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. 2021 Oct 27:11:763468.
doi: 10.3389/fonc.2021.763468. eCollection 2021.

Intestinal Microbiota and Gene Expression Reveal Similarity and Dissimilarity Between Immune-Mediated Colitis and Ulcerative Colitis

Kazuko Sakai  1 , Toshiharu Sakurai  2 , Marco A De Velasco  1 , Tomoyuki Nagai  2 , Takaaki Chikugo  3 , Kazuomi Ueshima  2 , Yurie Kura  1 , Takayuki Takahama  4 , Hidetoshi Hayashi  4 , Kazuhiko Nakagawa  4 , Masatoshi Kudo  2 , Kazuto Nishio  1
Affiliations

Intestinal Microbiota and Gene Expression Reveal Similarity and Dissimilarity Between Immune-Mediated Colitis and Ulcerative Colitis

Kazuko Sakai et al. Front Oncol. .

Abstract

Immune checkpoint inhibitors (ICIs) have become the standard of care for several cancers. However, ICI therapy has also been associated with various immune-related adverse events (irAEs). Clinical manifestations of immune-related colitis resemble those of inflammatory bowel diseases such as ulcerative colitis (UC). The composition of the bowel microflora is thought to influence the development of inflammatory bowel disease and irAE colitis. We profiled the gene expressions and microbe compositions of colonic mucosa from patients with solid cancers receiving anti-PD-L1 antibody treatment; we then compared the expression profiles associated with irAE colitis with those associated with UC. The pathway enrichment analysis revealed functional similarities between inflamed regions of irAE colitis and UC. The common enriched pathways included leukocyte extravasation and immune responses, whereas non-inflamed mucosa from patients with irAE colitis was distinct from patients with UC and was characterized by the recruitment of immune cells. A similarity between the microbiota profiles was also identified. A decreased abundance of Bacteroides species was observed in inflamed regions from both irAE colitis and UC based on a microbiota composition analysis of 16S rDNA sequencing. Pathways associated with molecule transport systems, including fatty acids, were enriched in inflamed and non-inflamed irAE colitis and inflamed UC, similar to Piphillin-inferred KEGG pathways. While UC is characterized by local regions of inflammation, ICI treatment extends to non-inflammatory regions of the colonial mucosa where immune cells are reconstituted. This analysis of the similarity and heterogeneity of irAE colitis and UC provides important information for the management of irAE colitis.

Keywords: gene expression; immune-checkpoint inhibitor; immune-related adverse event; microbiota; pathway enrichment analysis; ulcerative colitis.

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Conflict of interest statement

