Gut Microbiota Shifts from Onset to Remission in Immune Checkpoint Inhibitor-Induced Enterocolitis: A Case Report

Gut Microbiota Shifts from Onset to Remission in Immune Checkpoint Inhibitor-Induced Enterocolitis: A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Gut Microbiota Shifts from Onset to Remission in Immune Checkpoint Inhibitor-Induced Enterocolitis: A Case Report Yuki Hirata, Yoshiki Tanaka, Haruka Yokota, Hiroshi Ohno, Koji Nishida, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4318106/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background : Immune checkpoint inhibitors (ICIs) are crucial in cancer treatment; however, they carry the risk of immune-related adverse events (irAEs), such as enteritis. Case presentation : This study investigated the role of the gut microbiotaduring the onset and remission of irAE enteritis in a patient with stage IV melanoma undergoing anti-PD-1 and anti-CTLA-4 therapy. Following commencement of ICI treatment, the patient developed severe diarrhea and was diagnosed with grade 3 irAE enteritis. Steroid and probiotic treatments provided swift symptom relief and remission, as confirmed by reduced fecal calprotectin levels and gastrointestinal imaging. Microbiota diversity analysis conducted via 16S rRNA gene sequencing identified a decrease in Streptococcus prevalence with improvementin enteritis symptoms. Conversely, genera Fusobacterium , Faecalibacterium , Bacteroides , Prevotella , and Bifidobacterium showed increased representation after remission. These genera are associated with anti-inflammatory properties and fibrous substrate degradation, aiding gut health. Immunological assessment demonstrated fluctuations in cytokine expression and the modulation of costimulatory molecules, aligning with therapeutic interventions and microbiota alterations. Conclusions : Our findings indicate a significant correlation between gut microbiota and immune responses in irAE enteritis. This underscores the potential utility of microbiome profiling in predicting irAE occurrence and in providing treatment strategies, thereby promoting a more comprehensive approach to managing the adverse effects of ICIs. immune-related adverse events enteritis microbiota immune checkpoint inhibitors Figures Figure 1 Figure 2 Background As immune checkpoint inhibitors (ICIs) have become increasingly used across various cancer types, the associated immune-related adverse events (irAEs) have garnered attention. Among these, irAE-induced colitis has been reported in approximately 5.7–9.1% of patients treated with anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibodies and 0.7–1.6% of patients with anti-programmed cell death protein 1 (PD-1) antibodies. The incidence of colitis increases to 13.6% when these agents are used in combination [ 1 ]. Typically, colitis occurs after two–three administrations of ICIs or within 5–10 weeks of treatment initiation, although its onset can vary and it sometimes occurs after the first dose or during treatment interruption. The severity of symptoms of the irAE of colitis was standardized using the Common Terminology Criteria for Adverse Events grading, and steroids were recommended as the first-line treatment for irAE colitis. However, the mechanisms underlying irAE colitis remain largely unknown. Unlike cytotoxic chemotherapies, ICIs do not directly affect the intestinal epithelia, suggesting a role of immune effector cells and the gut microbiota. Numerous studies have demonstrated the influence of gut microbiota composition on the antitumor efficacy of ICIs [ 2 ]. Additionally, fecal microbiota transplantation has been reported to be effective in patients with irAE colitis, suggesting a link between gut bacteria and irAE colitis [ 3 ]. Gut microbiome diversity has been associated with a decreased risk of irAE colitis [ 4 ]. However, studies directly observing the impact of ICIs on gut microbiota during irAE colitis onset are scarce. This report provides a detailed investigation of the changes in gut microbiota from the onset to resolution of irAE colitis, highlighting the dynamic shifts within the microbial community. Case Presentation A 55-year-old male patient with stage IV melanoma was treated with systemic chemotherapy combined with anti-PD-1 antibody (nivolumab) and anti-CTLA-4 antibody (ipilimumab) treatment. Four days after initiation, he presented with acute symptoms of watery diarrhea, exceeding 10 episodes per day, and appetite loss (Fig. 1 a). Elevated C-reactive protein levels (5.89 mg/dL) and abdominal computed tomography findings of ileal and colonic wall thickening, along with enlarged pericolic lymph nodes, heightened the suspicion of irAE enteritis, leading to referral for further diagnosis and management. Colonoscopy revealed continuous edematous and friable mucosa extending from the terminal ileum to the rectum with purulent mucus attachments, indicative of significant inflammation (Fig. 1 b). Histological examination revealed lymphocytic infiltration and apoptotic bodies within the submucosa. Fecal calprotectin levels were markedly elevated at 1150 mg/kg, corroborating