The Role Of Gut Microbiota And Metabolites in Regulating The Immune Response in Drug-induced Enteritis

Abstract 

Drug-induced enteritis is an inflammatory disease that changes the morphology and function of the intestine as a result of medicine damage. With the increase in drug abuse in recent years, the incidence of drug-associated enteritis accordingly rises and becomes an important disease affecting the health and life quality of patients. Hence, elucidating the pathogenesis of drug-induced enteritis and finding cost-effective diagnostic and therapeutic tools have become current research focuses. The gut microbiota and metabolites regulate the immune response, playing a key role in the maintenance of homeostasis in the intestine. Numerous studies have found that many medicines can induce intestinal flora disorders, which are closely related to the development of drug-induced enteritis. Therefore, this paper analyses the role of gut microbiota and metabolites in regulating the immune response, and provides basic research direction and clinical reference strategies for drug-induced enteritis, taking into account the existing applications and perspectives.

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Keywords: drug-induced enteritis, gut microbiota, microbiota metabolites, innate immunity, acquired immunity 

Introduction 

Drug-induced enteritis is a morphological and functional alteration of the intestine following exposure to some pharmacological compound (Hamdeh et al. 2021b), clinical manifestations include diarrhea, vomiting, constipation, weight loss, mucosal bleeding or anemia, and in severe cases, stricture, perforation, shock, and even death (Brechmann et al. 2019). In the past, the threat of drug-induced enteritis to population health was often overlooked, but it is gradually gaining widespread attention as the incidence rises. The prevalence of antibiotic-associated diarrhea has been reported to be 23% in children (Guo et al. 2019) and 25% in adults (Ouwehand et al. 2014). Pittman et al. (2017) identified that 33% of renal transplant recipients had drug-induced enteritis, mainly mycophenolate mofetil (MMF) colitis. The incidence of small bowel mucosal rupture was as high as 51% in those taking long-term nonsteroidal anti-inflammatory drugs (NSAIDs) (Hara et al. 2018). Given the increasingly widespread use of medications, drug-induced enteritis has become an essential area of research. Facing drug-associated enterocolitis, the nonspecific clinical presentation and the identification of the causative drug pose a challenge to diagnose. Despite the convenience of discontinuation tests, when symptoms persist, clinicians may attempt to experiment with unpopular and expensive tools such as markers of inflammation and permeability testing (Grattagliano et al. 2018). For therapy, there are drawbacks to the existing corticosteroids, biologics, and surgical treatments (Chen et al. 2021). In-depth research on the pathogenic mechanisms of drug-associated enterocolitis will help to develop more economical, safe, and effective diagnostic and therapeutic strategies, which have made considerable progress in recent years. Studies have provided evidence that the interaction between intestinal flora and medications plays a key role in the development of drug-induced enteritis. The gut microbiota maintains intestinal homeostasis through dynamic interactions with the host's innate and adaptive immune systems. However, drugs can induce immune dysregulation by altering the composition and function of the intestinal flora, which in turn causes intestinal inflammation and tissue damage (Grattagliano et al. 2018, Maseda and Ricciotti 2020). Therefore, this paper aims to discuss the mechanism of gut microbiota regulation of intestinal immune response in drug-induced enteritis and the related application of research advances to provide theoretical support for further research. 

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Gut microbiota modulates the intestinal immune response 

The gut microbiota consists of ∼100 trillion microorganisms, including bacteria, viruses, fungi, and protozoa, which primarily function in nutrient metabolism, substance synthesis, and biological barriers (Di Tommaso et al. 2021) and live in mutually beneficial symbiosis with their hosts in immune, metabolic, endocrine, and neurological terms (Riccio and Rossano 2020). The intestinal immune system is mainly composed of the gut flora, specialized epithelial cells, mesenteric lymph nodes, innate and adaptive immune cells, and associated metabolites (Vancamelbeke and Vermeire 2017).

Abundant research evidence suggests that gut microbiota plays a crucial part in intestinal immune system regulation (Nagao-Kitamoto et al. 2020). 

