scholarly journals Colorectal cancer progression is potently reduced by a glucose-free, high-protein diet: comparison to anti-EGFR therapy

2021 ◽  
Author(s):  
Kerstin Skibbe ◽  
Ann-Kathrin Brethack ◽  
Annika Suenderhauf ◽  
Mohab Ragab ◽  
Annika Raschdorf ◽  
...  
Keyword(s):  
Immune Responses ◽  
Tumor Cells ◽  
Immune Cell ◽  
Aerobic Glycolysis ◽  
High Protein Diet ◽  
High Protein ◽  
Protein Diet ◽  
Intestinal Barrier Function ◽  
High Amino Acid ◽  
Tumor Load

Background & Aims: To enable rapid proliferation, colorectal tumor cells up-regulate epidermal growth factor receptor (EGFR) signaling and perform high level of aerobic glycolysis, resulting in substantial lactate release into the tumor microenvironment and impaired anti-tumor immune responses. We hypothesized that an optimized nutritional intervention designed to reduce aerobic glycolysis of tumor cells may boost EGFR-directed antibody (Ab)-based therapy of pre-existing colitis-driven colorectal carcinoma (CRC). Methods: CRC development was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS) administration to C57BL/6 mice. AOM/DSS treated mice were fed a glucose-free, high-protein diet (GFHPD) or an isoenergetic control diet (CD) in the presence or absence of i.p. injection of PBS, an irrelevant control mIgG2a or an anti-EGFR mIgG2a. Ex vivo, health status, tumor load, metabolism, colonic epithelial cell differentiation and immune cell infiltration were studied. Functional validation was performed in murine and human CRC cell lines MC-38 or HT29-MTX. Results: AOM/DSS treated mice on GFHPD displayed reduced systemic glycolysis, resulting in improved tumoral energy homeostasis and diminished tumor load. Comparable but not additive to an anti-EGFR-Ab therapy, GFHPD was accompanied by enhanced tumoral differentiation and decreased colonic PD-L1 and splenic PD-1 immune checkpoint expression, presumably promoting intestinal barrier function and improved anti-tumor immune responses. In vitro, glucose-free, high-amino acid culture conditions reduced proliferation but improved differentiation of CRC cells in combination with down-regulation of PD-L1 expression. Conclusion: We here found GFHPD to metabolically reprogram colorectal tumors towards balanced OXPHOS, thereby improving anti-tumor T-cell responses and reducing CRC progression with a similar efficacy as EGFR-directed antibody therapy.

scholarly journals Colorectal Cancer Progression Is Potently Reduced by a Glucose-Free, High-Protein Diet: Comparison to Anti-EGFR Therapy

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5817
Author(s):  
Kerstin Skibbe ◽  
Ann-Kathrin Brethack ◽  
Annika Sünderhauf ◽  
Mohab Ragab ◽  
Annika Raschdorf ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cancer Progression ◽  
Goblet Cell ◽  
Aerobic Glycolysis ◽  
Control Diet ◽  
High Protein Diet ◽  
High Protein ◽  
Protein Diet ◽  
High Amino Acid ◽  
Goblet Cell Differentiation

To enable rapid proliferation, colorectal tumor cells up-regulate epidermal growth factor receptor (EGFR) signaling and aerobic glycolysis, resulting in substantial lactate release into the tumor microenvironment and impaired anti-tumor immune responses. We hypothesized that a nutritional intervention designed to reduce aerobic glycolysis may boost the EGFR-directed antibody (Ab)-based therapy of pre-existing colitis-driven colorectal carcinoma (CRC). CRC development was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS) administration to C57BL/6 mice. AOM/DSS-treated mice were fed a glucose-free, high-protein diet (GFHPD) or an isoenergetic control diet (CD) in the presence or absence of an i.p. injection of an anti-EGFR mIgG2a or respective controls. AOM/DSS-treated mice on a GFHPD displayed a reduced systemic glucose metabolism associated with reduced oxidative phosphorylation (OXPHOS) complex IV expression and diminished tumor loads. Comparable but not additive to an anti-EGFR-Ab therapy, the GFHPD was accompanied by enhanced tumoral goblet cell differentiation and decreased colonic PD-L1 and splenic CD3e, as well as PD-1 immune checkpoint expression. In vitro, glucose-free, high-amino acid culture conditions reduced proliferation but improved goblet cell differentiation of murine and human CRC cell lines MC-38 and HT29-MTX in combination with down-regulation of PD-L1 expression. We here found GFHPD to systemically dampen glycolysis activity, thereby reducing CRC progression with a similar efficacy to EGFR-directed antibody therapy.