the observed inflammatory activity (Fig. 1 a). Gut microbiota diversity was assessed by 16S rRNA gene sequencing of the stool samples (Fig. 2 ). The patient was diagnosed with grade 3 irAE colitis and prompt treatment with prednisolone (40 mg/body) and probiotics (Lactomin Amylolytic Bacillus) was initiated. Symptoms rapidly ameliorated following the intervention, enabling tapering of outpatient prednisolone without recurrence. Subsequent colonoscopy and histological evaluations confirmed the resolution of enteritis, with fecal calprotectin levels reduced to 211 mg/kg (Fig. 1 a, 1 b). Comparative enzyme-linked immunosorbent assay analysis of blood cytokines during irAE onset and resolution indicated the following immunological shifts: upregulation of B and T lymphocyte attenuator (BTLA) and toll-like receptor 2 (TLR-2), stable cluster of differentiation 28 (CD28) expression, and reduction in T-cell immunoglobulin and mucin-domain containing-3, lymphocyte-activation gene 3, herpes virus entry mediator, CD40, and glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR). These changes illustrate modifications in the immune response mechanisms. Increased expression of the co-stimulatory molecules CD80/B7-1, CD86/B7-2, and PD-L1, with a decrease in PD-L2 expression, was observed. PD-1 levels decreased, aligning with the therapeutic targeting, whereas CTLA-4 levels remained minimally detectable throughout the treatment course (Fig. 1 c). Post-remission fecal sampling revealed significant changes in gut microbiota composition (Fig. 2 ). Alpha diversity decreased according to the Chao1 index but increased according to the Shannon index (Fig. 2 a). At the phylum level, a decrease in Firmicutes and an increase in Fusobacteria and Bacteroidetes was observed along with the resolution of irAE colitis (Fig. 2 b). Genus-level analysis revealed a substantial decline in Streptococcus species and an increase in Fusobacterium , Faecalibacterium , Bacteroides , Prevotella , and Bifidobacterium species post-remission (Fig. 2 c). Discussion and Conclusions With the increasing use of ICIs, irAEs, such as enteritis, are becoming more frequent. While the mechanisms underlying irAE enteritis remain elusive, emerging studies have suggested the involvement of the gut microbiota. Our analysis focused on longitudinal changes in the gut microbiota of a patient who developed irAE enteritis and achieved remission through treatment. Following the onset of irAE enteritis, the symptoms improved swiftly with steroid administration, and endoscopic and histological evaluations confirmed a reduction in inflammation. Fecal calprotectin has also been used as a marker of enteritis. Fecal calprotectin and lactoferrin are recognized as valuable markers of enteritis. The cutoff values for endoscopic remission and histological remission are reported to be less than 116 mg/kg and 80 mg/kg, respectively [ 5 ]. In our case, fecal calprotectin levels decreased from 1150 mg/kg at onset to 211 mg/kg at remission, paralleling the endoscopic findings and suggesting an improvement in enteritis. We also examined cytokine profile changes from onset to remission of irAE enteritis. Initially, an increase in BTLA suggested enhanced inhibitory signaling, which might prevent the overactivation of CD8 + T cells. Along with enteritis improvement, a significant reduction in GITR levels indicated the potential recovery of regulatory T cells (Tregs), underlining GITR's role in the pathogenesis and resolution of irAE enteritis. Moreover, a slight increase in TLR-2 expression corresponded with enteritis recovery, likely reflecting the immune system's response to gut microbiota diversity, and contributing to the resolution of inflammation. The expression of PD-1 and CTLA-4, the key treatment targets, was compared during enteritis onset and remission. PD-1 levels decreased as enteritis recovered, likely because anti-PD-1 antibodies activated lymphocytes, causing PD-1 cleavage, and potentially increasing soluble PD-1 levels in the bloodstream, which then gradually declined. Conversely, CTLA-4 was minimally detectable throughout the study period. Overall, these observations underscore the complex interplay among immune system activation, regulation, and microbial pattern recognition during the development and resolution of irAE enteritis. Recent reports have increasingly suggested a role of the gut microbiome in irAEs, including enteritis. Gut microbial diversity is known to affect not only the exacerbation of irAE enteritis but also the responsiveness of tumors to ICI therapy [ 2 ]. Methods to evaluate microbial diversity within a single sample include the estimated total number of bacterial species, the Chao1 index, and the Shannon diversity index, which emphasize species richness and evenness. In this study, the Chao1 index decreased with the improvement in irAE enteritis, whereas the Shannon diversity index increased, suggesting that species evenness recovery is also crucial for recovery from irAE enteritis-induced dysbiosis. Studies on the specific types of bacteria present before ICI administration have often investigated