). By modifying the development and activity of immune cells, SCFAs may be crucial in controlling asthma (Niu et al., 2023). The associated mechanisms that facilitate networking between the lungs and gut are still uncertain. More specifically, the pro-inflammatory responses in the lungs are inhibited by SCFAs derived from gut bacteria. Therefore, targeted focus on fostering SCFA-producing bacteria like Bifidobacterium and Prevotella might be a potential way to decrease asthma risk by promoting anti-inflammatory effects in the respiratory tract.

IBD is a multifactorial disease, caused by environmental factors, genetic factors, and immune-mediated factors caused by microbiota and it consists of Crohn's disease (CD) and ulcerative colitis (UC) (Diez-Martin et al., 2024). Rather than a single causative organism, several microbes dysbiosis is linked to the onset of IBD (Lepage et al., 2011). Several studies show that gut microbes, which differ in composition and functionality from healthy controls, play a critical role in the manifestation of IBD (Thursby and Juge, 2017; Pandey et al., 2024). B. longum Bar 33 and L. acidophilus Bar 13 decrease the quantity of intraepithelial lymphocytes and increase the growth of Treg cells in mice models of intestinal inflammation caused by 2,4,6-trinitrobenzene sulphonic acid-induced colitis (Roselli et al., 2009). By stimulating and growing colonic CD4+ FoxP3+ Treg cells, L. casei DN-114 001 reduces the severity of the disease in a mouse colitis paradigm (2,4-dinitrobenzene sulphonic acid) (Hacini-Rachinel et al., 2009). Recently, a study on mice colonized with B. fragilis and a healthy human microbiota, highlighted that colitis induction resulted in a decrease in PSA in the "ON" orientation, which was reversed when inflammation decreased (Carasso et al., 2024). Similarly, a study employing colitis-prone mice shown that Enterobacter ludwigii was successful in reducing colitis symptoms. When compared to other antibiotic treatments, metronidazole had the greatest effect in reducing colitis in a colitis prone mouse model caused by dextran sulfate sodium (DSS). This effect was linked to an increase in the abundance of the gut microbiota species E. ludwigii. By using metabolites from E. ludwigii to stimulate Treg cells differentiation, the immunological tolerance response was boosted and mice's susceptibility to DSS-induced colitis was decreased (Li et al., 2022a).

Reduced microbial diversity, particularly a decline in Firmicutes and an up rise in Proteobacteria taxa, is indicative of IBD-associated dysbiosis. Reductions in the number of Firmicutes bacteria from the Lachnospiraceae and Ruminococcaceae families (Matsuoka and Kanai, 2015; Halfvarson et al., 2017), which are essential for the synthesis of butyrate, are frequently observed in active CD. Decreased butyrate production capacity is one of the functional disturbances associated with this depletion (Marchesi et al., 2007). Researches have reported reduced abundance of Blautia faecis, Clostridium lavalense, Roseburia inulinivorans and Ruminococcus torques in individuals having CD (Takahashi et al., 2016; Pandey et al., 2024). Findings in the ileal CD microbiota showed a reduced number of genes involved in the SCFAs synthesis, along with a decline in the butyrate-producing bacteria F. prausnitzii and Roseburia sp. (Liu et al., 2021).

Butyrate is known to treat IBD due to its ability to support colonocyte energy, inhibiting inflammation and improving the integrity of the epithelial barrier. A few studies applied a different strategy that uses probiotics to uplift in situ butyrate production by consuming butyrate-producing bacteria (Miquel et al., 2013; Tamanai-Shacoori et al., 2017). In a recent study, mice were protected against sorbitol-induced diarrhea by inoculation with butyrate-producing Anaerostipes caccae, even after the elimination of probiotic, which returned the abundance of Clostridia back to normal (Lee et al., 2024). This strategy suggests that focusing on microbial dysbiosis through supplementation of bacterial species which produce butyrate may be helpful in reestablishing the gut homeostasis and improving health of IBD patients.