Gut microbiota and metabolites in innate immunity 

Short-chain fatty acids (SCFAs) 

SCFAs are the most abundant derived metabolites in the intestinal lumen, which are produced by anaerobic fermentation of the gut microbiota, including acetate, propionate, butyrate, etc (Yoo et al. 2020). In innate immunity, SCFAs inhibit the expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor- α (TNF-α), and interleukin-6 (IL-6) in macrophages by activating G protein-coupled receptors (GPCRs) (Li et al. 2018, He et al. 2020a). On the other hand, SCFAs induce the release of prostaglandin E2 and IL-10 from monocytes and suppress monocyte chemotactic protein-1 (MCP-1) expression, which together counteracts the inflammatory response (Parada Venegas et al. 2019). Zhang et al. (2016) found that butyrate enhanced IL-6 and TNF-α promoter acetylation through the inhibitory effect on histone deacetylases (HDACs), thereby reducing RNA polymerase II binding to the promoter, and inhibiting cytokine synthesis in mast cells. In a GPR43-dependent way, SCFAs promote the expression of regenerate islet-derived protein IIIγ (RegIIIγ ) and β-defensins in mouse intestinal epithelial cells (IECs) via the mechanistic target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3) signaling pathways, thereby limiting bacterial invasion and maintaining mucosal homeostasis (Zhao et al. 2018). Zheng et al. (2017) demonstrated that butyrate activates STAT3 in an IL-10 receptor-dependent manner, which in turn downregulates the expression of the tight junction protein claudin2 (CLDN2) and reduces epithelial permeability. By directly inhibiting the prolyl hydroxylase domPh.D. (Ph.D.), SCFAs promote stable expression hypoxia-induciblecible factor-1α (HIF-1αIEC IECs, for the regulation of genes such as CLDN1 and mucin 2 (MUC2) to enhance intestinal barrier function (Wang et al. 2021a). In addition, SCFAs also regulate the transcription of mucin genes in goblet cells to promote the production of the mucus layer (Rooks and Garrett 2016). 

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Tryptophan metabolites 

As an essential amino acid, tryptophan can be converted by intestinal flora into metabolites such as tryptamine and indole, which in turn participate in the regulation of body functions (Gasaly et al. 2021). By activating the aryl hydrocarbon receptor (AhR), tryptophan metabolites not only reduce mRNA levels of TNF-α and IL-8 in IECs, and increase the abundance of tight junction proteins (Liang et al. 2018), but also drive the secretion of IL-22 by group 3 innate lymphoid cells (ILC3s), which together maintain intestinal homeostasis (Shinde and McGaha 2018). The study by Alexeev et al. (2018) also demonstrated that indolepropionic acid (IPA) exerts anti-inflammatory effects through intestinal epitheIL-10L- 10 signaling in an AhR-dependent manner. IPA also promotes intestinal barrier integrity by activating the pregnane X receptor (PXR), downregulating intestinal epithelial TNF-α expression, and enhancing tight junctions (Venkatesh et al. 2014). Secondary bile acids (SBA) Bile acids (BA) are produced from cholesterol in the liver and modified by the gut microbiota to produce SBA, such as deoxycholic acid (DCA) and lithocholic acid (LCA), which in turn play key roles in physiological regulation (Kiriyama and Nochi 2021). SBA promotes macrophage polarization from M1 to M2 type by activating GPR131 and decreases the expression of proinflammatory genes such as gamma interferon (IFN-γ ) and IL-1β (Biagioli et al. 2017). In addition, SBA can reduce IL-6 expression in macrophages in the farnesoid X receptor (FXR)-dependent manner (Kiriyama and Nochi 2021). DCA and LCA maintain epithelial barrier integrity by activating FXR to increase the expression of antimicrobial peptides in IEC (Ding et al. 2015) (Fig. 1). 