patients prone to developing irAEs. For instance, the abundance of microbes such as Bacteroidetes and Bifidobacterium has been associated with a reduced risk of gastrointestinal irAEs [ 6 ], whereas patients who developed gastrointestinal irAEs were reported to have an abundance of Faecalibacterium and Firmicutes prior to ICI administration. However, studies examining the changes in the gut microbiome before and after the onset of irAE enteritis are rare. A transition of the gut microbiome in pancreatic irAEs has been reported, with a decreased Bacteroidetes / Firmicutes ratio at the onset of irAE pancreatitis [ 7 ]. In our case, a very high prevalence of Streptococcus was observed at the onset of irAE enteritis, which decreased as the enteritis improved. In studies on patients with inflammatory bowel disease, the Streptococcus genus has been suggested to be an intestinal pathogen possibly originating from the oral cavity [ 8 ], and its increase has also been reported in radiation enteritis. Other bacteria whose prevalence recovered with improvement in enteritis included Prevotella and Fusobacterium , which can degrade fiber and produce short-chain fatty acids, and Faecalibacterium and Bifidobacterium , which have anti-inflammatory effects. Recovery of the prevalence of these bacterial species is considered to have a positive effect on the normalization of the intestinal environment. In this case, the proportion of Bacteroidetes was low at the onset of irAE enteritis and recovered upon remission of the enteritis with prednisolone treatment. Within the Bacteroidetes species, Bacteroides fragilis has been reported to be involved in the downregulation of inflammatory Th17 cells [ 9 ], and Bacteroides has been reported to have a protective role against colitis [ 10 ]. Additionally, Bacteroidetes can decompose complex carbohydrates to produce simpler sugars and metabolites that can be utilized by other bacteria. Fusobacterium can grow using these metabolic products. Thus, the activity of Bacteroides may support an increase in Fusobacterium . Bacteroides fragilis produces polysaccharide A, which is involved in the regulation of the immune system and maintaining the balance of immune responses by activating T cells, particularly Tregs, in the gut. Thus, Bacteroides may play a significant role in the development of irAE enteritis. Understanding gut microbiome and immunological changes at the onset of irAE enteritis is important for establishing future strategies for the prevention and risk assessment of irAE. The findings from this case report demonstrate a significant shift in the gut microbiota profile during the occurrence of irAE enteritis, marked by an increase in the prevalence of specific bacteria and a recovery of diversity following treatment. These observations underscore the importance of the gut microbiome in the context of immune responses and irAE enteritis, suggesting that monitoring and potentially modulating the gut microbiota could serve as integral components of effective treatment strategies. Abbreviations ICIs, immune checkpoint inhibitors; irAEs, immune-related adverse events; CTLA-4, cytotoxic T-lymphocyte associated protein 4; PD-1, programmed cell death protein 1; BTLA, B and T lymphocyte attenuator; TLR-2, toll-like receptor 2; GITR, glucocorticoid-induced tumor necrosis factor receptor-related protein; CD28, cluster of differentiation 28; Tregs, regulatory T cells Declarations Ethics approval and consent to participate The study was conducted with the approval of the ethics committee of Osaka Medical and Pharmaceutical College in Japan (Research ID: 2228-01). Consent was obtained directly from the patient. Consent for publication The patient gave his informed consent for publication. This was also documented in his medical records. Availability of data and materials Data not publicly available. Competing interests The authors declare that they have no competing interests. Funding The authors have not declared any specific grant for this research from funding agencies in the public, commercial, or not-for-profit sectors. Authors’ contributions YH and YT, data acquisition; YH, YT, and HY, data analysis and interpretation; YH, manuscript drafting. All authors read and approved the final manuscript. Acknowledgements We would like to thank Editage [http://www.editage.com] for editing and reviewing this manuscript for English language. References Bishay K, Tandon P, Bourassa-Blanchette S, Laurie SA, McCurdy JD. The risk of diarrhea and colitis in patients with lung cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Curr Oncol. 2020;27:e486-94. Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91-7. Wang Y, Wiesnoski DH, Helmink BA, Gopalakrishnan V, Choi K, DuPont HL, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med. 2018;24:1804-8. Abu-Sbeih H, Wang Y. Gut microbiome and immune checkpoint inhibitor-induced enterocolitis. Dig Dis Sci. 2020;65:797–9. Zou F, Wang X, Glitza Oliva IC, McQuade JL, Wang J, Zhang HC, et al. Fecal calprotectin concentration to assess endoscopic and histologic remission in patients with cancer with immune-mediated diarrhea and colitis. J Immunother Cancer. 