Luminal dietary protein, not amino acids, induces pancreatic protease via CCK in pancreaticobiliary-diverted rats

2000 ◽  
Vol 278 (6) ◽  
pp. G937-G945 ◽  
Author(s):  
Hiroshi Hara ◽  
Sumika Ohyama ◽  
Tohru Hira
Keyword(s):  
Amino Acids ◽  
Direct Action ◽  
High Protein Diet ◽  
High Protein ◽  
Protein Diet ◽  
Intestinal Lumen ◽  
Casein Diet ◽  
Acid Diet ◽  
High Amino Acid ◽  
Pancreatic Proteases

We determined whether pancreatic adaptation to a high-protein diet depends on ingested protein in the intestinal lumen and whether such adaptation depends on a CCK or capsaicin-sensitive vagal afferent pathway in pancreaticobiliary-diverted (PBD) rats. Feeding a high-casein (60%) diet but not a high-amino acid diet to PBD rats increased pancreatic trypsin and chymotrypsin activities compared with those after feeding a 25% casein diet. In contrast, feeding both the high-nitrogen diets induced pancreatic hypertrophy in PBD rats. These pancreatic changes by the diets were abolished by treatment with devazepide, a CCK-A receptor antagonist. Protease zymogen mRNA abundance in the PBD rat was not increased by feeding the high-casein diet and was decreased by devazepide. Perivagal capsaicin treatment did not influence the values of any pancreatic variables in PBD rats fed the normal or high-casein diet. We concluded that luminal protein or peptides were responsible for the bile pancreatic juice-independent induction of pancreatic proteases on feeding a high-protein diet. The induction was found to be dependent on the direct action of CCK on the pancreas. Pancreatic growth induced by high-protein feeding in PBD rats may depend at least partly on absorbed amino acids.

scholarly journals A high-protein diet increases faecal IgA concentrations in baby pigs

2008 ◽  
Vol 67 (OCE5) ◽  
Author(s):  
F. Vitari ◽  
A. Morise ◽  
M. Formal ◽  
C. Garcia ◽  
K. Mace ◽  
...  
Keyword(s):  
High Protein Diet ◽  
High Protein ◽  
Protein Diet

scholarly journals Measurement of the Intestinal pH in Mice under Various Conditions Reveals Alkalization Induced by Antibiotics

Antibiotics ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 180
Author(s):  
Kouki Shimizu ◽  
Issei Seiki ◽  
Yoshiyuki Goto ◽  
Takeshi Murata
Keyword(s):  
Antibiotic Treatment ◽  
High Protein Diet ◽  
Intestinal Bacteria ◽  
High Protein ◽  
Protein Diet ◽  
Germ Free ◽  
Treatment Regimens ◽  
Ph Values ◽  
Specific Pathogen ◽  
The Stability

The intestinal pH can greatly influence the stability and absorption of oral drugs. Therefore, knowledge of intestinal pH is necessary to understand the conditions for drug delivery. This has previously been measured in humans and rats. However, information on intestinal pH in mice is insufficient despite these animals being used often in preclinical testing. In this study, 72 female ICR mice housed in SPF (specific pathogen-free) conditions were separated into nine groups to determine the intestinal pH under conditions that might cause pH fluctuations, including high-protein diet, ageing, proton pump inhibitor (PPI) treatment, several antibiotic treatment regimens and germ-free mice. pH was measured in samples collected from the ileum, cecum and colon, and compared to control animals. An electrode, 3 mm in diameter, enabled accurate pH measurements with a small amount of gastrointestinal content. Consequently, the pH values in the cecum and colon were increased by high-protein diet, and the pH in the ileum was decreased by PPI. Drastic alkalization was induced by antibiotics, especially in the cecum and colon. The alkalized pH values in germ-free mice suggested that the reduction in the intestinal bacteria caused by antibiotics led to alkalization. Alkalization of the intestinal pH caused by antibiotic treatment was verified in mice. We need further investigations in clinical settings to check whether the same phenomena occur in patients.

scholarly journals The Colonic Microbiome and Epithelial Transcriptome Are Altered in Rats Fed a High-Protein Diet Compared with a Normal-Protein Diet

2016 ◽  
Vol 146 (3) ◽  
pp. 474-483 ◽  
Author(s):  
Chunlong Mu ◽  
Yuxiang Yang ◽  
Zhen Luo ◽  
Leluo Guan ◽  
Weiyun Zhu
Keyword(s):  
High Protein Diet ◽  
High Protein ◽  
Protein Diet ◽  
Normal Protein Diet

scholarly journals Effect of a High Protein Diet on Calcium Metabolism in Sheep

1991 ◽  
Vol 62 (7) ◽  
pp. 628-635
Author(s):  
Masayuki FUNABA ◽  
Hajime NABETA ◽  
Hideo YANO ◽  
Ryoji KAWASHIMA
Keyword(s):  
Calcium Metabolism ◽  
High Protein Diet ◽  
High Protein ◽  
Protein Diet

Interactions of insulin-like growth factor (IGF)-II and growth hormone in vivo: circulating levels of IGF-I and IGF-binding proteins in transgenic mice

