Hepatocyte-Specific Fads1 Overexpression Attenuates Western Diet-Induced Metabolic Phenotypes in a Rat Model.

Fatty acid desaturase 1 (FADS1) is a rate-limiting enzyme in long-chain polyunsaturated fatty acid (LCPUFA) synthesis. Reduced activity of FADS1 was observed in metabolic dysfunction-associated steatotic liver disease (MASLD). The aim of this study was to determine whether adeno-associated virus serotype 8 (AAV8) mediated hepatocyte-specific overexpression of Fads1 (AAV8-Fads1) attenuates western diet-induced metabolic phenotypes in a rat model. Male weanling Sprague-Dawley rats were fed with a chow diet, or low-fat high-fructose (LFHFr) or high-fat high-fructose diet (HFHFr) ad libitum for 8 weeks. Metabolic phenotypes were evaluated at the endpoint. AAV8-Fads1 injection restored hepatic FADS1 protein levels in both LFHFr and HFHFr-fed rats. While AAV8-Fads1 injection led to improved glucose tolerance and insulin signaling in LFHFr-fed rats, it significantly reduced plasma triglyceride (by ~50%) and hepatic cholesterol levels (by ~25%) in HFHFr-fed rats. Hepatic lipidomics analysis showed that FADS1 activity was rescued by AAV8-FADS1 in HFHFr-fed rats, as shown by the restored arachidonic acid (AA)/dihomo-γ-linolenic acid (DGLA) ratio, and that was associated with reduced monounsaturated fatty acid (MUFA). Our data suggest that the beneficial role of AAV8-Fads1 is likely mediated by the inhibition of fatty acid re-esterification. FADS1 is a promising therapeutic target for MASLD in a diet-dependent manner.

Western diet increases brain metabolism and adaptive immune responses in a mouse model of amyloidosis.

Diet-induced increase in body weight is a growing health concern worldwide. Often accompanied by a low-grade metabolic inflammation that changes systemic functions, diet-induced alterations may contribute to neurodegenerative disorder progression as well. This study aims to non-invasively investigate diet-induced metabolic and inflammatory effects in the brain of an APPPS1 mouse model of Alzheimer's disease. [18F]FDG, [18F]FTHA, and [18F]GE-180 were used for in vivo PET imaging in wild-type and APPPS1 mice. Ex vivo flow cytometry and histology in brains complemented the in vivo findings. 1H- magnetic resonance spectroscopy in the liver, plasma metabolomics and flow cytometry of the white adipose tissue were used to confirm metaflammatory condition in the periphery. We found disrupted glucose and fatty acid metabolism after Western diet consumption, with only small regional changes in glial-dependent neuroinflammation in the brains of APPPS1 mice. Further ex vivo investigations revealed cytotoxic T cell involvement in the brains of Western diet-fed mice and a disrupted plasma metabolome. 1H-magentic resonance spectroscopy and immunological results revealed diet-dependent inflammatory-like misbalance in livers and fatty tissue. Our multimodal imaging study highlights the role of the brain-liver-fat axis and the adaptive immune system in the disruption of brain homeostasis in amyloid models of Alzheimer's disease.

Diet changes due to urbanization in South Africa are linked to microbiome and metabolome signatures of Westernization and colorectal cancer.

Transition from traditional high-fiber to Western diets in urbanizing communities of Sub-Saharan Africa is associated with increased risk of non-communicable diseases (NCD), exemplified by colorectal cancer (CRC) risk. To investigate how urbanization gives rise to microbial patterns that may be amenable by dietary intervention, we analyzed diet intake, fecal 16 S bacteriome, virome, and metabolome in a cross-sectional study in healthy rural and urban Xhosa people (South Africa). Urban Xhosa individuals had higher intakes of energy (urban: 3,578 ± 455; rural: 2,185 ± 179 kcal/d), fat and animal protein. This was associated with lower fecal bacteriome diversity and a shift from genera favoring degradation of complex carbohydrates (e.g., Prevotella) to taxa previously shown to be associated with bile acid metabolism and CRC. Urban Xhosa individuals had higher fecal levels of deoxycholic acid, shown to be associated with higher CRC risk, but similar short-chain fatty acid concentrations compared with rural individuals. Fecal virome composition was associated with distinct gut bacterial communities across urbanization, characterized by different dominant host bacteria (urban: Bacteriodota; rural: unassigned taxa) and variable correlation with fecal metabolites and dietary nutrients. Food and skin microbiota samples showed compositional differences along the urbanization gradient. Rural-urban dietary transition in South Africa is linked to major changes in the gut microbiome and metabolome. Further studies are needed to prove cause and identify whether restoration of specific components of the traditional diet will arrest the accelerating rise in NCDs in Sub-Saharan Africa.