2021;9:e002058. Dubin K, Callahan MK, Ren B, Khanin R, Viale A, Ling L, et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat Commun. 2016;7:10391. Tan B, Chen MJ, Guo Q, Tang H, Li Y, Jia XM, et al. Clinical-radiological characteristics and intestinal microbiota in patients with pancreatic immune-related adverse events. Thorac Cancer. 2021;12:1814–23. Abdelbary MMH, Hatting M, Bott A, Dahlhausen A, Keller D, Trautwein C, Conrads G. The oral-gut axis: Salivary and fecal microbiome dysbiosis in patients with inflammatory bowel disease. Front Cell Infect Microbiol. 2022;12:1010853. Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science. 2011;332:974–7. Liu W, Ma F, Sun B, Liu Y, Tang H, Luo J, et al. Intestinal microbiome associated with immunerelated adverse events for patients treated with anti-PD-1 inhibitors, a realworld study. Front Immunol. 2021;12:756872. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 20 Jun, 2024 Reviewers agreed at journal 17 Jun, 2024 Reviews received at journal 10 Jun, 2024 Reviewers agreed at journal 30 May, 2024 Reviewers invited by journal 01 May, 2024 Editor assigned by journal 24 Apr, 2024 Submission checks completed at journal 24 Apr, 2024 First submitted to journal 24 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4318106","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":296875989,"identity":"4e2042a8-10c1-46c4-a8d3-2a985ab377be","order_by":0,"name":"Yuki 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12:06:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4318106/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4318106/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55633529,"identity":"b78403b6-5fa3-473c-aeb7-422b7ccbdce1","added_by":"auto","created_at":"2024-04-30 20:04:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1224397,"visible":true,"origin":"","legend":"\u003cp\u003eClinical course of the patient after the first administration of immune checkpoint inhibitors (ICIs), with endoscopic and histopathological findings. (a) Clinical course: Patient's clinical timeline following the initial ICI administration, including onset and treatment of immune-related adverse event (irAE) enteritis, temporary remission, and recurrence after subsequent ICI treatment.\u003c/p\u003e\n\u003cp\u003e(b) Initial irAE enteritis findings: Endoscopic and histopathological images of the small and large intestines during the first episode of irAE enteritis, showing the initial inflammatory response.\u003c/p\u003e\n\u003cp\u003e(c) Recurrent irAE enteritis findings: Similar endoscopic and histopathological views during the recurrent episode of irAE enteritis.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4318106/v1/5eb7cf7475e5b05e4c3e7104.png"},{"id":55633528,"identity":"0152e6a2-0eec-4dcd-a641-97bb796a3b8e","added_by":"auto","created_at":"2024-04-30 20:04:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":462581,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in the gut microbiota during the onset and remission of immune-related adverse event (irAE) enteritis.\u003c/p\u003e\n\u003cp\u003e(a) Diversity of gut microbiota: This panel compares the α diversity of the gut microbiota at the onset and during the remission of irAE enteritis, utilizing the Chao1 and Shannon indices for assessment.\u003c/p\u003e\n\u003cp\u003e(b) This panel compares the gut microbiome at the phylum level between the onset and remission of irAE enteritis. (c) This panel illustrates a comparative analysis of the gut microbiome at the genus level during the onset and remission of irAE enteritis. Genera with a prevalence exceeding 1% are denoted in color. Downward arrows indicate a decrease in prevalence with the remission of enteritis, while upward arrows signify an increase. Changes in prevalence ranging from 3% to 10% are represented by double arrows, and changes exceeding 10% are depicted with triple arrows.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4318106/v1/cc48961561cb292af7afb1db.png"},{"id":55693765,"identity":"b35daa24-1add-4601-95fd-4da5bda42192","added_by":"auto","created_at":"2024-05-02 00:33:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1208061,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4318106/v1/2659ac5a-c408-4ee5-a782-df8fc696154e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Gut Microbiota Shifts from Onset to Remission in Immune Checkpoint Inhibitor-Induced Enterocolitis: A Case Report","fulltext":[{"header":"Background","content":"\u003cp\u003eAs immune checkpoint inhibitors (ICIs) have become increasingly used across various cancer types, the associated immune-related adverse events (irAEs) have garnered attention. Among these, irAE-induced colitis has been reported in approximately 5.7\u0026ndash;9.1% of patients treated with anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibodies and 0.7\u0026ndash;1.6% of patients with anti-programmed cell death protein 1 (PD-1) antibodies. The incidence of colitis increases to 13.6% when these agents are used in combination [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Typically, colitis occurs after two\u0026ndash;three administrations of ICIs or within 5\u0026ndash;10 weeks of treatment initiation, although its onset can vary and it sometimes occurs after the first dose or during treatment interruption. The severity of symptoms of the irAE of colitis was standardized using the Common Terminology Criteria for Adverse Events grading, and steroids were recommended as the first-line treatment for irAE colitis.