Gut microbiota and metabolites in acquired immunity

SCFAs

In acquired immunity, butyrate can upregulate forkhead box p3 (Foxp3) expression and promote regulatory T (Tcellcells differentiation by enhancing histone H3 acetylation in T cells (Sugihara and Kamada 2021). Through the inhibitory effect on HDACs, SCFAs significantly increase transforming growth factor β1 (TGFβ1) expression in IECs by specificity protein 1 (SP1) transcription factor in a GPR43-dependent manner, thereby promoting the accumulation and differentiation of Treg cells in the intestine (Martin-Gallausiaux et al. 2018, Martin-Gallausiaux et al. 2021). SCFAs also induced the expression of IL-10 and aldehyde dehydrogenase 1a1 (Aldh1a1) in intestinal macrophages and dendritic cells (DCs) through GPR109a, thereby promoting the differentiation of T cells into Treg cells and inhibiting Th17 cell development (Singh et al. 2014). Moreover, for Th17 cells, valeric acid not only promotes increased IL-10 secretion by mediating the enhancement of glycolysis but also exerts HDAC inhibitory activity to reduce IL-17a expression, which helps maintain intestinal homeostasis (Luu et al. 2019). Butyrate activates STAT3 and mTOR pathways mediated by PR43 and upregulates B lymphocyte-induced maturation protein 1 (Blimp-1) expression in Th1 cells, which in turn promotes IL-10 secretion and inhibits inflammatory drive in Th1 cells (Sun et al. 2018). Kim et al. (2016) showed that SCFAs can significantly increase acetyl coenzyme A levels and mitochondrial mass in B cells, then promote palmitic acid synthesis and increase levels of cellular metabolism to support B cell activation and antibody production. This is partly done through the mTOR pathway. SCFAs also upregulated the expression of genes such as Xbp1, Irf4, and Aicda to promote B cell differentiation (Zhang et al. 2019). Wu et al. (2017) demonstrated that the binding of acetate to GPR43 in DCs is critical for driving immunoglobulin A (IgA) production in B cells. Luu et al. (2019) found that valerate not merely significantly inhibited the apoptosis of regulatory B (Breg) cells, but induced IL-10 secretion from Breg cells to exert anti-inflammatory effects, the mechanism of which is thought to be related to enhanced glycolysis and activation of p38 mitogen-activated protein kinase (p38 MAPK). 

Tryptophan metabolites

Cervantes-Barragan et al. (2017) found that the symbiotic bacterium Lactobacillus uses tryptophan metabolites to activate AhR in CD4+ T cells, which in turn downregulates the transcription factor ThPOK, induces CD4+CD8αα+ doublepositive intraepithelial T cells to maintain intestinal homeostasis. Tryptophan metabolites also promote IL-22 transcription in T cells through the activation of AhR, maintaining mucosal integrity (Gasaly et al. 2021). In addition, IPA can promote Type 1 regulatory T (cell-cell differentiation, which in turn secretes high levels of IL-10 (Aoki et al. 2018). Indole-3-lactic acid induces anti-inflammatory effects by inhibiting the polarization of proinflammatory Th17 cells in an AhR-activating manner (Wilck et al. 2017). Similar to binding to AhR, kynurenine promotes T cell differentiation to CD25+FoxP3+ T cells (Mezrich et al. 2010). Moreover, tryptophan metabolites can induce B-cell differentiation in a GPR35-dependent way, thereby promoting antibody secretion (Wang et al. 2019a). 

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SBA 

Hang et al. (2019) and Paik et al. demonstrated that 3- oxoLCA and isoLCA inhibited the differentiation of proinflammatory Th17 cells by binding to the retinoid-related orphan receptor-γ t(RORγ t), which in turn reduces IL-17a production, attenuating intestinal inflammation (Paik et al. 2022). The binding of the isoDCA to FXR in DCs not only reduces the immunostimulatory properties of DCs but enhances cell-cell production, thereby balancing the immune response (Campbell et al. 2020). The isoalloLCA also enhances Treg cell differentiation by generating mitochondrial reactive oxygen species (Hang et al. 2019). In contrast, by studying genetically defective mice, Song et al. (2020) found that the SBA Vitamin D Receptor axis is critical for regulating the homeostasis of RORγ + Tregs in the intestine, but is not associated with the regulation of Foxp3+ Tregs. Moreover, DCA inhibits NF-κB activation in DCs by GPR131, which in turn inhibits the expression of proinflammatory genes, including IL-1, IL-6, and TNF-α (Hu et al. 2021).

Figure 1. Gut microbiota and metabolites in innate immunity. Crosstalk between the intestinal flora and the innate immune system can be mediated by metabolites of the flora as well as IECs and immune cells. SCFAs can bind to GPCRs to regulate the secretion of anti-inflammatory substances such as β-defensins, and inflammatory substances, including TNF-α by IECs and immune cells. In addition, SCFAs modulate IECs through multiple signaling pathways to promote mucus layer production. SBA regulates the expression of immune substances, such as antimicrobial peptides, by macrophages and IECs through binding to GPR131 and FXR. Tryptophan metabolites modulate the secretion of immune substances such as IL-22 by IECs and ILC3s through binding to PXR and AhR. IECs: Intestinal epithelial cells; SCFAs: Short-chain fatty acids; GPCRs: G protein-coupled receptors; IL: Interleukin; TNF-α: Tumor necrosis factor-α; SBA: Secondary bile acids; FXR: Farnesoid X receptor; ILC3s: 3 innate lymphoid cells; PXR: Pregnane X receptor; AhR: Aryl hydrocarbon receptor.

