Biology subjects

Sina, C.

Publications and source records attributed to Sina, C..

5 recordsLinked to original sources

bioRxiv2022

Experimental Diets Dictate the Metabolic Benefits of Lactobacillus Strains in Obesity

BackgroundGrowing evidence supports the use of probiotics to prevent or mitigate obesity-related dysmetabolism and non-alcoholic fatty liver disease (NAFLD). However, frequent reports of responders versus non-responders to probiotic treatment warrant a better understanding of key modifiers of host-microbe interactions. The influence of host diet on probiotic efficacy, in particular against metabolic diseases, remains elusive. MethodWe fed C57BL6/J mice a low fat reference diet or one of two energy-matched high fat and high sucrose diets for 12 weeks; a classical high fat diet (HFD) and a customized fast food-mimicking diet (FFMD). During the studies, mice fed either obesogenic diet were gavaged daily with one of two probiotic lactic acid bacteria (LAB) strains previously classified as Lactobaccillus, namely Limosilactobacillus reuteri (L. reuteri) or Lacticaseibacillus paracasei subsp. paracasei (L. paracasei), or vehicle. ResultsThe tested probiotics exhibited a reproducible efficacy but dichotomous response according to the obesogenic diets used. Indeed, L. paracasei prevented weight gain, improved insulin sensitivity, and protected against NAFLD development in mice fed HFD, but not FFMD. Conversely, L. reuteri improved glucoregulatory capacity, reduced NAFLD development, and increased distal gut bile acid levels associated with changes in predicted functions of the gut microbiota exclusively in the context of FFMD-feeding. ConclusionWe found that the probiotic efficacy of two LAB strains is highly dependent on experimental obesogenic diets. These findings highlight the need to carefully consider the confounding impact of diet in order to improve both the reproducibility of preclinical probiotic studies and their clinical research translatability. Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

microbiology↗

bioRxiv2021

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

Background & AimsTo 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). MethodsCRC 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. ResultsAOM/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. ConclusionWe 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. SynopsisConsumption of glucose-free, high protein diet (GFHPD), comparable to EGFR-directed antibody-based therapy, efficaciously dampens colorectal tumor burden but does not have additive effects in combination with anti-EGFR therapy. GFHPD boosts amino acid metabolism, resulting in improved tumor differentiation and anti-tumor immune responses. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/448354v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@e0c8fforg.highwire.dtl.DTLVardef@1abee36org.highwire.dtl.DTLVardef@a41e22org.highwire.dtl.DTLVardef@b678ab_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

Loss of p32 triggers energy deficiency and impairs goblet cell differentiation in ulcerative colitis

Cell differentiation in the colonic crypt is driven by a metabolic switch from glycolysis to mitochondrial oxidation. Mitochondrial and goblet cell (GC) dysfunction have been attributed to the pathology of ulcerative colitis (UC). We hypothesized that p32/gC1qR/HABP1, which critically maintains oxidative phosphorylation, is involved in GC differentiation and hence in the pathogenesis of UC. In UC patients in remission, colonic GC differentiation was significantly decreased compared to controls in a p32-dependent manner. Plasma/serum lactate and colonic pAMPK level were increased, pointing at high glycolytic activity and energy deficiency. Consistently, p32 silencing in mucus-secreting HT29-MTX cells abolished butyrate-induced differentiation and induced a shift towards glycolysis. In mitochondrial respiratory chain complex V-deficient mice, colonic p32 expression correlated with loss of differentiated GCs, resulting in a thinner mucus layer. Conversely, feeding mice an isocaloric glucose-free, high-protein diet increased mucosal energy supply that promoted colonic p32 level, GC differentiation and mucus production. We here describe a new molecular mechanism linking mucosal energy deficiency in UC to impaired p32-dependent GC differentiation that may be therapeutically prevented by nutritional intervention.

molecular biology↗

bioRxiv2019

Lysates of Methylococcus capsulatus Bath induce a lean-like microbiota, intestinal FoxP3+RORγt+IL-17+ Tregs and improve metabolism

Interactions between host and gut microbial communities may be modulated by diets and play pivotal roles in securing immunological homeostasis and health. Here we show that intake of feed based on whole-cell lysates of the non-commensal bacterium Methylococcus capsulatus Bath (McB) as protein source reversed high fat high sucrose-induced changes in the gut microbiota to a state resembling that of lean, low fat diet-fed mice, both under mild thermal stress (T22{degrees}C) and at thermoneutrality (T30{degrees}C). McB feeding selectively upregulated triple positive (Foxp3+ROR{gamma}t+IL-17+) regulatory T cells in the small intestine and colon, and enhanced mucus production and glycosylation status suggesting improved gut health. Mice receiving McB lysates further exhibited improved glucose regulation, reduced body and liver fat along with diminished hepatic immune infiltration. Collectively, these data points towards profound whole-body effects elicited by the McB lysate suggesting that it may serve as a potent modulator of immunometabolic homeostasis.

immunology↗

bioRxiv2018

Maternally inherited differences within mitochondrial Complex I control murine healthspan.

Mitochondrial complex I, the largest enzyme complex of the mitochondrial oxidative phosphorylation machinery, has been proposed to contribute to a variety of age-related pathological alterations as well as longevity. The enzyme complex-consisting proteins are encoded by both nuclear (nDNA) and mitochondrial DNA (mtDNA). While some association studies of mtDNA-encoded complex I genes and lifespan in humans have been reported, experimental evidence and the functional consequence of such variants is limited to studies using invertebrate models. Here, we present experimental evidence that a homoplasmic mutation in the mitochondrially encoded complex I gene mt-Nd2 modulates lifespan by altering cellular tryptophan levels and, consequently, ageing-related pathways in mice. A conplastic mouse strain carrying a mutation at m.4738C>A in mt-Nd2 lived significantly shorter than the controls did. The same mutation led to a higher susceptibility to glucose intolerance induced by high-fat diet feeding. These phenotypes were not observed in mice carrying a mutation in another mtDNA-encoded complex I gene, mt-Nd5, suggesting the functional relevance of particular mutations in complex I to ageing and age-related diseases.

genetics↗