\u003c/p\u003e \u003cp\u003eHowever, the mechanisms underlying irAE colitis remain largely unknown. Unlike cytotoxic chemotherapies, ICIs do not directly affect the intestinal epithelia, suggesting a role of immune effector cells and the gut microbiota. Numerous studies have demonstrated the influence of gut microbiota composition on the antitumor efficacy of ICIs [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Additionally, fecal microbiota transplantation has been reported to be effective in patients with irAE colitis, suggesting a link between gut bacteria and irAE colitis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Gut microbiome diversity has been associated with a decreased risk of irAE colitis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, studies directly observing the impact of ICIs on gut microbiota during irAE colitis onset are scarce.\u003c/p\u003e \u003cp\u003eThis report provides a detailed investigation of the changes in gut microbiota from the onset to resolution of irAE colitis, highlighting the dynamic shifts within the microbial community.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 55-year-old male patient with stage IV melanoma was treated with systemic chemotherapy combined with anti-PD-1 antibody (nivolumab) and anti-CTLA-4 antibody (ipilimumab) treatment. Four days after initiation, he presented with acute symptoms of watery diarrhea, exceeding 10 episodes per day, and appetite loss (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Elevated C-reactive protein levels (5.89 mg/dL) and abdominal computed tomography findings of ileal and colonic wall thickening, along with enlarged pericolic lymph nodes, heightened the suspicion of irAE enteritis, leading to referral for further diagnosis and management.\u003c/p\u003e \u003cp\u003eColonoscopy revealed continuous edematous and friable mucosa extending from the terminal ileum to the rectum with purulent mucus attachments, indicative of significant inflammation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). Histological examination revealed lymphocytic infiltration and apoptotic bodies within the submucosa. Fecal calprotectin levels were markedly elevated at 1150 mg/kg, corroborating the observed inflammatory activity (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Gut microbiota diversity was assessed by 16S rRNA gene sequencing of the stool samples (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe patient was diagnosed with grade 3 irAE colitis and prompt treatment with prednisolone (40 mg/body) and probiotics (Lactomin Amylolytic Bacillus) was initiated. Symptoms rapidly ameliorated following the intervention, enabling tapering of outpatient prednisolone without recurrence. Subsequent colonoscopy and histological evaluations confirmed the resolution of enteritis, with fecal calprotectin levels reduced to 211 mg/kg (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea, \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003eComparative enzyme-linked immunosorbent assay analysis of blood cytokines during irAE onset and resolution indicated the following immunological shifts: upregulation of B and T lymphocyte attenuator (BTLA) and toll-like receptor 2 (TLR-2), stable cluster of differentiation 28 (CD28) expression, and reduction in T-cell immunoglobulin and mucin-domain containing-3, lymphocyte-activation gene 3, herpes virus entry mediator, CD40, and glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR). These changes illustrate modifications in the immune response mechanisms. Increased expression of the co-stimulatory molecules CD80/B7-1, CD86/B7-2, and PD-L1, with a decrease in PD-L2 expression, was observed. PD-1 levels decreased, aligning with the therapeutic targeting, whereas CTLA-4 levels remained minimally detectable throughout the treatment course (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec).\u003c/p\u003e \u003cp\u003ePost-remission fecal sampling revealed significant changes in gut microbiota composition (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Alpha diversity decreased according to the Chao1 index but increased according to the Shannon index (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). At the phylum level, a decrease in \u003cem\u003eFirmicutes\u003c/em\u003e and an increase in \u003cem\u003eFusobacteria\u003c/em\u003e and \u003cem\u003eBacteroidetes\u003c/em\u003e was observed along with the resolution of irAE colitis (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). Genus-level analysis revealed a substantial decline in \u003cem\u003eStreptococcus\u003c/em\u003e species and an increase in \u003cem\u003eFusobacterium\u003c/em\u003e, \u003cem\u003eFaecalibacterium\u003c/em\u003e, \u003cem\u003eBacteroides\u003c/em\u003e, \u003cem\u003ePrevotella\u003c/em\u003e, and \u003cem\u003eBifidobacterium\u003c/em\u003e species post-remission (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec).\u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003cp\u003eWith the increasing use of ICIs, irAEs, such as enteritis, are becoming more frequent. While the mechanisms underlying irAE enteritis remain elusive, emerging studies have suggested the involvement of the gut microbiota. Our analysis focused on longitudinal changes in the gut microbiota of a patient who developed irAE enteritis and achieved remission through treatment.\u003c/p\u003e \u003cp\u003eFollowing the onset of irAE enteritis, the symptoms improved swiftly with steroid administration, and endoscopic and histological evaluations confirmed a reduction in inflammation. Fecal calprotectin has also been used as a marker of enteritis. Fecal calprotectin and lactoferrin are recognized as valuable markers of enteritis. The cutoff values for endoscopic remission and histological remission are reported to be less than 116 mg/kg and 80 mg/kg, respectively [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In our case, fecal calprotectin levels decreased from 1150 mg/kg at onset to 211 mg/kg at remission, paralleling the endoscopic findings and suggesting an improvement in enteritis.\u003c/p\u003e \u003cp\u003eWe also examined cytokine profile changes from onset to remission of irAE enteritis. Initially, an increase in BTLA suggested enhanced inhibitory signaling, which might prevent the overactivation of CD8\u0026thinsp;+\u0026thinsp;T cells. Along with enteritis improvement, a significant reduction in GITR levels indicated the potential recovery of regulatory T cells (Tregs), underlining GITR's role in the pathogenesis and resolution of irAE enteritis.\u003c/p\u003e \u003cp\u003eMoreover, a slight increase in TLR-2 expression corresponded with enteritis recovery, likely reflecting the immune system's response to gut microbiota diversity, and contributing to the resolution of inflammation.\u003c/p\u003e \u003cp\u003eThe expression of PD-1 and CTLA-4, the key treatment targets, was compared during enteritis onset and remission. PD-1 levels decreased as enteritis recovered, likely because anti-PD-1 antibodies activated lymphocytes, causing PD-1 cleavage, and potentially increasing soluble PD-1 levels in the bloodstream, which then gradually declined. Conversely, CTLA-4 was minimally detectable throughout the study period.\u003c/p\u003e \u003cp\u003eOverall, these observations underscore the complex interplay among immune system activation, regulation, and microbial pattern recognition during the development and resolution of irAE enteritis.\u003c/p\u003e \u003cp\u003eRecent reports have increasingly suggested a role of the gut microbiome in irAEs, including enteritis. Gut microbial diversity is known to affect not only the exacerbation of irAE enteritis but also the responsiveness of tumors to ICI therapy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Methods to evaluate microbial diversity within a single sample include the estimated total number of bacterial species, the Chao1 index, and the Shannon diversity index, which emphasize species richness and evenness. In this study, the Chao1 index decreased with the improvement in irAE enteritis, whereas the Shannon diversity index increased, suggesting that species evenness recovery is also crucial for recovery from irAE enteritis-induced dysbiosis.\u003c/p\u003e \u003cp\u003eStudies on the specific types of bacteria present before ICI administration have often investigated patients prone to developing irAEs. For instance, the abundance of microbes such as \u003cem\u003eBacteroidetes\u003c/em\u003e and \u003cem\u003eBifidobacterium\u003c/em\u003e has been associated with a reduced risk of gastrointestinal irAEs [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], whereas patients who developed gastrointestinal irAEs were reported to have an abundance of \u003cem\u003eFaecalibacterium\u003c/em\u003e and \u003cem\u003eFirmicutes\u003c/em\u003e prior to ICI administration. However, studies examining the changes in the gut microbiome before and after the onset of irAE enteritis are rare. A transition of the gut microbiome in pancreatic irAEs has been reported, with a decreased \u003cem\u003eBacteroidetes\u003c/em\u003e/\u003cem\u003eFirmicutes\u003c/em\u003e ratio at the onset of irAE pancreatitis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In our case, a very high prevalence of \u003cem\u003eStreptococcus\u003c/em\u003e was observed at the onset of irAE enteritis, which decreased as the enteritis improved. In studies on patients with inflammatory bowel disease, the \u003cem\u003eStreptococcus\u003c/em\u003e genus has been suggested to be an intestinal pathogen possibly originating from the oral cavity [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], and its increase has also been reported in radiation enteritis.