The components of the flora 

Apart from metabolites, components of the flora itself also are involved in the regulation of intestinal immunity. Bacterial flagellin can activate toll-like receptor 5 (TLR5), which leads to the differentiation of B lymphocytes to produce IgA to neutralize pathogen activity and prevent infection (Yoo et al. 2020). Lipopolysaccharide (LPS) from Bacteroides vulgatus stimulates IL-10 secretion by macrophages for anti-inflammatory activity (Di Lorenzo et al. 2020). Besides, polysaccharide A (PSA) of the Bacteroides fragilis can induce differentiation of human T cells into Tr1 cells, which in turn promotes IL-10 expression to maintain intestinal homeostasis (Arnolds et al. 2022). Exopolysaccharide (EPS) from Bacillus subtilis extensively inhibits T cell activation and thus regulates T cell-mediated inflammatory responses (Jenab et al. 2020). Clostridium butyricum cell wall component peptidoglycan (PGN) induces TGFβ1 expression in DCs via the TLR2-mediated ERK pathway, promoting Treg cells production in the intestine, and autocrine TGFβ-Smad3 signaling further promotes TGFβ expression (Kashiwagi et al. 2015) (Fig. 2).

Figure 2. Gut microbiota and metabolites in acquired immunity. Crosstalk between the intestinal flora and the acquired immunity system can be mediated by the flora and its metabolites, as well as immune cells. The components of the flora, such as flagellin, can regulate immune cells and promote the secretion of antibodies, IL-10, and so on, through binding to TLRs. The metabolites of the flora, like SCFAs, can bind to GPCRs to activate various signaling pathways that promote the secretion of immune substances such as IL-10 and activate immune cells. Tryptophan metabolites regulate immune cells such as B cells and T cells by binding to GPR35 and AhR, promoting the secretion of anti-inflammatory mediators and antibodies such as IL-10. SBA inhibits the secretion of inflammatory mediators such as IL-6 by binding to receptors such as FXR, promoting Treg cell generation, and suppressing Th17 cells. TLR: Toll-like receptor; IL: Interleukin; SCFAs: Short-chain fatty acids; GPCRs: G protein-coupled receptors; SBA: Secondary bile acids; FXR: Farnesoid X receptor; AhR: Aryl hydrocarbon receptor.

Drug-induced enteritis 

The pathophysiology of drug-induced enteritis is rather complex and multifactorial, for example, direct cytotoxicity, alterations in prostaglandin synthesis, and intestinal immune activation (Hamdeh et al. 2021a). With making clear that the stability of gut flora is essential for the maintenance of intestinal immune homeostasis, the induction of intestinal flora disorders by drugs has gained particular interest. Gut microbiota disorders are changes in the composition and function of the gut microbiota that have deleterious effects on host health through changes in the quality and quantity of the gut microbiota itself, its metabolic activity, and local distribution (Yoo et al. 2020), such as increased host susceptibility to various immune, inflammatory, and allergic diseases of the intestine and distal organs (Wang et al. 2019b). This is characterized by the proliferation of pathogenic bacteria, the loss of symbionts, and the loss of diversity (Levy et al. 2017). Disturbances in the gut microbiota and the consequent dysregulation of intestinal immunity have been supposed to play an important role in the development of drug-induced enteritis. Next, the pathogenic mechanisms by which the common causative drugs of drug-induced enteritis cause disruption of the gut microbiota, leading to dysregulation of the intestinal immune system and consequent damage to the gut, will be discussed separately. 

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Antibiotics 

As one of the most common causative agents of drug-induced enteritis, the upregulation of antibiotic-resistance genes and the emergence of resistant strains of bacteria caused by antibiotics are a major public health concern for researchers (Grattagliano et al. 2018). In particular, the horizontal transfer of resistance genes is more common in the treatment of broad-spectrum antibiotics, predisposing high-density drug-resistant pathogenic bacteria to colonize and grow in the gut (Andremont et al. 2021), causing immune dysregulation and promoting intestinal inflammation. As one of the common resistant pathogens in antibiotic-associated enteritis (Frieri et al. 2017), Clostridium difficile can produce toxins such as TcdA and TcdB, disrupt tight junctions and induce apoptosis in IECs, and promote the release of inflammatory mediators such as TNF-α, IL-1β, IL-6, and IL-8 from macrophages and monocytes, and induce neutrophil infiltration (Chandrasekaran and Lacy 2017, Yoo et al. 2020), leading to the development of complications such as diarrhea, pseudomembranous colitis, toxic megacolon, and even death (Srisajjakul et al. 2022).