A Perspective Review on Diet Quality, Excess Adiposity, and Chronic Psychosocial Stress and Implications for Early-Onset Colorectal Cancer.

Colorectal cancer (CRC) is the third most common cancer worldwide. Although the overall incidence of CRC has been decreasing over the past 40 y, early-onset colorectal cancer (EOCRC), which is defined as a CRC diagnosis in patients aged >50 y has increased. In this Perspective, we highlight and summarize the association between diet quality and excess adiposity, and EOCRC. We also explore chronic psychosocial stress (CPS), a less investigated modifiable risk factor, and EOCRC. We were able to show that a poor-quality diet, characterized by a high intake of sugary beverages and a Western diet pattern (high intake of red and processed meats, refined grains, and foods with added sugars) can promote risk factors associated with EOCRC development, such as an imbalance in the composition and function of the gut microbiome, presence of chronic inflammation, and insulin resistance. Excess adiposity, particularly obesity onset in early adulthood, is a likely contributor of EOCRC. Although the research is sparse examining CPS and CRC/EOCRC, we describe likely pathways linking CPS to tumorigenesis. Although additional research is needed to understand what factors are driving the uptick in EOCRC, managing body weight, improving diet quality, and mitigating psychosocial stress, may play an important role in reducing an individual's risk of EOCRC.

A Mouse Model of Non-Alcoholic Steatohepatitis and Hepatocellular Carcinoma Induced by Western Diet and Carbon Tetrachloride.

Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD). Obesity is a known risk factor of NASH, which, in turn, increases the risk of developing cirrhosis (liver scarring) and hepatocellular carcinoma (HCC). In addition to being a potentially life-threatening condition, public health concerns surrounding NASH are amplified by the lack of FDA-approved treatments. Although various preclinical models reflecting both the histopathology and the pathophysiological progression of human NASH exist, most of these models are diet-based and require 6-13 months for NASH symptom manifestation. Here, we describe a simple and rapid-progression model of NASH and NASH-driven HCC in mice. Mice received a western diet equivalent (WD; i.e., a high-fat, high-fructose, and high-cholesterol diet), high-sugar water (23.1 g/L fructose and 18.9 g/L glucose), and weekly intraperitoneal injections of carbon tetrachloride (CCl4) at a dose of 0.2 µL/g of body weight. The resulting phenotype, consisting in liver fibrosis and HCC, appeared within 24 weeks of diet/treatment initiation and presented similar histological and transcriptomic features as human NASH and NASH-driven HCC, thereby supporting the adequacy of this preclinical model for the development and evaluation of drugs that can prevent or reverse these diseases.

Spatial Omics Reveals that Cancer-Associated Glycan Changes Occur Early in Liver Disease Development in a Western Diet Mouse Model of MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disease and comprises different stages of liver damage; it is significantly associated with obese and overweight patients. Untreated MASLD can progress to life-threatening end-stage conditions, such as cirrhosis and liver cancer. N-Linked glycosylation is one of the most common post-translational modifications in the cell surface and secreted proteins. N-Linked glycan alterations have been established to be signatures of liver diseases. However, the N-linked glycan changes during the progression of MASLD to liver cancer are still unknown. Here, we induced different stages of MASLD in mice and liver-cancer-related phenotypes and elucidated the N-glycome profile during the progression of MASLD by quantitative and qualitative profiling in situ using matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS). Importantly, we identified specific N-glycan structures including fucosylated and highly branched N-linked glycans at very early stages of liver injury (steatosis), which in humans are associated with cancer development, establishing the importance of these modifications with disease progression. Finally, we report that N-linked glycan alterations can be observed in our models by MALDI-IMS before liver injury is identified by histological analysis. Overall, we propose these findings as promising biomarkers for the early diagnosis of liver injury in MASLD.

Highland barley ß-glucan supplementation attenuated hepatic lipid accumulation in Western diet-induced non-alcoholic fatty liver disease mice by modulating gut microbiota.

