Crosstalk Between Gut Microbiota And Host Immunity: Impact On Inflammation And Immunotherapy(2)

7.2. Gastrointestinal Infections

Depending on the context, the gut microbiota can either protect the host or increase the risk of infection from exogenous pathogens. The role of the microbiome as a protective force is supported by research indicating that immature microbiomes of neonates are more susceptible to invasion by pathobionts [222]. There are several different mechanisms by which commensals can prevent colonization by pathogens and protect against infections, including competing for resources, releasing bacteriophages, and producing antimicrobial metabolites [237–241]. In contrast, microbiome metabolites, such as 4-methyl benzoic acid, 3,4-dimethylbenzoic acid, hexanoic acid, and heptanoic acid, have been shown to increase colonic epithelial damage, as seen by enterohemorrhagic E. coli in an organ-on-a-chip model [223]. Moreover, supernatant taken from commensal Escherichia albertii can also increase the virulence of diarrheagenic E. coli species, resulting in a TLR5-mediated increase in IL-8 and an overall increased pro-inflammatory response by host intestinal cells [242]. The presence of certain commensals and changes in microbiome composition are linked to infection susceptibility by organisms such as Clostridium difficile, Salmonella typhimurium, Escherichia coli, vancomycin-resistant Enterococcus spp., and Citrobacter rodentium [238,239,241,243–245]. One of the best examples involves CDI, where innate immune cells are stimulated by C. difficile-toxins through the inflammasome and the TLR4, TLR5, and nucleotide-binding oligomerization domain-containing protein 1 (NOD1) signaling pathways [246,247]. Numerous pro-inflammatory cytokines (such as interleukin (IL)-12, IL-1β, IL-18, interferon-gamma (IFN-γ), and tumor necrosis factor α (TNFα)) and chemokines (MIP-1a, MIP-2, and IL-8) are subsequently produced, resulting in increased mucosal permeability, mast cell degranulation, epithelial cell death, and neutrophilic in- filtration [248]. Importantly, CDI is usually a result of antibiotic-mediated disruption of the gut microbiota [249]. Eradication of beneficial bacteria in the gut by certain antibiotics, particularly clindamycin, enables C. difficile to flourish [250], resulting in colitis and subsequent diarrhea [251,252]. Besides gut microbiota dysbiosis, immune cell populations, such as Th17- and IL-17-expressing cells, can promote recurrent CDI [253]. Comparatively, IL-33-activated ILCs can prevent CDI [254]. As gut microbiota depletion is a main cause of CDI, interventions that restore microbes could be of therapeutic value. Prebiotics, such as dietary fiber and their fermented byproducts, i.e., SCFA, are possible treatments for CDI. For instance, dietary fibers, such as pectin, were able to restore gut microbiota eubiosis (denoted by increased Lachnospiraceae and decreased Enterobacteriaceae) and alleviate inflammation following C. difficile-induced colitis [255]. The butyrate-producing bacterium Clostridium butyricum was similarly found to protect against CDI by increasing neutrophils, Th1, and Th17 cells in the early phase of infection; this was independent of GPR43 and GPR109a signaling [256]. As mentioned in Section 6.2, CDI can be effectively treated by FMT [152]. FMT is further supported in a prior study that showed that a Microbial Ecosystem Therapeutic, consisting of 33 bacterial strains isolated from human stool, could treat antibiotic-resistant C. difficile colitis [257]. Of note, similar observations were seen when the Microbial Ecosystem Therapeutic was applied to Salmonella typhimurium infection [258]. These findings emphasize that appropriate modulation of the gut microbiota and immune responses is imperative for preventing and fighting against infection.

effects of cistance-treat constipation

7.3. Inflammatory Bowel Diseases

Inflammatory bowel diseases (IBD) develop due to defects in various factors, such as environment, gut microbes, immune system, and genetic factors. IBD involves chronic inflammation of the GIT. Crohn’s disease (CD) and ulcerative colitis (UC) are two distinct clinical conditions of IBD based on histopathological features, location of disease in the GIT, and symptoms [259]. In IBD, mucolytic bacteria and pathogenic bacteria degrade the mucosal barrier and increase the invasion of pathogens into deep intestinal tissues [224,260–262]. Alterations in the gut microbiota composition have been highly linked to the development and progression of IBD. IBD patients show reduced populations of Firmicutes and an expansion of Proteobacteria, Bacteroidetes, Enterobacteriaceae, and Bilophila [263–265]. In addition, many pro-inflammatory bacterial species are coated with IgA, as seen in IBD patients and colitis mouse models [266,267]. Gut microbes appear to play a direct role in IBD development based on the evidence that germ-free mice are protected against colitis [268]. This is reinforced by the discovery that implantation of gut microbes from IBD mice to germ-free mice resulted in IBD for the latter group [268]. Likewise, dams with IBD can essentially transfer an ‘IBD microbiota’ to the offspring, for which the pups have reduced microbial diversity and fewer class-switched memory B cells and Treg cells in the colon [269]. The strong link between microbiota and IBD has moved forward metagenomic approaches to help better identify diagnostic and therapeutic targets [270]. FMT is proposed as a potential treatment, where treated UC patients were found to have an increased abundance of Faecalibaterium that corresponded with less RORγt + Th17 cells and more Foxp3+ CD4+ Treg cells [166]. Administration of SCFAs is also thought to be a potential therapeutic for IBD patients [271]. Supporting evidence includes butyrate-mediated inhibition of pro-inflammatory neutrophil responses, i.e., NETs in colitic mice [272]. There are conflicting reports as to whether dietary fiber, the precursor for SCFA, could be a beneficial intervention for IBD patients. On one side, a specific multi-fiber mix was found to counteract intestinal inflammation via increasing IL-10 and Treg cells [273]. Opposingly, our research findings indicate a dichotomy in prebiotic fiber reactions for colitic mice, where pectin could alleviate inflammation compared with inulin, which aggravated the disease pathology [274]. Moreover, our study suggested that butyrate could be a detrimental microbial metabolite by increasing NLRP3 inflammatory signaling [274]. A probiotic cocktail, comparatively, alleviated inflammation by shifting the gut microbiota to an anti-inflammatory profile which included Akkermansia and Bifidobacterium [275]. These findings collectively indicate that more investigation is required to understand prebiotic fibers and SCFAs in IBD before implementing them in the clinics. In addition to SCFA, secondary bile acids are implicated in IBD. DCA has been well-established to induce intestinal inflammation [276,277]. This could be due, in part, to bile-acid-mediated inhibition of Paneth cell function [278]. Yet, cholecystectomy-associated secondary bile acids, including DCA, ameliorated colitis in mice by inhibiting monocyte/macrophage recruitment [279]. Moreover, UDCA can also lower colitis severity by preventing the loss of Clostridium cluster XIVa and increasing the abundance of A. muciniphila [280]. The varying effects of bile acids could be related to their chemical structure and potential conjugated moieties. For instance, sulfated secondary bile acids may exert more pro-inflammatory effects compared with their unconjugated counterparts, as seen in IBD patients [281]. Certainly, more metabolomic profiling is necessary to understand the bile acid profile in IBD patients and determine the pro- or anti-inflammatory effects of each type of bile acid. In general, it appears that both SCFA and secondary bile acids have anti-inflammatory effects in the intestine (Figure 1A, B). Several susceptibility genes that increase the risk for IBD have been identified in recent years. Current research is focused on the idea that genetic predisposition, dysbiosis, and environmental factors, such as antibiotics, work in concert toward IBD. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2, an immunological intracellular recognition protein) identifies intracellular muramyl dipeptide (MDP), an integral component of bacterial cell walls [282]. Loss of NOD2 function impairs inhibition of TLR2-mediated activation of NF-κB, resulting in an overactive Th1 response and weakened immunological tolerance to microbes [282]. Moreover, several other genes that increase susceptibility to IBD, including autophagy-related 16-like 1 (ATG16L1), caspase recruitment domain-containing protein 9 (Card9), and C-type lectin domain family 7 member A (CLEC7A), dysregulate T cell responses and create gut microbiota dysbiosis, also contributing to IBD [283–285]. Future studies should explore whether there are single nucleotide polymorphisms in genes related to microbial metabolite production for IBD patients.