Besides all of the above, antibiotics can induce inflammatory damage to the intestine by causing loss of normal flora diversity and dysbiosis. Kim et al. (2021) showed that vancomycin reduced the relative abundance of Bacteroidetes and Firmicutes, and increased the relative abundance of Proteobacteria and Fusobacteria. This will lead to a reduction in SCFAs, particularly propionate, which in turn reduces the inhibitory effect on HDACs, promotes IL-17 secretion by γ δ T cells, and drives the inflammatory process (Dupraz et al. 2021). Abt et al. (2016) found that ampicillin reduces the level of IL-22 secretion in mouse ILCs by disrupting the microbiota, and then reduces RegIIIγ expression and impaired intestinal barrier function. Another study evaluated the gut microbiota of adults with a 1-week amoxicillin-clavulanic acid intervention and found a significant increase in the abundance of Porphyromonadaceae (MacPherson et al. 2018), which promoted elevated levels of LPS and butyrate, causing increased IL-6 and IL-1β secretion and IEC damage (Okumura et al. 2021, Si et al. 2021), leading to diarrhea-like defecation events (MacPherson et al. 2018). Strati et al. (2021) demonstrated that in vitro involved co-culture of human intestinal lamina propria mononuclear cells and iNKT cell clones from inflammatory bowel disease patients with vancomycin-pretreated sterile fecal water (FW) revealed a Th1/Th17 skewing in CD4 + T-cell populations; on the other hand, metronidazole caused the polarization of iNKT cells toward the production of IL10. They finally concluded that diverse antibiotic treatments could affect the ability of the gut microbiota to control intestinal inflammation by altering the structure of the microbial community and microbiota metabolites. Metronidazole causes a reduction in Bacteroidetes and decreases acetate and butyrate levels, which in turn leads to reduced expression of Muc2, intestinal trefoil factor 3 (TFF3), and resistin-like molecule β (Relmβ) in goblet cells, causing thinning of the inner mucus layer and disrupting intestinal barrier function (Wlodarska et al. 2011). Streptomycin can increase mucosal inflammatory tension (Litvak et al. 2018) by decreasing Firmicutes abundance and reducing fermentation product production to inhibit peroxisome proliferator-activated receptor-γ (PPAR-γ ) signaling (Byndloss et al. 2017), disrupting epithelial hypoxia, and reducing Treg cells numbers. Moreover, increased epithelial oxygenation promotes the secretion of immune molecules such as reactive oxygen species or nitrates, which exert oxidative stress on the flora and are even used by specific pathogens to colonize (Reese et al. 2018) and exacerbate the development of drug-induced enteritis.

NSAIDs 

As one of the most commonly used drugs in clinical, NSAIDs can cause a range of gastrointestinal adverse effects, including bleeding, ulceration, and perforation (Chao et al. 2020, Cho et al. 2021). In recent years, numerous studies have shown that intestinal flora plays an important role in the process (Maseda and Ricciotti 2020). Colucci et al. (2018) showed that diclofenac exacerbates inflammation by promoting PGN and lipoteichoic acid binding to TLR-2 through modulating gram-positive bacteria, which activates MyD88-dependent NF-κB signaling and releases TNF-α and IL-6. In addition, diclofenac significantly reduces Lactobacillus and decreases the expression of occludin, impairing the protective effect of the intestinal barrier (Liu et al. 2014, Colucci et al. 2018). Indomethacin drives drug-induced enterocolitis by inducing the overgrowth of gram-negative bacteria, promoting LPS binding to TLR4 to activate nod-like receptor protein 3 (NLRP3), leading to the release of proinflammatory cytokines such as TNF-α and IL-1β, and inducing neutrophil infiltration (Teran-Ventura et al. 2014, Higashimori et al. 2016). Maseda et al. (2019) found that indomethacin can cause an increase in Bacteroides, Akkermansia, and Parasutterella, and a decrease in Turicibacter and Porphyromonadaceae, which weakened the colonization resistance to pathogenic bacteria such as C. difficile, thereby exacerbating the imbalance in intestinal homeostasis. By inducing the decrease in Clostridiales, indomethacin can cause a reduced secretion of butyric acid, fecal mucin, and IgA levels, which in turn impair intestinal barrier function (Kawashima et al. 2020). These SCFAs such as acetic acid and butyric acid were probably produced in the procedure of Clostridiales order as good bacteria in the gut breaking down digestion-resistant saccharides. In addition, indomethacin can cause excessive proliferation of enterococci, which secrete β- glucuronidase (GUS) and thus promote the process of hepatically modified indomethacin metabolites, increasing drug exposure in the intestinal mucosa, and aggravating inflammatory damage (Mayo et al. 2016, Wang et al. 2021b). 