Non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases worldwide. NAFLD is caused by numerous factors, including the genetic susceptibility, oxidative stress, unhealthy diet, and gut microbiota dysbiosis. Among these, gut microbiota is a key factor and plays an important role in the development of NAFLD. Therefore, modulating the composition and structure of gut microbiota might provide a new intervention strategy for NAFLD. Highland barley ß-glucan (HBG) is a polysaccharide that can interact with gut microbiota after entering the lower gastrointestinal tract and subsequently improves NAFLD. Therefore, a Western diet was used to induce NAFLD in mouse models and the intervention effects and underlying molecular mechanisms of HBG on NAFLD mice based on gut microbiota were explored. The results indicated that HBG could regulate the composition of gut microbiota in NAFLD mice. In particular, HBG increased the abundance of short-chain fatty acids (SCFA)-producing bacteria (Prevotella-9, Bacteroides, and Roseburia) as well as SCFA contents. The increase in SCFA contents might activate the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway, thereby improving the liver lipid metabolism disorder and reducing liver lipid deposition.

Nut Consumption and Fertility: a Systematic Review and Meta-Analysis.

The high concentration of omega-3 polyunsaturated fats, dietary fibers, vitamins, minerals, and polyphenols found in nuts suggest their regular consumption may be a simple strategy for improving reproductive health. This systematic review and meta-analysis aimed to present up-to-date evidence regarding the association between nut intake and fertility outcomes in males and females. Ovid MEDLINE, Embase, CINAHL, and Scopus were searched from inception to 30 June 2023. Eligible articles were interventional or observational studies in human subjects of reproductive age (18-49 y) that assessed the effects (or association) of dietary nut consumption (for a minimum of 3 mo) on fertility-related outcomes. Random-effects meta-analyses were completed to produce a pooled effect estimate of nut consumption on sperm total motility, vitality, morphology, and concentration in healthy males. Four studies involving 875 participants (646 males, 229 females) were included in this review. Meta-analysis of 2 RCTs involving 223 healthy males indicated consumption of ≥ 60g nuts/d increased sperm motility, vitality, and morphology in comparison to controls but had no effect on sperm concentration. Nonrandomized studies reported no association between dietary nut intake and conventional sperm parameters in males, embryo implantation, clinical pregnancy or live birth in males and females undergoing ART. Our meta-analysis shows that including at least 2 servings of nuts daily as part of a Western-style diet in healthy males improves sperm parameters, which are predictors of male fertility. Due to their nutritional profile, nuts were found to have potential to promote successful reproductive outcomes. This trial was registered at PROSPERO (CRD42020204586).

High adherence to Western dietary pattern increases breast cancer risk (an EPIC-Spain study).

OBJECTIVE: To explore the association between three previously identified and validated dietary patterns (Western, Prudent and Mediterranean) and breast cancer risk by tumour subtype and menopausal status. METHODS: Data from the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition study provided epidemiological information (including diet and cancer incidence) from 24,892 women (639 breast cancer cases) recruited between 1992 and 1996. The associations between adherence to the three dietary patterns and breast cancer risk (overall and by tumour subtype) were explored by fitting multivariate Cox proportional hazards regression models stratified by region, among other variables. A possible interaction with menopausal status (changing over time) was explored. RESULTS: No clear association of the Prudent and Mediterranean dietary patterns with breast cancer risk was found. When compared with women with a level of adherence to the Western diet in the first quartile, women with a level of adherence in the third (hazard ratio (95 % confidence interval) (HR(95%CI)):1.37 (1.07;1.77)) and fourth quartiles (1.37 (1.03;1.83)); p for curvature of splines = 0.016) showed a non-linear increased risk, especially postmenopausal women (HR (95 % CI) 1.30 (0.98;1.72) in the third and 1.42 (1.04;1.94) in the fourth quartiles; p for curvature of splines = 0.081) and for estrogen or progesterone receptor positive with human epidermal growth factor receptor 2 negative tumours (HR (95 % CI) 1.62 (1.10;2.38) and 1.71 (1.11;2.63) for the third and fourth quartiles respectively; p for curvature of splines = 0.013). CONCLUSIONS: Intake of foods such as high-fat dairy products, red and processed meats, refined grains, sweets, caloric drinks, convenience food and sauces might be associated with a higher risk of breast cancer.

Oxidative Status of Ultra-Processed Foods in the Western Diet.

Ultra-processed foods (UPFs) have gained substantial attention in the scientific community due to their surging consumption and potential health repercussions. In addition to their well-established poor nutritional profile, UPFs have been implicated in containing various dietary oxidized sterols (DOxSs). These DOxSs are associated with a spectrum of chronic diseases, including cardiometabolic conditions, cancer, diabetes, Parkinson's, and Alzheimer's disease. In this study, we present a comprehensive database documenting the presence of DOxSs and other dietary metabolites in >60 UPFs commonly consumed as part of the Western diet. Significant differences were found in DOxS and phytosterol content between ready-to-eat (RTE) and fast foods (FFs). Biomarker analysis revealed that DOxS accumulation, particularly 25-OH and triol, can potentially discriminate between RTEs and FFs. This work underscores the potential utility of dietary biomarkers in early disease detection and prevention. However, an essential next step is conducting exposure assessments to better comprehend the levels of DOxS exposure and their association with chronic diseases.