Benefits of cistanche tubulosa-strengthen immune syste

7.4. Colorectal Carcinoma (CRC)

A growing body of literature suggests a role for microbiota in the development and progression of cancer. In scenarios where the immune system has maladaptive development, gut microbiota dysbiosis becomes a high risk, and the expansion of certain microbes can result in the production of mutagenic toxins [286]. These genotoxins include Bacteroides fragilis toxin (Bft), cytolethal distending toxin (CDT), and colibactin [225]. However, these highlight only a small number of bacterial-related toxins where more research is needed to identify and understand the carcinogenic potential with the full breadth of gut microbes [225]. Adenomatous and serrated polyps are two precancerous lesions that often progress to colorectal cancer (CRC). In patients with adenomas, several species, including Bilophila, Desulfovibrio, Mogibacterium, and the phylum Bacteroidetes, are increased in the feces, while patients with serrated polyps showed increases in the taxa Fusobacteria and class Erysipelotrichia [226]. Fusobacterium nucleatum (F. nucleatum) is characterized as an important microbe in CRC progression [287,288]. F. nucleatum promotes TLR4 signaling and E-cadherin/β-catenin signaling, ultimately leading to the activation of NF-κB and reduced miR-1322 expression [289]. Regulatory micro-RNAs, such as miR-1322, can directly regulate the expression of CCL20, a cytokine that promotes CRC metastasis [287]. Other literature points to F. nucleatum adhesin A (FadA) as a key virulence factor that allows F. nucleatum to adhere, invade, and erode the colonic epithelia [227]. More recently, one study found that F. nucleatum can promote CRC by suppressing anti-tumor immunity through activation of the inhibitory receptors CEACAM1 and TIGIT1, which downregulate NK cells and T cells [290]. The F. nucleatum strain Fn7-1 was also demonstrated to aggravate CRC development by elevating Th17 responses [74]. These findings on F. nucleatum are alarming because this is a SCFA-producing bacterium [291], and SCFA has been, in general, highlighted as a potential therapeutic avenue for many inflammatory diseases. F. nucleatum predominantly produces acetate and butyrate, where it was recently suggested that F. nucleatum induces Th17 via free fatty acid receptor 2 (FFAR2), an SCFA receptor [74]. Yet, loss of FFAR2 in mice aggravated tumor bacterial load and over-activated DCs, eventually promoting T cell exhaustion [292]. Moreover, butyrate from dietary fiber was found to be less metabolized in CRC cells because of the Warburg effect, allowing it to act as an HDAC inhibitor and promote acetylation of genes related to apoptosis [293]. These findings emphasize that the pathologic effects of F. nucleatum could be SCFA-independent, but further studies are needed to determine this possibility. Another proposed mechanism in the development of CRC suggests that excessive dietary intake of sugars, proteins, and lipids could promote the growth of bile-tolerant microbes, which increase the production of secondary bile acids, such as DCA and LCA, and by-products, such as hydrogen sulfide. Excessive secondary bile acids are genotoxic and may produce a pro-inflammatory environment that could promote the development of CRC [226]. In particular, DCA can stimulate intestinal carcinogenesis by activating epidermal growth factor receptor-dependent release of the metalloprotease ADAM-17 [294]. 

effects of cistance-treat constipation

DCA also activates β-catenin signaling [295] and drives malignant transformations in Lgr5-expressing (Lgr5+) cancer stem cells [296] for CRC growth and invasiveness. However, bacteria associated with secondary bile acid production, i.e., Clostridium cluster XlVa, were significantly decreased in IBD patients, which was accompanied by reduced transformation of primary to secondary bile acids [297]. In addition to bile acids, the gut microbial metabolite folate can worsen CRC pathogenesis by triggering AhR signaling and expanding Th17 levels [298]. Similar to SCFA, more investigation is needed to discern the potential pro-tumorigenic effects of gut-microbiota-derived bile acids. There are distinct microbiota-dependent immunological responses in CRC. In terms of innate immune responses, A. muciniphila enrichment facilitated M1 macrophage polarization in an NLRP3-dependent manner that suppressed colon tumorigenesis [299]. Likewise, intestinal adherent E. coli can increase IL-10-producing macrophages, which limits intestinal inflammation and restricts tumor formation [300]. In terms of adaptive immunity, microbial dysbiosis hyperstimulates CD8+ T cells to promote chronic inflammation and early T cell exhaustion, which contributes to colon tumor susceptibility [301]. Intestinal cancer cells can also respond to the microbiota by inducing calcineurin-dependent IL-6 secretion, which promotes tumor expression of the co-inhibitory molecules B7H3/B7H4 that diminish antitumor CD8+ T cells [302]. Comparatively, the introduction of Helicobacter hepaticus induced T follicular helper cells that restored anti-tumor immunity in a mouse CRC model [303]. Compared with macrophages and Th17 cells, γδ T cells and resident memory T cells were found at lower frequencies in the colonic tissue of CRC patients [60]. It would be interesting to investigate whether an immune cell panel could be developed for early diagnosis of CRC.

cistanche tubulosa-improve immune system

7.5. Hepatocellular Carcinoma (HCC)

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is the fourth leading cause of cancer-related mortality worldwide [304]. The main etiology for HCC pathogenesis comes from pre-existing liver diseases, such as nonalcoholic fatty liver disease (NAFLD) and steatohepatitis, that lead to cirrhosis [305]. This is further complicated by other concomitants in NAFLD patients, including insulin resistance, obesity, and metabolic disorders that further promote hepatic inflammation and tumorigenesis through IL-6 and TNF-α [306]. The liver is the ‘first stop’ for venous blood coming from the intestines, making it vulnerable to the gut microbiota via microbial translocation across the intestinal–epithelial barrier or contact with absorbed microbial metabolites [307]. The aforementioned well-known effects of gut microbiota dysbiosis, including disruption of the gut barrier, translocation of microbes into the bloodstream, and subsequent inflammatory immune responses via induction of PRRs by PAMPs, such as LPS, are strongly correlated to the pathogenesis of NAFLD, liver cirrhosis, and HCC [228,307]. While it has long been thought that gut microbiota dysbiosis precedes the development of HCC, this causal relationship has not been explored in depth until more recently. Behary, Raposo, et al. recently found, before HCC progression, that gut microbiota dysbiosis is in tandem with early onset liver injury that is followed by an LPS-dependent Th1- and Th17-mediated cytokine response [308]. Further investigation should determine whether gut microbiota dysbiosis is a cause or consequence of the liver injury preceding HCC. Increased Enterobacteriaceae and Streptococcus and reduction in Akkermansia, alongside elevated levels of inflammatory mediators, such as CCL3, CCL4, CCL5, IL-8, and IL-13, have been noted in patients with NAFLD-associated HCC [309]. A more recent study found a decreased abundance of SCFA-producing bacteria and increased LPS-producing bacteria in patients with cirrhosis-induced HCC but no significant evidence of gut microbiota dysbiosis in other liver diseases, such as hepatitis C, hepatitis B, or alcoholic liver disease [310]. Broadly speaking, however, it should be noted that altered microbial populations observed among multiple studies are not consistent with each other [309,311–313]. Furthermore, while it is generally thought that SCFAs produced by gut microbes have several benefits for humans, it was recently discovered that inulin, a precursor of the SCFA butyrate, can promote the progression to HCC in genetically altered dysbiotic mice [229]. Other studies have focused on the impact of microbial metabolites on HCC. For instance, a high-fat diet led to gut overgrowth of Gram-positive organisms that generate secondary bile acids, i.e., DCA [230]. DCA can work in concert with lipoteichoic acid to activate TLR2 and subsequently downregulate anti-tumor immunity, creating a microenvironment favorable for the development of HCC [314,315]. Overall, it appears that gut microbiota metabolites are potentially pro-tumorigenic for the liver.