MMF 

As an immunosuppressive drug, MMF is widely used in bone marrow and solid organ transplants, and various autoimmune diseases (Farooqi et al. 2020). Data suggest that patients on MMF can exhibit constipation (38%), diarrhea (45%), and colitis (9%) (Farooqi et al. 2020). Although the underlying mechanisms have not been elucidated, studies have found that the enterotoxicity of MMF requires the gut microbiota to initiate and maintain it (Flannigan et al. 2018). MMF causes a decrease in the abundance of Bacteroidetes and Firmicutes (Jardou et al. 2021), which in turn reduces the production of SCFAs, lessens the inhibitory effect on HDACs, increases the expression of IL-6 and IL-12 in local macrophages and DCs, promotes inflammatory processes, and tissue damage, causing complications such as weight loss, diarrhea, and colitis (Flannigan et al. 2018, Hosseinkhani et al. 2021). In addition, MMF can be involved in gene enrichment for LPS biosynthesis (Flannigan et al. 2018). Increased intestinal LPS levels not only activate TLR4 to enhance NF-κB signaling pathway activation and promote the secretion of TNF-α and IL-1β (O'Mahony et al. 2022), but also disrupt tight junctions or increase intestinal epithelial permeability, compromising mucosal barrier function (Justino et al. 2020). Taylor et al. (2019) found that MMF selectively promoted the enrichment of GUS gene-expressing bacteria in the mouse intestine (Zhang et al. 2021). In contrast, GUS regenerates mycophenolic acid (MPA) by cleaving the MMF metabolite mycophenolic acid glucuronide (MPAG), thereby prolonging the half-life of MPA and increasing the intestinal exposure of MPA (Jia et al. 2018, Baghai Arassi et al. 2020). MPA can inhibit intestinal fluid absorption interrupt epithelial cell replication, and can even impair overall intestinal barrier function by disrupting tight junction function and inducing massive cell apoptosis, thereby inducing intestinal inflammation (Bentata 2020).

Proton pump inhibitor (PPI) 

The safety of PPIs, which are commonly applied for the treatment of gastric acid-related disorders, has recently been questioned. Despite being used to alleviate gastrointestinal side effects caused by NSAIDs, PPIs have been found to exacerbate NSAID-induced intestinal damage (Grattagliano et al. 2018). It is hypothesized that this is related to a decrease in the production of indole metabolites due to the reduced abundance of Lactobacillus johnsonii caused by PPI, thereby reducing the secretion of IL-22 and antimicrobial peptides (Nadatani et al. 2019, Hosseinkhani et al. 2021). In addition, a study by Yuji et al. established that chronic use of PPIs can promote small intestinal bacterial overgrowth (SIBO) (Naito et al. 2018). The inhibitory effect of PPIs on gastric acid secretion leads to loss of the gastric acid defense barrier, allowing overgrowth of Streptococcus, Escherichia coli, and Klebsiella, among others. This in turn promotes elevated levels of bacterial components and metabolites such as PGN, flagellin, and ammonia (Bruno et al. 2019). PGN uses nucleotide-binding oligomerization domain (NOD) to activate the NF-κB, MAPK, and caspase-1 pathways, increase the expression of IL-1β, TNF-α, IL-6, IL-12p40, and IL-8, and promote immune recruitment of cells such as DCs, neutrophils, and monocytes, and drive the inflammatory process (Potrykus et al. 2021). Increased flagellin over-activates TLR5 and induces the expression of proinflammatory mediators such as MCP-1 and granulocyte colony-stimulating factor (G-CSF), which in turn causes inflammatory damage (Hajam et al. 2017, Potrykus et al. 2021). The above effects together lead to the development of symptoms such as weight loss, diarrhea, and malabsorption (Rizzatti et al. 2017).