KS reports personal fees from Roche Diagnostics, Bio‐Rad, SRL Diagnostics, AstraZeneca, Chugai Pharmaceutical outside the submitted work. KU has received personal fees and honoraria from Eisai. HH reported grants from the Japan Agency for Medical Research and Development during the conduct of the study and grants and personal fees from AstraZeneca, Boehringer Ingelheim Japan Inc, Chugai Pharmaceutical, Ono Pharmaceutical, and Bristol-Myers Squibb and personal fees from Eli Lilly Japan, Kyorin Pharmaceutical, Merck Biopharma, MSD, Novartis, Pfizer Japan, Shanghai Haihe Biopharma, and Taiho Pharmaceutical outside the submitted work. KNa reports grants from Novartis, Boehringer Ingelheim, Pfizer, Takeda, SymBio Pharmaceuticals, Kyorin Pharmaceutical, CareNet, Nichi-Iko Pharmaceutical, Daiichi-Sankyo, Hisamitsu Pharmaceutical, Yodosha, Clinical Trial, Medicus Shuppan Publishers, Ayumi Pharmaceutical, Nikkei Business Publications, Thermo Fisher Scientific, Nanzando, Medical Review, Yomiuri Telecasting, Reno Medical, MSD, Eli Lilly, Bristol-Myers Squibb, Taiho Pharmaceutical, Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Astellas, and grants from Novartis, Boehringer Ingelheim, Pfizer, Takeda, SymBio Pharmaceuticals, Daiichi-Sankyo, Merck Serono, ICON, Parexel International, IQVIA Services, A2 Healthcare, AbbVie, EP-CRSU, Linical, Otsuka Pharmaceutical, EPS, Quintiles, CMIC Shift Zero, Eisai, Kissei Pharmaceutical, Kyowa Hakko Kirin, Bayer, inVentiv Health, Gritstone Oncology, GlaxoSmithKline, Covance, MSD, Eli Lilly, Bristol-Myers Squibb, Taiho Pharmaceutical, Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Astellas outside the submitted work. MK received fees for advisory role from Eisai, Ono, MSD, Bristol-Myers Squibb, and Roche, lecture fees from Eisai, Bayer, MSD, Bristol-Myers Squibb, Eli Lilly, and EA Pharma, and research funding from Gilead Sciences, Taiho, Sumitomo Dainippon Pharma, Takeda, Otsuka, EA Pharma, Abbvie, and Eisai. KNi reports personal fees from Otsuka Pharmaceutical, Life Technologies Japan, Boehringer Ingelheim, Eli Lilly, Chugai Pharmaceutical, Eisai, Pfizer, Novartis, MSD, Ono Pharmaceutical, Bristol‐Myers Squibb, SymBio Pharmaceuticals Limited, Solasia Pharma, Yakult Honsha, Roche Diagnostics, AstraZeneca, Sanofi, Guardant Health, Takeda, Kobayashi Pharmaceutical, and grants from Otsuka Pharmaceutical, Life Technologies Japan, Boehringer Ingelheim, Eli Lilly, Ignyta, Astellas outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Biological trends for I-irAE, I-UC, A-irAE, and A-UC regions compared with normal samples. The size and color of each tile reflect the p value (−log) and the z-score, which reflect the overall predicted activation state (<0: inhibited, >0: activated), respectively, compared with the normal sample. The intensity scale of the z-score ranges from dark blue (low value) to dark orange (high value). (A) Featured canonical pathways of inactive irAE (n = 14) and normal control (n = 3). (B) Featured canonical pathways of inactive UC (n = 9) and normal control (n = 3). (C) Featured canonical pathways of active irAE (n = 15) and normal control (n = 3). (D) Featured canonical pathways of active UC (n = 9) and normal control (n = 3).
Figure 2
Figure 2
Diagrams of the top 10 canonical pathways in an enrichment analysis. The bar plots show the z-score, which reflects the overall predicted activation state (<0: inhibited, >0: activated) (left), and the p value (−log) (right). (A) Ten most statistically significant canonical pathways of inactive irAE and a normal control. (B) Ten most statistically significant canonical pathways of inactive UC and a normal control. (C) Ten most statistically significant canonical pathways of active irAE and a normal control. (D) Ten most statistically significant canonical pathways of active UC and a normal control.
Figure 3
Figure 3
Comparison of biodiversity indices between different groups of tissue microbiota. (A) Redundancy analysis (RDA) plot showing the relationship of inflammation and disease status. Plot at operational taxonomic units (OTUs) level. The contribution rate of each component is shown in parentheses. (B) Non-metric multidimensional scaling (NMDS) plot showing the relationship of inflammation and disease status. Plot at operational taxonomic units (OTUs) level. The NMDS stress value was 0.134, which is considered to be statistically reliable due to it is less than 0.2.
Figure 4
Figure 4
Heatmap of unsupervised hierarchical clustering of tissue microbiota composition at species level based on the Bray-Curtis distance metric. The bacteria that are shown represent the 50 most abundant taxa across all fraction samples. Taxa abundance is shown according to color ranging from red (highly abundant) to blue (rare or absent) and the values of taxa correspond to the heatmap scale on top of the main heatmap.
Figure 5
Figure 5
Correlation heatmap of relative abundance of 50 most abundant inferred KEGG orthology pathways selected by Piphillin in I-irAE (n = 14), I-UC (n = 9), A-irAE (n = 15), A-UC (n = 9), and normal samples (n = 3) using Pearson’s correlation metric. Values were scaled to z-score and colors correspond to correlation, red = high correlation and blue = low correlation. Dendrograms represent average distance. Two main clusters were identified, and samples characterized by inflamed (A-irAE and A-UC) and non-inflamed (I-irAE, I-UC, and normal) status were correlated accordingly.
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