7.6. Cardiovascular Disease

Cardiovascular disease (CVD) is heavily linked to metabolic syndrome, a condition that involves a set of interrelated diseases—mainly atherosclerosis, NAFLD, hypertension, and type II diabetes mellitus (TIIDM)—that arise from chronic, low-grade inflammation [316]. Many cells with high metabolic activity, such as parenchymal cells in the liver and pancreas, adipocytes, and skeletal myocytes, participate in extensive crosstalk with immune cells. Any perturbation of the microbiome has the potential to alter host immune function and, by extension, may have the ability to cause or alter disease processes in metabolically active tissues. The recognition of LPS and other microbial PAMPs by PRRs is thought to be a key driver in this low-grade inflammatory state [231]. Trimethylamine N-oxide (TMAO), a microbial co-metabolite, is also noted to cause low-grade inflammation through NF-κB signaling, inflammasome activation, and increased production of free radicals [317,318]. Furthermore, TMAO leads to atherosclerosis and, thus, heart disease by impairing cholesterol metabolism in macrophages and contributing to the formation of foam cells [319]. Indeed, higher serum TMAO is correlated with increased risk of atherosclerosis, coronary artery disease, stroke, and vascular inflammation [232,233], and TMAO is currently being considered as a biomarker for adverse cardiovascular events [320]. More recent research has discovered phenylacetylglutamine (PAGln) as a microbial metabolite related to CVD via adrenergic receptor activation and pro-thrombotic effects [321,322]. There are multiple potential emerging roles for PAGln in cardiovascular medicine, such as being used as a diagnostic marker or even as a predictor for responsiveness to β-blocker therapy for CVD patients [322].

7.7. Diabetes

Diabetes mellitus is a disease separated into two classes: type I diabetes mellitus (TIDM) involves autoimmune destruction of pancreatic islet cells, while type II diabetes mellitus (TIIDM) involves acquired insulin insensitivity. Though much research involving microbiota and diabetes revolves around TIIDM and obesity, it has been shown that increasing dietary SCFA consumption can lead to altered microbiota and distinct immune profiles in TIDM patients [323]. Increasing dietary SCFAs, such as butyrate and acetate, were also shown to work synergistically to confer protection against autoreactive T cell populations and TIDM in mice [100]. Comparatively, administration of Parabacteroides distasonis accelerated the development of T1DM in a mouse model, and this was because of aberrant immune responses, including elevated CD8+ T cells and decreased Foxp3+ CD4+ Treg cells [324]. Of note, dysregulated bile acid metabolism was found to be a potential predisposing factor for islet autoimmunity and type 1 diabetes [325]. The microbiome and immune systems are both heavily involved in the pathogenesis of TIIDM. Branched-chain amino acids are produced by Prevotella copri (P. copri) and Bacteroides vulgatus spp., and P. copri directly induces insulin resistance in mouse models [326,327]. Depletion of commensal A. muciniphila compromises the intestinal barrier, resulting in the translocation of endotoxin into the bloodstream and subsequent activation of CCR2+ monocytes. This results in the conversion of pancreatic B1a cells into 4BL cells, which release inflammatory mediators and cause reversible or irreversible insulin resistance [328]. On the other hand, microbial metabolites, such as linoleic acid and docosahexaenoic acid, have protective effects against insulin resistance and TIIDM through anti-inflammatory effects and prevention of lipotoxicity [329]. FMT has also been shown to reduce fasting blood glucose levels and decrease insulin resistance in mice with TIIDM [330]. Furthermore, some of the therapeutic effects of several anti-diabetic drugs can be due, in part, to their ability to alter the microbiota [331–333].

7.8. Hypertension

Several studies have observed significantly altered microbiome compositions between normotensive and hypertensive mice, though specific microbial profiles in hypertensive mice are dependent on the hypertension model used [334–337]. In the angiotensin II model of hypertension, the lack of microbiota in germ-free mice protected against hypertension partly by decreasing inflammatory cell populations in the blood [338]. Yet, germ-free mice were more prone to kidney injury following an angiotensin II and high-salt diet combination regimen [339]. Furthermore, the reintroduction of microbiota to hypotensive germ-free mice re-established vascular contractility [340]. Generally, the microbiota composition differs between hypertensive and normotensive animals and, interestingly, cross-fostering hypertensive pups with normotensive dams can reduce blood pressure in the former group [341]. Similar to CVD, the gut metabolite TMAO also has relevance to hypertension. A recent study discovered that TMAO exacerbated vasoconstriction via ROS in angiotensin II-induced hypertensive mice [342]. Similarly, high-salt-induced DC activation is associated with microbial dysbiosis-mediated hypertension [343]. Comparatively, the ketone body β-hydroxybutyrate is decreased in high-salt-fed hypertensive rats; rescuing with the β-hydroxybutyrate precursor 1,3 butanediol decreased blood pressure and kidney inflammation through prevention of the NLRP3-mediated inflammasome [344]. While HSD has been shown elsewhere to decrease Lactobacillus spp. and induce Th17 cell populations, this appears to be through a distinctly different mechanism [176].

7.9. Rheumatoid Arthritis

The pathogenesis of rheumatoid arthritis (RA), a systemic autoimmune disease characterized primarily by inflammation of joints, is becoming more understood. RA is a multifactorial disease with multiple identified alleles and environmental factors conferring increased susceptibility to the disease. A potentially important microbial genus in the development of RA is Prevotella. This was first identified in 2013 by Scher et al., which found that patients with new-onset RA had significantly increased abundance of Prevotella spp., particularly Prevotella copri, compared with healthy controls [234]. However, the Prevotella population did not increase in patients with chronic RA [234]. Since then, multiple studies have found further correlations between various Prevotella species and RA [345–347]. However, it is unclear whether Prevotella spp. itself contributes to the pathogenesis of RA, or the immunological environment created by RA increases abundance of Prevotella in the gut. Other notable bacterial shifts in the gut microbiota for RA patients include a bloom in Proteobacteria, Clostridium cluster XlVa, and Ruminococcus, which were correlated with fewer CD4+ T cells and Treg cells [348]. Using the K/BxN autoimmune arthritis model, it was found that SFB-mediated cytotoxic T lymphocyte antigen-4 (CTLA-4) reduction caused autoreactive T follicular helper cells [349,350]. The accumulation of T follicular helper cells and Th17 cells in arthritis appears to be age-dependent [351], which helps to explain why RA is found mostly in the older population. Interestingly, though, the gut microbiota seems to predominantly affect T follicular helper cells, not Th17 cells, as confirmed by antibiotic treatment of the K/BxN autoimmune arthritis model [352]. Of note, it was recently reported that collagen-induced RA in mice causes an aberrancy in circadian rhythmic patterns in the gut microbiome, resulting in reduced barrier integrity due to an alteration in circulating microbial-derived factors, such as tryptophan metabolites [353]. SCFAs, specifically butyrate, have been proposed as a therapeutic option for RA. Butyrate supplementation was found to promote Treg cells by inhibiting HDAC expression, and it downregulated pro-inflammatory cytokine genes in RA [354]. Moreover, butyrate alleviated arthritis by directly inducing the differentiation of functional follicular Treg cells in vitro by enhancing histone acetylation via HDAC inhibition [355]. Furthermore, butyrate reduced arthritis severity by increasing the levels of AhR ligands, i.e., serotonin-derived metabolite 5-hydroxyindole-3-acetic acid, where AhR activation supported regulatory B cell function [356]. In addition to SCFA, the gut-microbiota-derived metabolites LCA, DCA, isoLCA, and 3-oxoLCA were also very recently found to exhibit anti-arthritis effects. Specifically, isoLCA and 3-oxoLCA inhibited Th17 differentiation and promoted M2 macrophage polarization [357]. These effects of secondary bile acids could be synergized with Parabacteroides distasonis probiotic supplementation [357]. The newfound findings of secondary bile acids are monumental and need additional investigation.