Diet-induced shifts in the gut microbiota influence anastomotic healing in a murine model of colonic surgery.

Host diet and gut microbiota interact to contribute to perioperative complications, including anastomotic leak (AL). Using a murine surgical model of colonic anastomosis, we investigated how diet and fecal microbial transplantation (FMT) impacted the intestinal microbiota and if a predictive signature for AL could be determined. We hypothesized that a Western diet (WD) would impact gut microbial composition and that the resulting dysbiosis would correlate with increased rates of AL, while FMT from healthy, lean diet (LD) donors would reduce the risk of AL. Furthermore, we predicted that surgical outcomes would allow for the development of a microbial preclinical translational tool to identify AL. Here, we show that AL is associated with a dysbiotic microbial community characterized by increased levels of Bacteroides and Akkermansia. We identified several key taxa that were associated with leak formation, and developed an index based on the ratio of bacteria associated with the absence and presence of leak. We also highlight a modifiable connection between diet, microbiota, and anastomotic healing, potentially paving the way for perioperative modulation by microbiota-targeted therapeutics to reduce AL.

Refined mackerel oil increases hepatic lipid accumulation and reduces choline and choline-containing metabolites in the liver tissue in mice fed a Western diet.

In this study, we aimed to evaluate the impact of consuming refined mackerel oil (MO) from rest raw material on hepatic fat accumulation, glucose tolerance, and metabolomic changes in the liver from male C57BL/6N mice. The mice were fed either a Western diet (WD) or a chow diet, with 30 g or 60 g MO per kg of diet (3% or 6%) for 13 weeks. Body weight, energy intake, and feed efficiency were monitored throughout the experiment. A glucose tolerance test was conducted after 11 weeks, and metabolomic analyses of the liver were performed at termination. Inclusion of MO in the WD, but not in the chow diet, led to increased liver weight, hepatic lipid accumulation, elevated fasting blood glucose, reduced glucose tolerance, and insulin sensitivity. Hepatic levels of eicosapentaenoic and docosahexaenoic acid increased, but no changes in levels of saturated and monounsaturated fatty acids were observed. The liver metabolomic profile was different between mice fed a WD with or without MO, with a reduction in choline ether lipids, phosphatidylcholines, and sphingomyelins in mice fed MO. This study demonstrates that supplementing the WD, but not the chow diet, with refined MO accelerates accumulation of hepatic fat droplets and negatively affects blood glucose regulation. The detrimental effects of supplementing a WD with MO were accompanied by increased fat digestibility and overall energy intake, and lower levels of choline and choline-containing metabolites in liver tissue.

Adherence to Data-Driven Dietary Patterns and Lung Cancer Risk: A Systematic Review and Dose-Response Meta-Analysis.

The effect of dietary patterns on lung cancer risk is currently debated. In this study, we evaluated the association between different "a posteriori" dietary patterns and lung cancer risk. The search was carried out (February 2023) through Scopus, Web of Science, and PubMed databases. Meta-analysis was performed by a random-effects model using risk values (RR and OR) extracted from the 12 selected studies. Two main dietary patterns were identified and named "Western/meat" and "Healthy/prudent". The highest adherence to the "Western/meat" dietary pattern significantly increased the lung cancer risk (OR = 1.39; 95% CI: 1.17-1.65; p = 0.0002) while the highest adherence to the "Healthy/prudent" pattern reduced it (OR = 0.65; 95% CI: 0.51-0.83; p = 0.001). A linear trend between both dietary patterns and lung cancer risk was observed. However, a statistically significant inverse dose-response trend was found only for the "Healthy/prudent" dietary pattern (regression coefficient = -0.0031, p = 0.003). Subgroup analyses showed that the "Western/meat" pattern significantly increased the lung cancer risk in former (n = 4) (OR = 1.93, 95% CI: 1.11-3.36) and current smokers (n = 7) (OR = 1.35, 95% CI: 1.06-1.71). Similarly, the "Healthy/prudent" pattern exerts a protective effect on former (n = 4) (OR = 0.61, 95% CI: 0.44-0.85) and current smokers (n = 8) (OR = 0.64, 95% CI: 0.46-0.88). For both dietary patterns, no significant effect was observed on never-smokers.