A rising global health concern, NAFLD is associated with an increased risk of cancer and liver disease. In this disease, there is excessive buildup of fat in the liver which is not linked with consumption of alcohol (Tang et al., 2024). Through a variety of immunological, epigenetic and metabolic processes, intestinal dysbiosis is a major contributor of NAFLD (Chen et al., 2020; Wolfe et al., 2023). The gut microbiota profile in individuals having NAFLD is strongly associated with systemic inflammation and can coexist with the development of hepatocellular carcinoma (Ponziani et al., 2019). Research indicates that in both NAFLD and non-alcoholic steatohepatitis (NASH), there is a reduction in alpha and beta diversities accompanied by modified microbial signatures (Caussy et al., 2019). These signatures include a rise in Enterobacteriaceae, Proteobacteria and genera like Collinsella, Dorea, Escherichia, and a decline in Coprococcus, Faecalibacterium, Eubacterium and Prevotella (Hoyles et al., 2018; Boursier et al., 2016). Despite the fact that these preliminary findings point to a detectable difference in microbial profiles between hepatic steatosis patients and controls, significant differences are recorded between studies with opposing findings in the literature. P. copri was found to be linked with a higher progression risk in both NAFLD and NASH, that may have connection with reduced capacity of butyrate production and elevated intestinal permeability (Moran-Ramos et al., 2023). Moreover, in the NASH, there is a reduction in the levels of the butyrate producer F. prausnitzii, a common microbial signature linked to other metabolic diseases (Caussy et al., 2019; Iebba et al., 2018).

Furthermore, it is possible that the increased Lactobacillus presence increases the amount of SCFAs in the gut, which have been demonstrated to reduce fat accumulation (Hou et al., 2022). According to another study, yinchen linggui zhugan decoction (YLZD) improved NAFLD treatment and raised Christensenellaceae abundance (Jiang et al., 2022). As for now, it is unknown how Christensenellaceae affects NAFLD. It is possible therefore, that this association is related to the improvement of fat metabolism (Tavella et al., 2021). There is a documented inverse relationship between insulin resistance and Christensenellaceae abundance. There may be a connection between Christensenellaceae and the onset of NAFLD because lower quantity of this bacterium is linked to more severe insulin resistance and consequent fat storage (Chen et al., 2021b). Through different mechanisms, the gut microbiota is linked to the onset and progression of NAFLD. When bacteria, like Collinsella sp. metabolize bile acids into oxo-bile acid intermediates, it can lead to increased intestinal permeability, which can exacerbate NAFLD (Doden et al., 2018; Purohit et al., 2024).

A large number of toxic metabolites that cause liver fibrosis and inflammation may be accessible to the liver due to dysbiosis and increased intestinal permeability. To shield liver cells from harmful or toxic metabolites the gut mucosal barriers must remain intact (Park et al., 2022). A. muciniphila not only improves the gut barrier integrity but also boosts Treg cell numbers and inhibits pro-inflammatory Th17 responses, both of which can help to prevent or lessen NAFLD condition (Nian et al., 2023). It is interesting to note that although butyrate and propionate were more common in mild to moderate NAFLD, the SCFAs especially acetate, were enriched in advanced NAFLD stages, suggesting different roles in disease severity (Aoki et al., 2021). Thus, the modulation of NAFLD progression is influenced by specific microbial metabolites that alter host metabolic and immune pathways. Moreover, more production of oxo-bile acids and SCFAs, by bacteria such as Collinsella sp. and Lactobacillus impact intestinal permeability and systemic inflammation. Targeting these microbial metabolic pathways could provide novel therapeutic strategies and personalized medicine methods for the control and therapy of NAFLD. Table 3 highlights the associations between the changes in gut microbiota, the role of SCFAs, and the mechanisms that leads to the development and progression of each autoimmune disease mentioned in this section.