\u003c/p\u003e \u003cp\u003eOther bacteria whose prevalence recovered with improvement in enteritis included \u003cem\u003ePrevotella\u003c/em\u003e and \u003cem\u003eFusobacterium\u003c/em\u003e, which can degrade fiber and produce short-chain fatty acids, and \u003cem\u003eFaecalibacterium\u003c/em\u003e and \u003cem\u003eBifidobacterium\u003c/em\u003e, which have anti-inflammatory effects. Recovery of the prevalence of these bacterial species is considered to have a positive effect on the normalization of the intestinal environment. In this case, the proportion of \u003cem\u003eBacteroidetes\u003c/em\u003e was low at the onset of irAE enteritis and recovered upon remission of the enteritis with prednisolone treatment.\u003c/p\u003e \u003cp\u003eWithin the \u003cem\u003eBacteroidetes\u003c/em\u003e species, \u003cem\u003eBacteroides fragilis\u003c/em\u003e has been reported to be involved in the downregulation of inflammatory Th17 cells [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and \u003cem\u003eBacteroides\u003c/em\u003e has been reported to have a protective role against colitis [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Additionally, \u003cem\u003eBacteroidetes\u003c/em\u003e can decompose complex carbohydrates to produce simpler sugars and metabolites that can be utilized by other bacteria. \u003cem\u003eFusobacterium\u003c/em\u003e can grow using these metabolic products. Thus, the activity of \u003cem\u003eBacteroides\u003c/em\u003e may support an increase in \u003cem\u003eFusobacterium\u003c/em\u003e. \u003cem\u003eBacteroides fragilis\u003c/em\u003e produces polysaccharide A, which is involved in the regulation of the immune system and maintaining the balance of immune responses by activating T cells, particularly Tregs, in the gut. Thus, \u003cem\u003eBacteroides\u003c/em\u003e may play a significant role in the development of irAE enteritis.\u003c/p\u003e \u003cp\u003eUnderstanding gut microbiome and immunological changes at the onset of irAE enteritis is important for establishing future strategies for the prevention and risk assessment of irAE.\u003c/p\u003e \u003cp\u003eThe findings from this case report demonstrate a significant shift in the gut microbiota profile during the occurrence of irAE enteritis, marked by an increase in the prevalence of specific bacteria and a recovery of diversity following treatment. These observations underscore the importance of the gut microbiome in the context of immune responses and irAE enteritis, suggesting that monitoring and potentially modulating the gut microbiota could serve as integral components of effective treatment strategies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eICIs, immune checkpoint inhibitors; irAEs, immune-related adverse events; CTLA-4, cytotoxic T-lymphocyte associated protein 4; PD-1, programmed cell death protein 1; BTLA, B and T lymphocyte attenuator; TLR-2, toll-like receptor 2; GITR, glucocorticoid-induced tumor necrosis factor receptor-related protein; CD28, cluster of differentiation 28; Tregs, regulatory T cells\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted with the approval of the ethics committee of Osaka Medical and Pharmaceutical College in Japan (Research ID: 2228-01).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eConsent was obtained directly from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient gave his informed consent for publication. This was also documented in his medical records.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData not publicly available.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have not declared any specific grant for this research from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYH and YT, data acquisition; YH, YT, and HY, data analysis and interpretation; YH, manuscript drafting. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Editage [http://www.editage.com] for editing and reviewing this manuscript for English language.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eBishay K, Tandon P, Bourassa-Blanchette S, Laurie SA, McCurdy JD. The risk of diarrhea and colitis in patients with lung cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Curr Oncol. 2020;27:e486-94. \u0026nbsp;\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eRouty B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91-7.\u003c/li\u003e\n \u003cli\u003eWang Y, Wiesnoski DH, Helmink BA, Gopalakrishnan V, Choi K, DuPont HL, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med. 2018;24:1804-8.\u003c/li\u003e\n \u003cli\u003eAbu-Sbeih H, Wang Y. Gut microbiome and immune checkpoint inhibitor-induced enterocolitis. Dig Dis Sci. 2020;65:797\u0026ndash;9.\u003c/li\u003e\n \u003cli\u003eZou F, Wang X, Glitza Oliva IC, McQuade JL, Wang J, Zhang HC, et al. Fecal calprotectin concentration to assess endoscopic and histologic remission in patients with cancer with immune-mediated diarrhea and colitis. J Immunother Cancer. 2021;9:e002058.\u003c/li\u003e\n \u003cli\u003eDubin K, Callahan MK, Ren B, Khanin R, Viale A, Ling L, et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat Commun. 2016;7:10391.