cistanche tubulosa-improve immune system

Click here to view  Cistanche Enhance Immunity products

【Ask for more】 Email:cindy.xue@wecistanche.com /  Whats App:  0086 18599088692 /  Wechat:  18599088692

7.10. Allergic Diseases

Allergies occur when the immune system becomes hypersensitized to nonpathogenic foreign antigens. Common hypersensitivities include allergic rhinitis, food allergy, eczema, atopic dermatitis, and asthma. Several factors responsible for the development of allergies, such as reduced microbial exposure, cesarean delivery, diet, and antibiotic use are strongly linked to changes in gut microbiome composition [358–361]. Gut microbiota dysbiosis, in turn, increases the risk for allergies, particularly food allergies [235,236]. Dysbiosis induced by antibiotic use is sufficient to increase allergic symptoms, elevate intestinal inflammation, and disrupt gut mucosal tight junction in sensitized mice [362]. A high-fat diet generally has effects similar to antibiotics, causing gut microbiota dysbiosis and subsequently increasing the risk for food allergies [363]. Changes in gut microbiota composition immediately after birth, when the microbiome is still established, appear to have a particularly large impact on the development of allergic diseases later in life [364]. Of note, the vaginal microbiota can also reflect allergy risk, where Lactobacillus-dominated vaginal microbiota clusters were related to infant serum IgE status at 1 year of age [365]. Several studies reinforce the concept that dysbiosis is heavily linked to allergic diseases, especially asthma. Individuals with atopic asthma have significantly higher fecal levels of Lactobacillus and E. coli compared with healthy individuals [366]. In terms of microbiota metabolites, 12,13-diHOME (a relatively uncharacterized linoleic acid) is commonly found in neonates at high risk for asthma [367]. It was recently found that the bacterial epoxide hydrolase, which produces 12,13-diHOME, is also higher in concentration during pulmonary inflammation, and 12,13-diHOME reduced Treg cells in the lung [368,369]. Comparatively, the AhR ligand tetrachlorodibenzo-p-dioxin was able to attenuate delayed-type hypersensitivity by inducing Treg cells, suppressing Th17 cells, and reversing gut microbiota dysbiosis [370]. Likewise, individuals with higher fecal SCFAs, such as butyrate and propionate, early in life had markedly decreased risk for the development of asthma and atopy [371]. Of potential therapeutic value, SCFA supplementation could modulate T cells and DCs to alleviate asthma [372]. Similarly, maternal supplementation with dietary fiber or acetate was shown to protect neonates from asthma by promoting acetylation of the Foxp3 gene [373]. Dietary fiber feeding also gave protection from food allergens via retinal dehydrogenase activity in CD103+ DCs [374]. Of note, the dietary fiber inulin was recently found to promote allergen- and helminth-induced type 2 inflammation, and this was bile-acid dependent [375]. Overall, it appears that the influence of gut microbiota on allergies is highly regulated by metabolites, but each microbial product has independent effects that can either promote or demote hypersensitivity.

7.11. Psychiatric Disorders: The Gut-Brain Axis

The aforementioned information describes the gut microbiota to influence both intraand extraintestinal diseases. One other organ that the gut microbiota can impact is the brain where a ‘stressed gut’ is becoming more recognized as a pathologic entity in several neurological disorders. For pre-term infants with immature gut microbiota, Klebsiella overgrowth is highly predictive of brain damage and is associated with a pro-inflammatory immunological tone [376]. Parkinson’s disease is marked by an accumulation of alpha-synuclein in the gut, and patients often suffer from a leaky gut due to microbiota dysbiosis with higher populations of Prevotellaceae [13]. These symptoms can be reversed by administering probiotics [377,378]. Recently, the idea that microbiota shapes mental health has started gaining traction. Taxonomic and metabolic signatures have been proposed as a biomarker for stratifying major depressive disorder into mild, moderate, and severe symptom categories [379]. Several studies studying differences in microbiota between those who are mentally healthy and those with mental health disorders, such as anxiety and/or depression, have suggested that microbial colonization before and after birth plays a major role later in life. For instance, maternal stress can induce abnormal neurodevelopment in the offspring, which has been marked by a significant reduction of Bifidobacterium spp. [380]. Moreover, neonates delivered by C-section, as opposed to vaginal birth, have a greater risk of developing psychosis later in life [377,381]. Impressively, early-life oxytocin treatment can minimize behavior deficits seen in C-section-delivered pups [382]. A cocktail of broad-spectrum, gut-microbiota-depleting antibiotics, specifically at the postnatal and weaning stages, can cause long-lasting effects of anxiety-related behavioral outcomes into adolescence and adulthood [383]. A recent elegant study by Li et al. delineated that infant exposure to antibiotics resulted in anxiety- and depression-like behaviors and memory impairments that were concurrent with an increased inflammatory milieu; similar findings were seen following long-term antibiotic treatment at the adolescent and adult stages in mice [384]. Early-life disruption of the gut microbiota could also cause sex-specific anxiety-like behavior, where LPS treatment in Wistar rats resulted in less social interaction in males compared with the females, who had an increase in social behavior [385]. It is noteworthy that FMT from an ‘aged microbiome’ to germ-free mice decreased SCFAs, and this was associated with cognitive decline [386]. The gut microbiota–immunity–brain axis is still in its nascency and requires investigation to establish mechanisms involved in immune regulation responsible for behavioral abnormalities and neurological disorders. However, it must be emphasized to look at other microorganisms besides bacteria because mucosal fungi were found to promote social behavior through complementary Th17 immune mechanisms [387].