1997 ◽  
pp. 701-708 ◽  
Author(s):  
A Blackburn ◽  
RA Dressendorfer ◽  
WF Blum ◽  
M Erhard ◽  
G Brem ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Transgene Expression ◽  
High Protein Diet ◽  
High Protein ◽  
Protein Diet ◽  
Standard Diet ◽  
Igf I ◽  
Igf Binding ◽  
B Mice

To study interactions between insulin-like growth factor-II (IGF-II) and growth hormone (GH) in vivo, we crossed hemizygous transgenic mice carrying phosphoenolpyruvate carboxykinase (PEPCK)-IGF-II fusion genes with hemizygous PEPCK-bovine GH (bGH) transgenic mice. Offspring harbouring both transgenes (IB), the IGF-II transgene (I) or the bGH transgene (B), and non-transgenic littermates (C) were obtained. Blood samples were taken before (end of week 12) and after (end of week 14) the mice had received a diet high in protein and low in carbohydrates to stimulate PEPCK promoter-controlled transgene expression. Mean serum GH concentrations of both B and IB mice corresponded to 900 ng/ml and increased more than twofold (P < 0.001) after 1 week of the high-protein diet. GH concentrations in controls and I mice were less than 20 ng/ml. Serum IGF-II concentrations in I and IB mice were three-to fourfold higher than those in C and B mice. Whereas IGF-II concentrations were not changed by the high-protein diet in the last two groups, serum IGF-II increased significantly in I (P < 0.001) and IB mice (P < 0.05). This increase was significantly (P < 0.05) less pronounced in IB than in C and I mice. Circulating IGF-I concentrations were about twofold (P < 0.001) higher in B and IB than in C and I mice, and showed a tendency to be lower in I than in C and in IB than in B mice when animals were maintained on the standard diet. The high-protein diet did not change circulating IGF-I concentrations in controls and B mice, but resulted in a significant reduction of serum IGF-I concentrations in I (P < 0.05) and IB mice (P < 0.001). Consequently, after PEPCK-IGF-II transgene expression was stimulated, serum IGF-I concentrations were significantly (P < 0.05) lower in I than in C and in IB than in B mice. Serum IGF-binding protein (IGFBP)-2 concentrations were significantly (P < 0.05) higher in I mice than in all other groups when mice were maintained on the standard diet, with a tendency to reduced IGFBP-2 concentrations in B mice. After the high-protein diet, serum IGFBP-2 concentrations did not change in C and I mice, but increased by two- to threefold in B and IB mice (P < 0.001). Serum IGFBP-3 concentrations tended to be greater in B and IB than in C and I mice, but these differences were mostly not significant. IGFBP-4 concentrations were significantly (P < 0.001) increased by GH overproduction in B and IB mice. Our data suggest that the reduction in circulating IGF-I concentrations by increased IGF-II is most probably due to the limited serum IGF binding capacity and the short half-life of free IGFs, rather than to a reduction in GH-dependent IGF-I production. Effects of GH overproduction on serum IGFBP-2 concentrations depend on dietary factors and may be both inhibitory and stimulatory.

scholarly journals Adaptive changes in the capacity of systems used for the synthesis of citrulline in rat liver mitochondria in response to high- and low-protein diets

1974 ◽  
Vol 142 (2) ◽  
pp. 359-364 ◽  
Author(s):  
J. D. McGivan ◽  
Norah M. Bradford ◽  
J. B. Chappell
Keyword(s):  
Nitrogen Source ◽  
High Protein Diet ◽  
Liver Mitochondria ◽  
High Protein ◽  
Protein Diet ◽  
Rat Liver Mitochondria ◽  
Standard Diet ◽  
Adaptive Changes ◽  
Low Protein ◽  
Citrulline Synthesis

1. Citrulline synthesis was measured in mitochondria from rats fed on a standard diet, a high-protein diet, or on glucose. 2. With NH4Cl as the nitrogen source the rate of citrulline synthesis was higher in mitochondria from rats fed on a high-protein diet than in those from rats fed on a standard diet. When rats were fed solely on glucose the rate of synthesis of citrulline from NH4Cl was very low. 3. With glutamate as the nitrogen source the relative rates of citrulline synthesis were much lower than when NH4Cl was present, but similar adaptive changes occurred. 4. The activity of the mitochondrial glutamate-transporting system increased two to three times on feeding rats on a high-protein diet, but the Km for glutamate was unchanged. 5. Adaptive changes in certain intramitochondrial enzymes were also measured. 6. The results were interpreted to indicate that when an excess of substrate was present, citrulline synthesis from NH4Cl was rate-limited by the intramitochondrial concentration of N-acetyl-glutamate, but citrulline synthesis from glutamate was rate-limited primarily by the activity of the glutamate-transporting system.

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