\u003c/li\u003e\n \u003cli\u003eTan B, Chen MJ, Guo Q, Tang H, Li Y, Jia XM, et al. Clinical-radiological characteristics and intestinal microbiota in patients with pancreatic immune-related adverse events. Thorac Cancer. 2021;12:1814\u0026ndash;23.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAbdelbary MMH, Hatting M, Bott A, Dahlhausen A, Keller D, Trautwein C, Conrads G. The oral-gut axis: Salivary and fecal microbiome dysbiosis in patients with inflammatory bowel disease. Front Cell Infect Microbiol. 2022;12:1010853.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eRound JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science. 2011;332:974\u0026ndash;7.\u003c/li\u003e\n \u003cli\u003eLiu W, Ma F, Sun B, Liu Y, Tang H, Luo J, et al. Intestinal microbiome associated with immunerelated adverse events for patients treated with anti-PD-1 inhibitors, a realworld study. Front Immunol. 2021;12:756872.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"gut-pathogens","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"gutp","sideBox":"Learn more about [Gut Pathogens](http://gutpathogens.biomedcentral.com/)","snPcode":"13099","submissionUrl":"https://submission.nature.com/new-submission/13099/3","title":"Gut Pathogens","twitterHandle":"@GutPathogens","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"immune-related adverse events, enteritis, microbiota, immune checkpoint inhibitors","lastPublishedDoi":"10.21203/rs.3.rs-4318106/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4318106/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Immune checkpoint inhibitors (ICIs) are crucial in cancer treatment; however, they carry the risk of immune-related adverse events (irAEs), such as enteritis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation\u003c/strong\u003e: This study investigated the role of the gut microbiotaduring the onset and remission of irAE enteritis in a patient with stage IV melanoma undergoing anti-PD-1 and anti-CTLA-4 therapy. Following commencement of ICI treatment, the patient developed severe diarrhea and was diagnosed with grade 3 irAE enteritis. Steroid and probiotic treatments provided swift symptom relief and remission, as confirmed by reduced fecal calprotectin levels and gastrointestinal imaging. Microbiota diversity analysis conducted via 16S rRNA gene sequencing identified a decrease in \u003cem\u003eStreptococcus\u003c/em\u003eprevalence with improvementin enteritis symptoms. Conversely, genera \u003cem\u003eFusobacterium\u003c/em\u003e, \u003cem\u003eFaecalibacterium\u003c/em\u003e, \u003cem\u003eBacteroides\u003c/em\u003e, \u003cem\u003ePrevotella\u003c/em\u003e, and \u003cem\u003eBifidobacterium\u003c/em\u003eshowed increased representation after remission. These genera are associated with anti-inflammatory properties and fibrous substrate degradation, aiding gut health. Immunological assessment demonstrated fluctuations in cytokine expression and the modulation of costimulatory molecules, aligning with therapeutic interventions and microbiota alterations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: Our findings indicate a significant correlation between gut microbiota and immune responses in irAE enteritis. This underscores the potential utility of microbiome profiling in predicting irAE occurrence and in providing treatment strategies, thereby promoting a more comprehensive approach to managing the adverse effects of ICIs.\u003c/p\u003e","manuscriptTitle":"Gut Microbiota Shifts from Onset to Remission in Immune Checkpoint Inhibitor-Induced Enterocolitis: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-30 20:04:47","doi":"10.21203/rs.3.rs-4318106/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2024-06-20T06:57:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"9048993601927366027802488454724413011","date":"2024-06-17T21:56:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-11T00:50:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"36266644169739335460839151976423819097","date":"2024-05-31T00:29:42+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-01T13:32:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-24T14:54:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-24T14:54:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"Gut Pathogens","date":"2024-04-24T12:03:54+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"gut-pathogens","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"gutp","sideBox":"Learn more about [Gut Pathogens](http://gutpathogens.biomedcentral.com/)","snPcode":"13099","submissionUrl":"https://submission.nature.com/new-submission/13099/3","title":"Gut Pathogens","twitterHandle":"@GutPathogens","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6390fef6-f7a5-4ec3-869e-9da50ff744c8","owner":[],"postedDate":"April 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-06-28T15:00:31+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-30 20:04:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4318106","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4318106","identity":"rs-4318106","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}