8. Relationship between the Gut Microbiota and Their Metabolites in Immunotherapy

Presently, frontline immunotherapy treatments include T cells (checkpoint inhibitors, costimulatory receptor agonists), T cell modification, adoptive T cell transfer, autologous cytokine-induced killer cells, chimeric antigen receptor therapy, cytokines, oncolytic viruses, and vaccines [388,389]. In recent years, immunotherapy based on the application of immune checkpoint inhibitors (ICIs), including antibodies against CTLA-4, programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L1), has been approved as firstor second-line treatments in a variety of tumors [390]. In particular, ICIs that target PD-1 and its ligand PD-L1 have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of 10 different cancer types [391]. Recent studies suggest that gut microbiota could be a significant determinant of the response to cancer immunotherapy in some preclinical and clinical studies [392–394]. Matson et al. showed that Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium have higher abundance in patients responding to PD-1 inhibitors [395]. Several studies have found significant differences in the microbiomes of responders vs. non-responders to PD-1 inhibitors, including increases in Faecalibacterium, Ruminococcus, and Akkermansia in responders and increases in Bacteroides in non-responders [392,396,397]. In addition, anti-PD-1 treatment for liver cancer patients resulted in elevated Faecalibacterium abundance and better progression-free survival [398]. Additional studies have further shown that the composition of gut bacteria can influence the metabolism of certain immunotherapeutic drugs. The fecal transfer from PD-1-treated responding patients to germ-free mice enhanced T-cell responses and improved the effectiveness of PD-1 inhibitor therapy [395]. Inosine, which is produced by Bifidobacterium pseudolongum and Akkermansia muciniphila, also promoted anti-CTLA-4 and anti-PD-L1 therapy by activating T cells [213]. Comparatively, a recent study by Coutzac et al. showed that butyrate and propionate limited the efficacy of CTLA-4 inhibitors, which was associated with a higher Treg population and lower survival [399]. Of note, a newly isolated probiotic Lactobacillus strain (L. paracasei sh2020) promoted anti-PD-1 effects in CRC tumor-bearing mice by upregulating the expression of CXCL10 in the tumors and subsequently enhancing CD8+ T cell recruitment [400]. Remarkably, these anti-tumor effects occurred even in the presence of gut microbiota dysbiosis. These preclinical and clinical pieces of evidence support continued investigation to determine the requirement for gut microbiota to provide the maximum efficacy of immunotherapies (Figure 3). This includes possibly utilizing the gut microbiota to limit negative side effects from immunotherapies, such as ICI-related cardiotoxicity. Chen et al. elegantly described PD-1/PD-L1 inhibitor to deplete the Prevotellaceae and Rikenellaceae microbiota populations, reduce butyrate levels, and promote pro-inflammatory macrophage M1 polarization via downregulation of the PPARα-CYP4 × 1 axis [401]. Of therapeutic relevance, Prevotella loescheii recolonization and butyrate supplementation alleviated PD-1/PD-L1 inhibitor-related cardiotoxicity [401]. As immune checkpoints are often heterogeneous and not persistent, which can result in a lower treatment response rate, drug resistance, and adverse reactions [402–404], gut-microbiota-targeted therapies could be essential adjuvants (Figure 3). The currently approved and available IBD therapies are anti-TNF agents, anti-integrin agents, anti-β7 monoclonal antibodies, and Janus kinase (JAK) inhibitors. JAK inhibitors (e.g., baricitinib) were successful in restoring insulin signaling and improving myosteatosis following high-fat–high-sugar feeding, but they did not reverse diet-induced alterations to the gut microbiota in mice [405]. Anti-TNF inhibitors have improved clinical outcomes in both CD and UC, but they still require more randomized clinical trials [402]. However, it is notable that FMT was recently found to be a potential alternative therapy for CD patients with prior loss of response or intolerance to anti-TNF therapy (i.e., infliximab) [406]. Impressively, the probiotic Bifidobacterium longum (B. longum) CECT 7894 promoted infliximab efficacy in a mouse colitis model by reducing the abundance of opportunistic pathogens, i.e., Enterococcus and Pseudomonas, and increasing secondary bile acids [407]. Another recent study similarly found that both anti-TNF and anti-IL-12/23 therapies altered the gut microbiota to favor microbial species capable of secondary bile acid production [408]. The elevation in secondary bile acids may be due to anti-TNF treatment promoting the bloom of Clostridia spp. as part of the restoration of intestinal microbiota [409]. Bile acids are considered to be a potential metabolic biomarker for anti-TNF therapy response [410], but more research is needed to determine whether bile acids improve immunotherapy efficacy (Figure 3). There is a hint that secondary bile acids could be beneficial when considering the evidence for UDCA treatment to prevent CRC reoccurrence by inhibiting NF-κB signaling [411,412]. Moreover, UDCA was found to synergize with anti-PD1 effects to inhibit cancer progression in tumor-bearing mice [413]. Overall, it appears that the gut microbiota could be exploited as both a biomarker and therapeutic target to improve immunotherapy response.

Figure 3. Modifying the abundance of the gut microbiota population may influence the outcomes of immunotherapy. A healthy gut microbiome can increase the bioavailability and efficacy of drugs in the host. Dysbiosis, caused by several depicted factors, may decrease the efficacy of the therapeutic drugs, leading to poor therapeutic outcomes. Modifying gut microbiota could increase the effectiveness of certain immunotherapeutic drugs, such as anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-CTL4 antibody treatments. Gut microbiota can be changed by supplementation with antibiotics, probiotics, prebiotics, secondary bile acids, short-chain fatty acids (e.g., butyrate), inosine, or fecal matter transplantation.

9. Promises, Challenges, and Risks in Immune–Microbiome Research

The interplay between the microbiota and immune systems and their impact on diseases, including IBD, autoimmune arthritis, and cancer, is incredibly complex. One layer of complexity includes the challenge of showing the exact implication of a certain single or group of bacteria in the onset of disease or general host physiology. Colonization of microbes to germ-free models is a relevant strategy to better understand the potential effects of gut microorganisms in host health and disease [414]. However, the gut microbiota is much more than just a select few species. There is a strong dynamic in the microbiome environment, where species are either mutually exclusive or competitive for resources, and many microbes depend on one another for growth [415]. Another layer of complexity includes other interacting genetic and environmental factors, such as diet, smoking, drugs, and medications (Figure 2). This includes differences in the microbiota (and potentially immune responses) between urban vs. rural areas for individuals [416]. Notwithstanding, observations seen in rodent models are not always translatable to humans. It can be generally stated that humans and other mammals live in a ‘dirtier’ environment when compared with research rodents living in specific pathogen-free environments. Therefore, the cleanliness of the environment, reflecting the hygiene hypothesis, could impact the microbiota composition and disease susceptibility. This notion is supported by the recent finding that fertilized mice (animals continuously exposed to a livestock farmyard-type environment) had a more stable gut microbiota and remained resistant to mutagen- and colitis-induced neoplasia when compared with hygienically born mice [417].

Several studies focusing on microbiome–immunity research have employed 16S rRNA sequencing to characterize the microbiome, but this method has limitations in that it can successfully identify genera but cannot provide distinctions at the species level [418]. Therefore, to achieve a more inclusive study of microbiomes, it is advisable that metagenomics must be combined with other -omics approaches [419]. Most recently, metatranscriptomics and metabolomics are rapidly becoming important to microbiome studies. Metagenomics generates the taxonomical profile of the sample, metatranscriptomics obtains a functional profile, and metabolomics finalizes the depiction by determining which byproducts are released by the microbiota in the environment [419]. Though each of these -omics approaches provide valuable information by themselves, it is suggested that a more complete picture comes from combined -omics. One important benefit of these -omics approaches is that the raw files can be deposited into databases and then later mined for analysis by other research groups. One limitation that can arise when applying machine learning to compare multiple databases is the unevenness in sample size [420]. Moreover, -omics results could be considered study-specific, as it can be difficult to find overlapping patterns of gut microbiota changes between research and/or clinical studies. This is because the gut microbiota (plus their metabolites) and disease susceptibility can vary in humans depending on their geographic origin [421], and even the bacterial composition in common laboratory rodents can be different among research facilities and vendors [422]. Overall, -omics are surely advancing the biomedical field to identify potential diagnostic and therapeutic targets, but there are still some limitations to overcome.

10. Conclusions

In summary, the host immune system and the gut microbiome are heavily dependent upon each other for normal function and well-being of the host (summarized in Graphical Abstract). This review covered novel findings, including how fetal immune fitness is environmentally dependent on the maternal microbiota (healthy vs. dysbiosis or stressed). New mechanistic pathways have been discussed, such as SCFA and secondary bile acids modulating gut homeostasis by inducing Treg cells and IL-10 secretion (Figure 1A, B). Throughout the review, butyrate and its precursor dietary fiber were repeatedly mentioned to influence immune responses and act as potential therapeutics for many diseases, but some evidence suggests that their clinical practice may need to be disease-contextualized. Comparatively, probiotics and FMT look to be more promising in restoring gut microbiota eubiotics and alleviating inflammatory diseases. Moreover, gut microbiota appears to be a relevant target to improve current immunotherapies and abate their negative side effects (Figure 3). We also discussed the current challenges in microbiome research, which is essentially rooted in genetic and environmental factors (Figure 2), that make each microbiota unique among humans and when comparing species models. We posit that recent developments in multi-omics methods, including epigenomics, meta-genomics, meta-proteomics, metabolomics, culturomics, and single-cell transcriptomics, will elucidate interactions between the gut microbiome and the immune system in health and disease [423]. As such, it will be exciting to predict the ‘specific’ host immune responses based on gut microbiome profiles, which will support the development of ‘personalized microbiome-targeted’ therapy for immunologic diseases.

