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Enhanced gut barrier integrity sensitizes colon cancer to immune therapy.

ABSTRACT: Oral IL-10 suppressed tumor growth in the APC^min/+ mouse/Bacteroides fragilis colon cancer model while a similar formulation of IL-12 exacerbated disease. In contrast, combined treatment with IL-10 and IL-12 resulted in near-complete tumor eradication and a significant extension of survival. The cytokines mediated distinct immunological effects in the gut, i.e. IL-10 diminished Th17 cell prevalence whereas IL-12 induced IFNγ and enhanced CD8 + T-cell activity. Loss-of-function studies demonstrated that IL-12-driven CD8 + T-cell expansion was only partially responsible for the synergy, and that both the detrimental and the beneficial activities of IL-12 required IFNγ. Examination of colon physiology in mice receiving single vs dual treatment revealed that exacerbation of disease by IL-12 monotherapy was associated with compromised gut barrier integrity whereas combined treatment reversed this effect, uncovering additional activity by the cytokines on the stroma. Further analysis showed that the stromal effects of IL-12 included a 6-fold increase in IL-10RA expression in the colon epithelium, linking the epithelial activity of the cytokines. Finally, dual but not monotherapy induced a 3-fold increase in tight junction protein levels in the colon, identifying the mechanism by which IL-10 blocked the detrimental effect of the IL-12-IFNγ axis on barrier function without interfering with its beneficial immunological activity. These findings establish that the synergy between IL-12 and IL-10 was mediated by pleiotropic effects on the immune and the non-immune compartments and that the latter activity was critical to therapeutic outcome.

SUBMITTER: Bhutiani N

PROVIDER: S-EPMC6204984 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Acute pancreatitis (AP) is a common abdominal inflammatory disorder and one of the leading causes of hospital admission for gastrointestinal disorders. No specific pharmacological or nutritional therapy is available but highly needed. Inulin-type fructans (ITFs) are capable of modifying gut immune and barrier homeostasis in a chemistry-dependent manner and hence potentially applicable for managing AP, but their efficacy in AP has not been demonstrated yet. The current study aimed to examine and compare modulatory effects of ITFs with different degrees of fermentability on pancreatic-gut immunity and barrier function during experimentally induced AP in mice. BALB/c mice were fed short (I)- or long (IV)-chain ITFs supplemented diets for up to 3 days before AP induction by caerulein. Attenuating effects on AP development were stronger with ITF IV than with ITF I. We found that long-chain ITF IV attenuated the severity of AP, as evidenced by reduced serum amylase levels, lipase levels, pancreatic myeloperoxidase activity, pancreatic edema, and histological examination demonstrating reduced pancreatic damage. Short-chain ITF I demonstrated only partial protective effects. Both ITF IV and ITF I modulated AP-associated systemic cytokine levels. ITF IV but not ITF I restored AP-associated intestinal barrier dysfunction by upregulating colonic tight junction modulatory proteins, antimicrobial peptides, and improved general colonic histology. Additionally, differential modulatory effects of ITF IV and ITF I were observed on pancreatic and gut immunity: ITF IV supplementation prevented innate immune cell infiltration in the pancreas and colon and tissue cytokine production. Similar effects were only observed in the gut with ITF I and not in the pancreas. Lastly, ITF IV but not ITF I downregulated AP-triggered upregulation of IL-1 receptor-associated kinase 4 (IRAK-4) and phosphor-c-Jun N-terminal kinase (p-JNK), and a net decrease of phosphor-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 (p-NF-κB p65) nuclear translocation and activation in the pancreas. Our findings demonstrate a clear chain length-dependent effect of inulin on AP. The attenuating effects are caused by modulating effects of long-chain inulin on the pancreatic-gut immunity via the pancreatic IRAK-4/p-JNK/p-NF-κBp65 signaling pathway and on prevention of disruption of the gut barrier.

Project description:Limosilactobacillus reuteri plays an important role in regulating intestinal functions and maintaining barrier integrity in animals. In this study, Limosilactobacillus reuteri strain SLZX19-12 was isolated from the fecal microbiota of Tibetan pigs, and it was found that this strain is sensitive to common antibiotics and has strong resistance to stress. Upon being administered by gavage at different doses, including low, medium, and high doses, for 14 days, Limosilactobacillus reuteri SLZX19-12 may enhance the intestinal barrier. After administration of a high dose of SLZX19-12, mice were challenged with Salmonella enterica serovar Typhimurium SL1344. Infection with Salmonella Typhimurium SL1344 led to disordered colonic microbiotas, colonic inflammation through the S100A8/S100A9-NF-κB pathway and potential apoptosis, and translocation of pathogens to parenteral visceral organs in mice. However, the mice pretreated with Limosilactobacillus reuteri SLZX19-12 showed lower loads of Salmonella in visceral organs, less colonic inflammation, and higher barrier integrity. More importantly, the administration of strain SLZX19-12 resulted in a more stable microbiota structure of the colon, in which the abundance of Alloprevotella was greatly enhanced. Therefore, this study suggests that Limosilactobacillus reuteri SLZX19-12 can protect the colon from infection by enhancing the stability of gut microbiota and barrier integrity and reducing inflammation. IMPORTANCE The use of antibiotics to treat bacterial infections leads to a series of side effects. As an alternative method, the biocontrol strategy, which uses probiotics to suppress pathogens, is considered a potential way to deal with bacterial infections in gut. However, there are few probiotics that are currently safe and can protect against infection. In this study, Limosilactobacillus reuteri strain SLZX19-12 was obtained from Tibetan pigs, which have higher resistance to infection. This strain is sensitive to conventional antibiotics, secretes a wide spectrum of enzymes, and also promotes the intestinal barrier function in mice. In addition, Limosilactobacillus reuteri SLZX19-12 can promote the stability of the gut microbiota to avoid or alleviate the occurrence or development of foodborne infections.

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Enhanced gut barrier integrity sensitizes colon cancer to immune therapy.

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