The study also found that patients on long-term PPI use were at increased risk of infection with pathogenic bacteria such as C. difficile and diarrheal E. coli (Bruno et al. 2019), in which the gut microbiota plays an important role (Imhann et al. 2016). It is hypothesized to be associated with a decrease in SCFAs and an increase in LPS caused by the expansion of Proteobacteria induced by PPI, which in turn causes the secretion of cytokines such as TNF-α and IL-1β, leading to the formation and maintenance of an inflammatory environment (Rizzatti et al. 2017). Moreover, the proliferation of Aerotolerant anaerobe disrupts epithelial hypoxia and interferes with HIF signaling in concert with TNF-α and IL-1β, leading to reduced mucus production and barrier dysfunction, and disrupting intestinal homeostasis (Yoon and Yoon 2018, Malkov et al. 2021). In addition, a study by Wauters et al. (2021) found an association between the increase in Streptococcus caused by long-term PPI treatment and eosinophil infiltration in the duodenum, which further caused dyspepsia and other adverse effects.

Other drugs 

Apart from the drugs covered above, many other drugs can cause drug-induced enteritis. Cyclophosphamide can modulate changes in gut microbiota, significantly reducing levels of SCFAs, promoting massive production of reactive oxygen species by epithelial cells (Yang et al. 2016), and downregulating the mRNA levels of CLDN1 and zonula occludens-1 (ZO-1) (Kong et al. 2020), which can impair intestinal barrier function. Irinotecan-induced gut microbiota disorders caused impaired production of BAs and SCFAs (Yue et al. 2021), which reduced CLDN1 expression (Wang et al. 2019c), inhibited the proliferation and differentiation of intestinal stem cells (Lee et al. 2018), and caused H2S production to impair the epithelial barrier (Lam et al. 2015). Menezes-Garcia et al. (2020) demonstrated that 5-fluorouracil triggers intestinal mucosal inflammation by promoting the expansion and colonization of Enterobacteriaceae, which increases LPS levels to activate TLR4, upregulating TNF mRNA expression, and inducing leukocyte recruitment (Zhao et al. 2022). Furthermore, Enterobacteriaceae can modulate circulating basal corticosterone levels to exacerbate the host's response to inflammatory stimuli (Menezes-Garcia et al. 2020). Changes in gut microbiota regulation of immune responses caused by commonly used drugs are summarized as follows (Table 1). 

Gut microbiota modulation on intestinal immunity applied to drug-induced enteritis 

The role of gut microbiota and intestinal immunity in the development of drug-induced enteritis is unquestionable and provides new ideas for diagnostic tools and therapeutic approaches to drug-induced enteritis, which are still deficient.

Diagnostic potential 

As an emerging biomarker, bacterial extracellular vesicles (BEVs) contain pathogen-associated molecular patterns, such as PGN and LPS (Stott et al. 2021), which can be involved in the development of multiple diseases by influencing host immune signaling (Yang et al. 2022). Based on metagenomic and metabolomic analyses, researchers have found that the status of the gut microbiota and the level of related metabolite secretion can be assessed by BEV, and thus indirectly evaluate the immune function of the organism (Kim et al. 2020). A study by Tulkens et al. (2020) found that plasma BEV density was higher in patients with enteritis compared to healthy subjects, reflecting stronger LPS activity, and was associated with upregulated expression of proinflammatory mediators such as IL-6, IL-8, and MCP-1. Thus, BEV has the potential as a diagnostic and assessment tool for drug-induced enteritis. 

Therapeutic approaches 

Microbiota transplantation can be used to optimize the composition and function of colonies by transferring intestinal microbiota from healthy donors, restoring homeostasis of the patient's gut microbiota, and thereby alleviating immune dysregulation and improving symptoms (Nishida et al. 2018, Vaughn et al. 2019). Fecal microbiota transplantation (FMT) can alleviate the upregulation of IL-1βand TNF-α expression induced by TLRs/MyD88/NF-κB signaling pathway of 5-fluorouracil and oxaliplatin and alleviate symptoms such as diarrhea (Chang et al. 2020). FMT can also increase the integrity of the epithelial barrier by restoring the level of SCFAs and promoting the expression of tight junctions (Geirnaert et al. 2017). Xie et al. (2021) showed that small intestinal microbiota transplantation caused a significant increase in Lactobacillus spp. compared to untreated mice, leading to a decrease in IFN-γ, TNF-α, and IL-1β, and a significant increase in IL-4. Therefore, microbiota transplantation is expected to be one of the safe options for an effective cure of drug-induced enteritis, pending further reliable evidence being generated. Probiotics are live microorganisms that exert beneficial effects on the host by modulating intestinal flora and alleviating gut microbiota disorders (Nishida et al. 2018). Chang et al. (2018) showed that Lactobacillus casei variety rhamnosus not only reversed gut microbiota disorders but also inhibited NF-κB activity, thereby attenuating drug-induced upregulation of TNF-α and IL-6. Lactobacillus casei and Lactobacillus paracasei inhibit the excessive production of reactive oxygen species and proinflammatory cytokines by macrophages, increasing intestinal antimicrobial activity, and enhancing the intestinal epithelial barrier (Monteros et al. 2021). The combination of Bifidobacterium longum and lactoferrin inhibited intestinal inflammation by modulating the TLRs/NF-κB pathway (Fornai et al. 2020a, Fornai et al. 2020b). In summary, probiotics will also be a hot spot in the treatment of drug-induced enteritis.