References

1. Donne, J. No Man Is an Island; Illustrated by Paul Peter Piech; Taurus Press: Willow Dene, UK, 1975. 

2. Beam, A.; Clinger, E.; Hao, L. Effect of Diet and Dietary Components on the Composition of the Gut Microbiota. Nutrients 2021, 13, 2795. [CrossRef] [PubMed] 

3. Shanahan, F.; Ghosh, T.S.; O0 Toole, P.W. The Healthy Microbiome-What Is the Definition of a Healthy Gut Microbiome? Gastroenterology 2021, 160, 483–494. [CrossRef] [PubMed] 

4. Valdes, A.M.; Walter, J.; Segal, E.; Spector, T.D. Role of the gut microbiota in nutrition and health. BMJ 2018, 361, k2179. [CrossRef] [PubMed] 

5. Bull, M.J.; Plummer, N.T. Part 1: The Human Gut Microbiome in Health and Disease. Integr. Med. 2014, 13, 17–22. 

6. Sacks, D.; Baxter, B.; Campbell, B.C.; Carpenter, J.S.; Cognard, C.; Dippel, D.; Eesa, M.; Fischer, U.; Hausegger, K.; Hirsch, J.A. Multisociety Consensus Quality Improvement Revised Consensus Statement for Endovascular Therapy of Acute Ischemic Stroke. Int. J. Stroke 2018, 13, 612–632. [CrossRef] 

7. Matijasic, M.; Mestrovic, T.; Paljetak, H.C.; Peric, M.; Baresic, A.; Verbanac, D. Gut Microbiota beyond Bacteria-Mycobiome, Virome, Archaeome, and Eukaryotic Parasites in IBD. Int J. Mol. Sci. 2020, 21, 2668. [CrossRef] 

8. Giuffre, M.; Campigotto, M.; Campisciano, G.; Comar, M.; Croce, L.S. A story of liver and gut microbes: How does the intestinal flora affect liver disease? A review of the literature. Am. J. Physiol. Gastrointest. Liver Physiol. 2020, 318, G889–G906. [CrossRef] 

9. Gomaa, E.Z. Human gut microbiota/microbiome in health and diseases: A review. Antonie Van Leeuwenhoek 2020, 113, 2019–2040. [CrossRef] 

10. Mills, S.; Stanton, C.; Lane, J.A.; Smith, G.J.; Ross, R.P. Precision Nutrition and the Microbiome, Part I: Current State of the Science. Nutrients 2019, 11, 923. [CrossRef] 

11. Adak, A.; Khan, M.R. An insight into gut microbiota and its functionalities. Cell. Mol. Life Sci. 2019, 76, 473–493. [CrossRef]

12. Gensollen, T.; Iyer, S.S.; Kasper, D.L.; Blumberg, R.S. How colonization by microbiota in early life shapes the immune system. Science 2016, 352, 539–544. [CrossRef] [PubMed] 

13. Giuffre, M.; Moretti, R.; Campisciano, G.; da Silveira, A.B.M.; Monda, V.M.; Comar, M.; Di Bella, S.; Antonello, R.M.; Luzzati, R.; Croce, L.S. You Talking to Me? Says the Enteric Nervous System (ENS) to the Microbe. How Intestinal Microbes Interact with the ENS. J. Clin. Med. 2020, 9, 3705. [CrossRef] 

14. Cho, Y.; Shore, S.A. Obesity, Asthma, and the Microbiome. Physiology 2016, 31, 108–116. [CrossRef] [PubMed] 

15. McComb, S.; Thiriot, A.; Akache, B.; Krishnan, L.; Stark, F. Introduction to the Immune System. Methods Mol. Biol. 2019, 2024, 1–24. [CrossRef] [PubMed] 

16. Chan, L.; Karimi, N.; Morovati, S.; Alizadeh, K.; Kakish, J.E.; Vanderkamp, S.; Fazel, F.; Napoleoni, C.; Alizadeh, K.; Mehrani, Y.; et al. The Roles of Neutrophils in Cytokine Storms. Viruses 2021, 13, 2318. [CrossRef] 

17. Dominguez-Bello, M.G.; Costello, E.K.; Contreras, M.; Magris, M.; Hidalgo, G.; Fierer, N.; Knight, R. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl. Acad. Sci. USA 2010, 107, 11971–11975. [CrossRef] 

18. Mitchell, C.M.; Mazzoni, C.; Hogstrom, L.; Bryant, A.; Bergerat, A.; Cher, A.; Pochan, S.; Herman, P.; Carrigan, M.; Sharp, K.; et al. Delivery Mode Affects Stability of Early Infant Gut Microbiota. Cell Rep. Med. 2020, 1, 100156. [CrossRef] 

19. Selma-Royo, M.; Calatayud Arroyo, M.; Garcia-Mantrana, I.; Parra-Llorca, A.; Escuriet, R.; Martinez-Costa, C.; Collado, M.C. Perinatal environment shapes microbiota colonization and infant growth: Impact on host response and intestinal function. Microbiome 2020, 8, 167. [CrossRef] 

20. Subramanian, S.; Geng, H.; Du, C.; Chou, P.M.; Bu, H.F.; Wang, X.; Swaminathan, S.; Tan, S.C.; Ridlon, J.M.; De Plaen, I.G.; et al. Feeding mode influences dynamic gut microbiota signatures and affects susceptibility to anti-CD3 mAb-induced intestinal injury in neonatal mice. Am. J. Physiol. Gastrointest. Liver Physiol. 2022, 323, G205–G218. [CrossRef] 

21. Wampach, L.; Heintz-Buschart, A.; Fritz, J.V.; Ramiro-Garcia, J.; Habier, J.; Herold, M.; Narayanasamy, S.; Kaysen, A.; Hogan, A.H.; Bindl, L.; et al. Birth mode is associated with the earliest strain-conferred gut microbiome functions and immunostimulatory potential. Nat. Commun. 2018, 9, 5091. [CrossRef] 22. Negi, S.; Hashimoto-Hill, S.; Alenghat, T. Neonatal microbiota-epithelial interactions that impact infection. Front. Microbiol. 2022, 13, 955051. [CrossRef] [PubMed] 

23. Senn, V.; Bassler, D.; Choudhury, R.; Scholkmann, F.; Righini-Grunder, F.; Vuille-Dit-Bile, R.N.; Restin, T. Microbial Colonization from the Fetus to Early Childhood-A Comprehensive Review. Front. Cell. Infect. Microbiol. 2020, 10, 573735. [CrossRef] [PubMed] 

24. Rackaityte, E.; Halkias, J.; Fukui, E.M.; Mendoza, V.F.; Hayzelden, C.; Crawford, E.D.; Fujimura, K.E.; Burt, T.D.; Lynch, S.V. Viable bacterial colonization is highly limited in the human intestine in utero. Nat. Med. 2020, 26, 599–607. [CrossRef] 

25. Li, Y.; Toothaker, J.M.; Ben-Simon, S.; Ozeri, L.; Schweitzer, R.; McCourt, B.T.; McCourt, C.C.; Werner, L.; Snapper, S.B.; Shouval, D.S.; et al. In utero human intestine harbors a unique metabolome, including bacterial metabolites. JCI Insight 2020, 5, e138751. [CrossRef] [PubMed] 

26. Jain, N. The early life education of the immune system: Moms, microbes and (missed) opportunities. Gut Microbes 2020, 12, 1824564. [CrossRef] 

27. Gierynska, M.; Szulc-Dabrowska, L.; Struzik, J.; Mielcarska, M.B.; Gregorczyk-Zboroch, K.P. Integrity of the Intestinal Barrier: The Involvement of Epithelial Cells and Microbiota-A Mutual Relationship. Animals 2022, 12, 145. [CrossRef]

