Numerous metagenomics-based studies have associated gut microbiota dysbiosis with the progression and resistance to immunotherapy of intestinal and non-intestinal cancers. It remains unclear whether the dysbiosis is causing the tumorigenic process or the consequence of carcinogenesis. In their paper, Yonnekura and colleagues showed in mice that tumor implantation triggered a stress ileopathy associated with microbiome dysbiosis dominated by Clostridium species. They also found signs of stress ileopathy in humans. By comparing 1906 cancer patients across 8 different malignancies and disease staging against 5570 healthy individuals, they identified a gut “oncomicrobiome” signature of cancer patients.
Tumor implantation promotes intestinal permeability, terminal ileopathy and dysbiosis
In a murine model, changes in gut permeability were observed with a transient elevation at 9 days, but not at day 12 after inoculation of RET melanoma cells. The hallmarks of a leaky gut syndrome were also found in serum with elevation of soluble ST2 (IL-33R) and/or CD14. This transient increase in gut permeability was accompanied by morphological changes of the mucosa, starting on day 3, peaking on day 6-9, and resolving by day 12. Four out of the 7 murine tumor models carried out in this study, showed a cancer-associated ileopathy characterized by a transient epithelial atrophy of the terminal ileum.
Gut microbiome profiling by 16S rRNA gene sequencing revealed a common microbial signature after tumor implantation with the dominance of the Clostridiales order (including several members of the families Clostridiaceae, Ruminococcaceae, and Vallitaleaceae) at the expense of the Lactobacillus genus. Contrary to the transient nature of the cancer-associated ileopathy, the cancer-induced gut dysbiosis persisted over time (until animal sacrifice at day 19 in the RET murine model)
The mechanisms triggering or maintaining the ileopathy during the cancer progression are mainly unknown. Yonnekura and colleagues speculate that the gut microbiota dysbiosis favoring the Clostridiums may induce enteroendocrine cell production of biogenic amines, that in turn, stimulate Paneth cell neighbors to produce and release antimicrobial peptides to control ileal dysbiosis.
Cancer-induced dysbiosis affects tumor size, survival, treatment efficacy
To test the clinical significance of the gut microbiota dysbiosis, Yonnekura and colleagues tested different courses of antibiotics on the RET melanoma murine model. The vancomycin, targeting most of the Gram-positive bacteria (such as Clostridiums), prevented the reduction of the ileal villus/crypt height ratio and crypt cell apoptosis, as well as retarded the tumor growth. The colistin treatment, only targeting Gram-negative bacteria, failed to show the same effects, supporting the role of the Clostridiums in the cancer-induced ileopathy.
Co-housing between RET tumor bearers with tumor-free mice prevented the transient increase of gut permeability. Fibrosarcoma formation was also significantly retarded with slower tumor growth in mice reared with healthy controls as compared with 3MCA-isolated animals.
The oral gavage with Clostridium clostridioforme significantly compromised the efficacy of the immunotherapy anti-PD1. No similar effect was observed by oral feeding with Lactobacillus reuteri.
Cancer patients also exhibit the gut “oncomicrobiome” signature
As described in mice, increased proportion of CgA+ enteroendocrine cells in the crypts, correlating with ileal crypt apoptosis, was observed in patients with colon, genitourinary, or neuroendocrine tumors. Serum hallmarks of increased gut permeability were also found in 76 advanced-stage cancer patients.
In a prospective cohort of 1906 cancer patients across 8 different malignancies and disease staging, Yonnekura et al. collected the stools from patients harboring kidney cancer (N=69), breast cancer (N=84), lung cancers (N=368), colon cancer (N=291), prostate cancers (N=47), ovarian cancers (N=36), and chronic myelomonocytic leukemia (N=17). These samples were integrated to 994 colon cancers from the publicly available database and compared with 5570 healthy individuals. Differential analyses identified 25 bacterial taxa overrepresented in healthy individuals, including members of the Prevotellaceae, the Lachnospiraceae, the Actinobacteriaceae, and the Lactobacillaceae families. Conversely, in cancer patients across 6/8 cancer types, 10 Gram-positive bacteria belonging to the Clostridia class, Gamma- and Delta- proteobacteria, were overrepresented.
So, Yonnekura and colleagues identified a “gut oncomicrobiome fingerprint” shared across several tumor types and mammalian species (rodents and humans), in which ATB-induced dysbiosis and immunoresistance (mostly Gram-positive bacteria belonging to the Clostridiales order or Proteobacteria) take over beneficial microbes (such as Lactobacillaceae).
Yonnekura et al. showed that the cancer-associated ileopathy is a debilitating corollary syndrome of the tumorigenic process, inducing a long-lasting dysbiosis perturbing the delicate host-tumor balance. These data illustrate the importance of considering microbiomes in the ongoing efforts to identify new biomarkers and develop new effective cancer therapies.
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Cancer Induces a Stress Ileopathy Depending on β-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis
Yonekura S, Terrisse S, Alves Costa Silva C, Lafarge A, Iebba V, Ferrere G, Goubet AG, Fahrner JE, Lahmar I, Ueda K, Mansouri G, Pizzato E, Ly P, Mazzenga M, Thelemaque C, Fidelle M, Jaulin F, Cartry J, Deloger M, Aglave M, Droin N, Opolon P, Puget A, Mann F, Neunlist M, Bessard A, Aymeric L, Matysiak-Budnik T, Bosq J, Hofman P, Duong CPM, Ugolini S, Quiniou V, Berrard S, Ryffel B, Kepp O, Kroemer G, Routy B, Lordello L, Bani MA, Segata N, Yengej FY, Clevers H, Scoazec JY, Pasolli E, Derosa L, Zitvogel L. Cancer Discov. 2022 Apr 1;12(4):1128-1151. doi: 10.1158/2159-8290.CD-21-0999. PMID: 34930787.
Gut dysbiosis has been associated with intestinal and extraintestinal malignancies, but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here, we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. The rapid onset of tumorigenesis induced a burst of REG3γ release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long-lasting dysbiosis dominated by Gram-positive Clostridium species. Pharmacologic blockade of β-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin, or cohousing of tumor bearers with tumor-free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Patients with cancer harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extraintestinal malignancies requiring specific therapies.
Keywords : cancer, immunology, microbiota, immuno-oncology, ileum, immune checkpoint inhibitors, betablockade, β-adrenergic receptors, biogenic amines, Clostridiales, Lactobacilli
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