Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis

Beyaz, Semir; Chung, Charlie; Mou, Haiwei; Bauer-Rowe, Khristian E.; Xifaras, Michael E.; Ergin, Ilgin; Dohnalová, Lenka; Biton, Moshe; Shekhar, Karthik; Eskiocak, Onur; Papciak, Katherine; Ozler, Kadir; Almeqdadi, Mohammad; Yueh, Brian; Fein, Miriam R.; Annamalai, Damodaran; Valle-Encinas, Eider; Erdemir, Ayşegül Demirhan; Dogum, Karoline; Shah, Vyom; Alici-Garipcan, Aybuke; Meyer, Hannah; Özata, Deniz M.; Elinav, Eran; Küçükural, Alper; Kumar, Perikala V.; McAleer, Jeremy P.; Fox, James G.; Thaiss, Christoph A.; Regev, Aviv; Roper, Jatin; Orkin, Stuart H.; Yılmaz, Ömer H.

doi:10.1016/j.stem.2021.08.007

Cited by 82 publications

(81 citation statements)

References 105 publications

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“…Differentiated gut microbiota compositions are often used to study the regulatory function of intestinal flora. Previous studies showed that a variety of food or drug components, such as pectin, 22 , 50 a high-fiber diet, 51 a high-fat diet, 52 emodin, 53 quercetin 54 and various antibiotics, 55 changed the composition of the intestinal flora and affected its function. Artificially induced intestinal flora dysbiosis using antibiotics in healthy mice raised in the same living environment generated large differences in gut microbiota due to the distinct antimicrobial spectrum, which likely produces considerable differences in pathological responses.…”

Section: Discussionmentioning

confidence: 99%

Bacteroides acidifaciens in the gut plays a protective role against CD95-mediated liver injury

Wang

Yang

et al. 2022

Gut Microbes

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The intestinal flora plays an important role in the development of many human and animal diseases. Microbiome association studies revealed the potential regulatory function of intestinal bacteria in many liver diseases, such as autoimmune hepatitis, viral hepatitis and alcoholic hepatitis. However, the key intestinal bacterial strains that affect pathological liver injury and the underlying functional mechanisms remain unclear. We found that the gut microbiota from gentamycin (Gen)-treated mice significantly alleviated concanavalin A (ConA)-induced liver injury compared to vancomycin (Van)-treated mice by inhibiting CD95 expression on the surface of hepatocytes and reducing CD95/CD95L-mediated hepatocyte apoptosis. Through the combination of microbiota sequencing and correlation analysis, we isolated 5 strains with the highest relative abundance, Bacteroides acidifaciens (BA), Parabacteroides distasonis (PD), Bacteroides thetaiotaomicron (BT), Bacteroides dorei (BD) and Bacteroides uniformis (BU), from the feces of Gen-treated mice. Only BA played a protective role against ConA-induced liver injury. Further studies demonstrated that BA-reconstituted mice had reduced CD95/CD95L signaling, which was required for the decrease in the L-glutathione/glutathione (GSSG/GSH) ratio observed in the liver. BA-reconstituted mice were also more resistant to alcoholic liver injury. Our work showed that a specific murine intestinal bacterial strain, BA, ameliorated liver injury by reducing hepatocyte apoptosis in a CD95-dependent manner. Determination of the function of BA may provide an opportunity for its future use as a treatment for liver disease.

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Section: Discussionmentioning

confidence: 99%

Bacteroides acidifaciens in the gut plays a protective role against CD95-mediated liver injury

Wang

Yang

et al. 2022

Gut Microbes

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“…A 60% fat diet repressed these pathways in Lgr5 hi cells, suggested to be pro-tumorigenic by dampening immune surveillance (Beyaz et al, 2021). The contrasting results in the NWD1 and 60% fat diet models can be due to: first, substantial differences in dietary formulation; second, the dependence of pathway repression by 60% dietary fat on mouse microbiome composition, differing significantly among mouse rooms at the same institution (Beyaz et al, 2021), and likely different among institutions and with different diets; third, NWD1 pathway elevation is in cells derived from mobilized Bmi1+, Ascl2 hi cells, not a feature of the 60% fat model, with the interesting possibility that response may be a function of stem cell of origin. Most important, however, the NWD1 increase in these pathways recapitulates results in humans, with highest expression reported in the upper villi of the human small intestine (Wosen et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Dynamic intestinal stem cell plasticity and lineage remodeling by a nutritional environment relevant to human risk for tumorigenesis

Choi

Zhang

et al. 2022

Preprint

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NWD1, a mouse purified western diet uniquely relevant to human nutritional exposures elevating risk for human sporadic colon cancer rapidly and reversibly altered the stem cell signature and transcriptome of Lgr5hi intestinal stem cells. Down-regulated Ppargc1a expression altered mitochondrial structure and function, metabolically reprogramming Lgr5hi cells, suppressing developmental maturation of their progeny as they progress through progenitor cell compartments. This recruited Bmi1+, Ascl2 cells, remodeling the mucosa, including cell adaptation to the altered nutritional environment and elevated pathways of antigen processing and presentation, especially in mature enterocytes, a pathogenic mechanism in human Inflammatory Bowel Disease resulting in chronic low-level pro-tumorigenic inflammation. Plasticity of intestinal cells to function as stem-like cells encompasses a physiological and continual response to changing nutritional environments, supporting historic concepts of tissue homeostasis as a process of continual adaptation to the environment, with important consequences for mechanisms establishing probability for tumor development. The data emphasize importance of better reflecting human nutritional exposures in mouse models of development and disease.

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“…Recently, Beyaz et al. 3 discovered a new mechanism linking diet and CRC risk via gut microbiota-mediated modulation of anti-tumor immunity.…”

Section: Main Textmentioning

confidence: 99%

“…found that HFDs reduced MHC class II expression in intestinal epithelial cells, and in particular, in ISCs, that was independent of PPAR-δ signaling and obesity that was not diet-related. 3 Using an orthotopic mouse model of CRC in which Lgr5+ ISCs with loss of the tumor suppressor Apc are implanted into the colon, Beyaz et al. demonstrated that MHC class II-negative ISCs exhibited greater tumor-initiating capacity than their MHC class II-positive counterparts in HFD-fed mice.…”

Section: Main Textmentioning

confidence: 99%

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High fat stems tumor immune surveillance

Caruso

Chen

2021

Cell Reports Medicine

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Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis

Cited by 82 publications

References 105 publications

Bacteroides acidifaciens in the gut plays a protective role against CD95-mediated liver injury

Bacteroides acidifaciens in the gut plays a protective role against CD95-mediated liver injury

Dynamic intestinal stem cell plasticity and lineage remodeling by a nutritional environment relevant to human risk for tumorigenesis

High fat stems tumor immune surveillance

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