28. Westrom, B.; Arevalo Sureda, E.; Pierzynowska, K.; Pierzynowski, S.G.; Perez-Cano, F.J. The Immature Gut Barrier and Its Importance in Establishing Immunity in Newborn Mammals. Front. Immunol. 2020, 11, 1153. [CrossRef] 

29. Rabe, H.; Lundell, A.C.; Sjoberg, F.; Ljung, A.; Strombeck, A.; Gio-Batta, M.; Maglio, C.; Nordstrom, I.; Andersson, K.; Nookaew, I.; et al. Neonatal gut colonization by Bifidobacterium is associated with higher childhood cytokine responses. Gut Microbes 2020, 12, 1847628. [CrossRef] 

30. Henrick, B.M.; Rodriguez, L.; Lakshmikanth, T.; Pou, C.; Henckel, E.; Arzoomand, A.; Olin, A.; Wang, J.; Mikes, J.; Tan, Z.; et al. Bifidobacteria-mediated immune system imprinting early in life. Cell 2021, 184, 3884–3898. [CrossRef] 

31. Chin, N.; Mendez-Lagares, G.; Taft, D.H.; Laleau, V.; Kieu, H.; Narayan, N.R.; Roberts, S.B.; Mills, D.A.; Hartigan-O0 Connor, D.J.; Flaherman, V.J. Transient Effect of Infant Formula Supplementation on the Intestinal Microbiota. Nutrients 2021, 13, 807. [CrossRef] 

32. Al Nabhani, Z.; Dulauroy, S.; Marques, R.; Cousu, C.; Al Bounny, S.; Dejardin, F.; Sparwasser, T.; Berard, M.; Cerf-Bensussan, N.; Eberl, G. A Weaning Reaction to Microbiota Is Required for Resistance to Immunopathologies in the Adult. Immunity 2019, 50, 1276–1288. [CrossRef] [PubMed] 

33. Roubaud-Baudron, C.; Ruiz, V.E.; Swan, A.M., Jr.; Vallance, B.A.; Ozkul, C.; Pei, Z.; Li, J.; Battaglia, T.W.; Perez-Perez, G.I.; Blaser, M.J. Long-Term Effects of Early-Life Antibiotic Exposure on Resistance to Subsequent Bacterial Infection. mBio 2019, 10, e02820-19. [CrossRef] [PubMed] 

34. Cahenzli, J.; Koller, Y.; Wyss, M.; Geuking, M.B.; McCoy, K.D. Intestinal microbial diversity during early-life colonization shapes long-term IgE levels. Cell Host Microbe 2013, 14, 559–570. [CrossRef] [PubMed] 

35. El Aidy, S.; Hooiveld, G.; Tremaroli, V.; Backhed, F.; Kleerebezem, M. The gut microbiota and mucosal homeostasis: Colonized at birth or adulthood, does it matter? Gut Microbes 2013, 4, 118–124. [CrossRef] 

36. Wang, C.; Li, Q.; Ren, J. Microbiota-Immune Interaction in the Pathogenesis of Gut-Derived Infection. Front. Immunol. 2019, 10, 1873. [CrossRef] 

37. McGuckin, M.A.; Linden, S.K.; Sutton, P.; Florin, T.H. Mucin dynamics and enteric pathogens. Nat. Rev. Microbiol. 2011, 9, 265–278. [CrossRef] 

38. Mogensen, T.H. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin. Microbiol. Rev. 2009, 22, 240–273. [CrossRef] 

9. Minarrieta, L.; Ghorbani, P.; Sparwasser, T.; Berod, L. Metabolites: Deciphering the molecular language between DCs and their environment. Semin. Immunopathol. 2017, 39, 177–198. [CrossRef] 

40. Levy, M.; Kolodziejczyk, A.A.; Thaiss, C.A.; Elinav, E. Dysbiosis and the immune system. Nat. Rev. Immunol. 2017, 17, 219–232. [CrossRef] 

41. Morikawa, M.; Tsujibe, S.; Kiyoshima-Shibata, J.; Watanabe, Y.; Kato-Nagaoka, N.; Shida, K.; Matsumoto, S. Microbiota of the Small Intestine Is Selectively Engulfed by Phagocytes of the Lamina Propria and Peyer0 s Patches. PLoS ONE 2016, 11, e0163607. [CrossRef] 

42. Kohler, A.; Delbauve, S.; Smout, J.; Torres, D.; Flamand, V. Very early-life exposure to microbiota-induced TNF drives the maturation of neonatal pre-cDC1. Gut 2021, 70, 511–521. [CrossRef] [PubMed] 

43. Johansson, M.E.; Hansson, G.C. Immunological aspects of intestinal mucus and mucins. Nat. Rev. Immunol. 2016, 16, 639–649. [CrossRef] [PubMed] 

44. Humayun, M.; Ayuso, J.M.; Park, K.Y.; Martorelli Di Genova, B.; Skala, M.C.; Kerr, S.C.; Knoll, L.J.; Beebe, D.J. Innate immune cell response to host-parasite interaction in a human intestinal tissue microphysiological system. Sci. Adv. 2022, 8, eabm8012. [CrossRef] [PubMed] 

45. Artis, D.; Spits, H. The biology of innate lymphoid cells. Nature 2015, 517, 293–301. [CrossRef] [PubMed] 

46. Lankelma, J.M.; van Vught, L.A.; Belzer, C.; Schultz, M.J.; van der Poll, T.; de Vos, W.M.; Wiersinga, W.J. Critically ill patients demonstrate large interpersonal variation in intestinal microbiota dysregulation: A pilot study. Intensive Care Med. 2017, 43, 59–68. [CrossRef] 

47. Fournier, B.M.; Parkos, C.A. The role of neutrophils during intestinal inflammation. Mucosal Immunol. 2012, 5, 354–366. [CrossRef] 

48. Loh, J.T.; Lee, K.G.; Lee, A.P.; Teo, J.K.H.; Lim, H.L.; Kim, S.S.; Tan, A.H.; Lam, K.P. DOK3 maintains intestinal homeostasis by suppressing JAK2/STAT3 signaling and S100a8/9 production in neutrophils. Cell Death Dis. 2021, 12, 1054. [CrossRef] 

49. Seo, D.H.; Che, X.; Kim, S.; Kim, D.H.; Ma, H.W.; Kim, J.H.; Kim, T.I.; Kim, W.H.; Kim, S.W.; Cheon, J.H. Triggering Receptor Expressed on Myeloid Cells-1 Agonist Regulates Intestinal Inflammation via Cd177(+) Neutrophils. Front. Immunol. 2021, 12, 650864. [CrossRef] 

50. Vong, L.; Yeung, C.W.; Pinnell, L.J.; Sherman, P.M. Adherent-invasive Escherichia coli Exacerbates Antibiotic-associated Intestinal Dysbiosis and Neutrophil Extracellular Trap Activation. Inflamm. Bowel Dis. 2016, 22, 42–54. [CrossRef] 

51. Delano, M.J.; Ward, P.A. The immune system's role in sepsis progression, resolution, and long-term outcome. Immunol. Rev. 2016, 274, 330–353. [CrossRef] 

52. Apostolov, A.K.; Hamani, M.; Hernandez-Vargas, H.; Igalouzene, R.; Guyennon, A.; Fesneau, O.; Marie, J.C.; Soudja, S.M. Common and Exclusive Features of Intestinal Intraepithelial gammadelta T Cells and Other gammadelta T Cell Subsets. Immunohorizons 2022, 6, 515–527. [CrossRef] [PubMed]

53. Ismail, A.S.; Severson, K.M.; Vaishnava, S.; Behrendt, C.L.; Yu, X.; Benjamin, J.L.; Ruhn, K.A.; Hou, B.; DeFranco, A.L.; Yarovinsky, F.; et al. Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc. Natl. Acad. Sci. USA 2011, 108, 8743–8748. [CrossRef] 