As exploration moved along, researchers discovered that herb extracts also could play a role in drug-induced enteritis by modulating intestinal flora. Qu et al. (2021) found that fermented ginseng reduced the expression levels of TLR4 and NF-κB by restoring intestinal flora abundance to alleviate colitis symptoms in rats with antibiotic-associated diarrhea. Schisandra chinensis polysaccharides induce an increase in Blautia and Lachnospiraceae, and a decrease in Erysipelatoclostridium and Ruminococcus, promoting the secretion of SCFAs, which in turn inhibited NF-κB pathway-mediated secretion of IL-8 and TNF-α, and alleviated the symptoms of antibiotic-induced enteritis (Qi et al. 2019). Total Flavonoids of Glycyrrhiza uralensis alleviated irinotecan-induced weight loss and colonic shortening by modulating intestinal flora and down-regulating the expression levels of TNF-α, IL-1β, and IL-6 (Yue et al. 2021). Therefore, the application of herbal medicine is expected to be the future direction of the treatment of drug-induced enterocolitis. Although much space was spent above describing the induction of intestinal inflammation by drugs, it is undeniable that some medications can be part of the treatment strategy. Researchers have found that stachyose promotes the proliferation of Lactobacillus and Akkermansia, which in turn causes the decrease of IL-6, IL-10, IL-17a, and TNF-α, improving intestinal inflammation (He et al. 2020b). The binding of vitamin D to colonic vitamin D receptors increases the abundance of beneficial bacteria and inhibits bacteria-stimulated NF-κB activity, reducing intestinal inflammation (Battistini et al. 2020).

Diet can also control gut flora to regulate intestinal inflammation. The Mediterranean diet regulates the production of metabolites such as SCFAs and SBA by increasing the abundance of Faecalibacterium prausnitzii and Eubacterium, then promotes the level of anti-inflammatory factor IL-10 increase and the level of proinflammatory factors such as C-reactive protein, IL-2, and IL-17 decrease (Ghosh et al. 2020). In conclusion, researchers need further exploration and generalization to provide new strategies for clinical application (Table 2).

Table 1. Disturbances in gut microbiota and corresponding changes in immune response caused by commonly used drugs.

Table 1. Continued

Table 2. Therapeutic approaches for drug-induced enteritis by modulating immune response through regulating intestinal microbiota

Conclusions and perspectives 

Drugs contribute to the development of enteritis by inducing disturbances in gut microbiota and metabolites, causing the secretion of proinflammatory mediators, inflammatory cell infiltration, and damage to the intestinal barrier. Research continues to improve our understanding of the disease, and provides new diagnostic and therapeutic strategies. Nevertheless, abundant highly relevant but unresolved questions remain: many mechanisms remain to be elucidated in the process of immune dysregulation caused by drug-induced intestinal flora and metabolites disorder. Given the differences in the immune system, developing humanized models to replace animal models with limited basic research will contribute to progress in this field (Yoo et al. 2020). Personalized specificity-based biomarkers of gut flora can help identify individuals at risk and thus guide clinical drug use. For example, the type and dose of medicines can be determined based on the patient's tolerance to drug exposure, rather than a blanket adherence to clinical guidelines and average ranges across the population. Moreover, assessment of probiotic susceptibility can also help to tailor individualized treatment regimens and improve implantation effectiveness. In conclusion, research on gut microbiota and metabolites in intestinal immunity holds great promise in drug-induced enteritis. However, the existing studies still do not meet the clinical needs and further exploration is still needed.

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