54. Holtmeier, W.; Kabelitz, D. Gammadelta T cells link innate and adaptive immune responses. Chem. Immunol. Allergy 2005, 86, 151–183. [CrossRef] 

55. Tyler, C.J.; McCarthy, N.E.; Lindsay, J.O.; Stagg, A.J.; Moser, B.; Eberl, M. Antigen-Presenting Human gammadelta T Cells Promote Intestinal CD4(+) T Cell Expression of IL-22 and Mucosal Release of Calprotectin. J. Immunol. 2017, 198, 3417–3425. [CrossRef] [PubMed]

56. Li, Y.; Wang, Y.; Shi, F.; Zhang, X.; Zhang, Y.; Bi, K.; Chen, X.; Li, L.; Diao, H. Phospholipid metabolites of the gut microbiota promote hypoxia-induced intestinal injury via CD1d-dependent gamma delta T cells. Gut Microbes 2022, 14, 2096994. [CrossRef] [PubMed] 

57. Tomasello, E.; Bedoui, S. Intestinal innate immune cells in gut homeostasis and immunosurveillance. Immunol. Cell Biol. 2013, 91, 201–203. [CrossRef] [PubMed] 

58. Grimaldi, D.; Le Bourhis, L.; Sauneuf, B.; Dechartres, A.; Rousseau, C.; Ouaaz, F.; Milder, M.; Louis, D.; Chiche, J.D.; Mira, J.P.; et al. Specific MAIT cell behavior among innate-like T lymphocytes in critically ill patients with severe infections. Intensive Care Med. 2014, 40, 192–201. [CrossRef] 

59. Andreu-Ballester, J.C.; Tormo-Calandin, C.; Garcia-Ballesteros, C.; Perez-Griera, J.; Amigo, V.; Almela-Quilis, A.; Ruiz del Castillo, J.; Penarroja-Otero, C.; Ballester, F. Association of gamma delta T cells with disease severity and mortality in septic patients. Clin. Vaccine Immunol. 2013, 20, 738–746. [CrossRef] 

60. Noble, A.; Pring, E.T.; Durant, L.; Man, R.; Dilke, S.M.; Hoyles, L.; James, S.A.; Carding, S.R.; Jenkins, J.T.; Knight, S.C. Altered immunity to microbiota, B cell activation and depleted gamma-delta/resident memory T cells in colorectal cancer. Cancer Immunol. Immunother. 2022, 71, 2619–2629. [CrossRef] 

61. Suzuki, H.; Jeong, K.I.; Itoh, K.; Doi, K. Regional variations in the distributions of small intestinal intraepithelial lymphocytes in germ-free and specific pathogen-free mice. Exp. Mol. Pathol. 2002, 72, 230–235. [CrossRef] 

62. Bedoui, S.; Heath, W.R.; Mueller, S.N. CD4(+) T-cell help amplifies innate signals for primary CD8(+) T-cell immunity. Immunol. Rev. 2016, 272, 52–64. [CrossRef] [PubMed] 

63. Belz, G.T.; Shortman, K.; Bevan, M.J.; Heath, W.R. CD8alpha+ dendritic cells selectively present MHC class I-restricted noncytolytic viral and intracellular bacterial antigens in vivo. J. Immunol. 2005, 175, 196–200. [CrossRef] [PubMed] 

64. Sztein, M.B.; Bafford, A.C.; Salerno-Goncalves, R. Salmonella enterica serovar Typhi exposure elicits ex vivo cell-type-specific epigenetic changes in human gut cells. Sci. Rep. 2020, 10, 13581. [CrossRef] 

65. Becattini, S.; Littmann, E.R.; Seok, R.; Amoretti, L.; Fontana, E.; Wright, R.; Gjonbalaj, M.; Leiner, I.M.; Plitas, G.; Hohl, T.M.; et al. Enhancing mucosal immunity by transient microbiota depletion. Nat. Commun. 2020, 11, 4475. [CrossRef] 

66. De Wit, J.; Souwer, Y.; Jorritsma, T.; Klaasse Bos, H.; ten Brinke, A.; Neefjes, J.; van Ham, S.M. Antigen-specific B cells reactivate an effective cytotoxic T cell response against phagocytosed Salmonella through cross-presentation. PLoS ONE 2010, 5, e13016. [CrossRef] [PubMed] 

67. Schnell, A.; Huang, L.; Singer, M.; Singaraju, A.; Barilla, R.M.; Regan, B.M.L.; Bollhagen, A.; Thakore, P.I.; Dionne, D.; Delorey, T.M.; et al. Stem-like intestinal Th17 cells give rise to pathogenic effector T cells during autoimmunity. Cell 2021, 184, 6281–6298.e23. [CrossRef] 

68. Omenetti, S.; Bussi, C.; Metidji, A.; Iseppon, A.; Lee, S.; Tolaini, M.; Li, Y.; Kelly, G.; Chakravarty, P.; Shoaie, S.; et al. The Intestine Harbors Functionally Distinct Homeostatic Tissue-Resident and Inflammatory Th17 Cells. Immunity 2019, 51, 77–89. [CrossRef] 69. Ivanov, I.I.; Atarashi, K.; Manel, N.; Brodie, E.L.; Shima, T.; Karaoz, U.; Wei, D.; Goldfarb, K.C.; Santee, C.A.; Lynch, S.V.; et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009, 139, 485–498. [CrossRef] 

70. Tan, T.G.; Sefik, E.; Geva-Zatorsky, N.; Kua, L.; Naskar, D.; Teng, F.; Pasman, L.; Ortiz-Lopez, A.; Jupp, R.; Wu, H.J.; et al. Identifying species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in mice. Proc. Natl. Acad. Sci. USA 2016, 113, E8141–E8150. [CrossRef] 

71. Sano, T.; Kageyama, T.; Fang, V.; Kedmi, R.; Martinez, C.S.; Talbot, J.; Chen, A.; Cabrera, I.; Gorshko, O.; Kurakake, R.; et al. Redundant cytokine requirement for intestinal microbiota-induced Th17 cell differentiation in draining lymph nodes. Cell Rep. 2021, 36, 109608. [CrossRef] 

72. Irons, E.E.; Cortes Gomez, E.; Andersen, V.L.; Lau, J.T.Y. Bacterial colonization and TH17 immunity are shaped by intestinal sialylation in neonatal mice. Glycobiology 2022, 32, 414–428. [CrossRef] [PubMed] 

73. Alexander, M.; Ang, Q.Y.; Nayak, R.R.; Bustion, A.E.; Sandy, M.; Zhang, B.; Upadhyay, V.; Pollard, K.S.; Lynch, S.V.; Turnbaugh, P.J. Human gut bacterial metabolism drives Th17 activation and colitis. Cell Host Microbe 2022, 30, 17–30. [CrossRef] [PubMed] 

74. Brennan, C.A.; Clay, S.L.; Lavoie, S.L.; Bae, S.; Lang, J.K.; Fonseca-Pereira, D.; Rosinski, K.G.; Ou, N.; Glickman, J.N.; Garrett, W.S. Fusobacterium nucleatum drives a pro-inflammatory intestinal microenvironment through metabolite receptor-dependent modulation of IL-17 expression. Gut Microbes 2021, 13, 1987780. [CrossRef] [PubMed] 

75. Malchow, S.; Leventhal, D.S.; Lee, V.; Nishi, S.; Socci, N.D.; Savage, P.A. Aire Enforces Immune Tolerance by Directing Autoreactive T Cells into the Regulatory T Cell Lineage. Immunity 2016, 44, 1102–1113. [CrossRef] 

76. Yang, S.; Fujikado, N.; Kolodin, D.; Benoist, C.; Mathis, D. Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science 2015, 348, 589–594. [CrossRef]