Multi-omic network analysis identified betacellulin as a novel target of omega-3 fatty acid attenuation of western diet-induced nonalcoholic steatohepatitis.

Clinical and preclinical studies established that supplementing diets with ω3 polyunsaturated fatty acids (PUFA) can reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH) but molecular underpinnings of this action were elusive. Herein, we used multi-omic network analysis that unveiled critical molecular pathways involved in ω3 PUFA effects in a preclinical mouse model of western diet induced NASH. Since NASH is a precursor of liver cancer, we also performed meta-analysis of human liver cancer transcriptomes that uncovered betacellulin as a key EGFR-binding protein upregulated in liver cancer and downregulated by ω3 PUFAs in animals and humans with NASH. We then confirmed that betacellulin acts by promoting proliferation of quiescent hepatic stellate cells, inducing transforming growth factor-ß2 and increasing collagen production. When used in combination with TLR2/4 agonists, betacellulin upregulated integrins in macrophages thereby potentiating inflammation and fibrosis. Taken together, our results suggest that suppression of betacellulin is one of the key mechanisms associated with anti-inflammatory and anti-fibrotic effects of ω3 PUFA on NASH.

Differential effects of Western diet and traumatic muscle injury on skeletal muscle metabolic regulation in male and female mice.

BACKGROUND: This study was designed to develop an understanding of the pathophysiology of traumatic muscle injury in the context of Western diet (WD; high fat and high sugar) and obesity. The objective was to interrogate the combination of WD and injury on skeletal muscle mass and contractile and metabolic function. METHODS: Male and female C57BL/6J mice were randomized into four groups based on a two-factor study design: (1) injury (uninjured vs. volumetric muscle loss [VML]) and (2) diet (WD vs. normal chow [NC]). Electrophysiology was used to test muscle strength and metabolic function in cohorts of uninjured + NC, uninjured + WD, VML + NC and VML + WD at 8 weeks of intervention. RESULTS: VML-injured male and female mice both exhibited decrements in muscle mass (-17%, P < 0.001) and muscle strength (-28%, P < 0.001); however, VML + WD females had a 28% greater muscle mass compared to VML + NC females (P = 0.034), a compensatory response not detected in males. VML-injured male and female mice both had lower carbohydrate- and fat-supported muscle mitochondrial respiration (JO2 ) and less electron conductance through the electron transport system (ETS); however, male VML-WD had 48% lower carbohydrate-supported JO2 (P = 0.014) and 47% less carbohydrate-supported electron conductance (P = 0.026) compared to male VML + NC, and this diet-injury phenotype was not present in females. ETS electron conductance starts with complex I and complex II dehydrogenase enzymes at the inner mitochondrial membrane, and male VML + WD had 31% less complex I activity (P = 0.004) and 43% less complex II activity (P = 0.005) compared to male VML + NC. This was a diet-injury phenotype not present in females. Pyruvate dehydrogenase (PDH), ß-hydroxyacyl-CoA dehydrogenase, citrate synthase, α-ketoglutarate dehydrogenase and malate dehydrogenase metabolic enzyme activities were evaluated as potential drivers of impaired JO2 in the context of diet and injury. There were notable male and female differential effects in the enzyme activity and post-translational regulation of PDH. PDH enzyme activity was 24% less in VML-injured males, independent of diet (P < 0.001), but PDH enzyme activity was not influenced by injury in females. PDH enzyme activity is inhibited by phosphorylation at serine-293 by PDH kinase 4 (PDK4). In males, there was greater total PDH, phospho-PDHser293 and phospho-PDH-to-total PDH ratio in WD mice compared to NC, independent of injury (P ≤ 0.041). In females, PDK4 was 51% greater in WD compared to NC, independent of injury (P = 0.025), and was complemented by greater phospho-PDHser293 (P = 0.001). CONCLUSIONS: Males are more susceptible to muscle metabolic dysfunction in the context of combined WD and traumatic injury compared to females, and this may be due to impaired metabolic enzyme functions.

Western diet-induced obesity interferes with the HPA axis-blunting effects of palatable food in male rats.

Limited intermittent consumption of palatable food reduces HPA axis responses to stress in chow-fed rats, and this effect is dependent on the rewarding properties of the palatable food. However, obesity may be a state of reduced consummatory food reward, suggesting that palatable foods may be less effective at blunting HPA axis reactivity in the context of diet-induced obesity (DIO). To test this hypothesis, adult male Long-Evans rats were given unlimited access to Western (high-fat, high-sugar) diet (WD) vs. normal chow (controls). After 8 weeks of diet exposure, rats were given limited sucrose intake (LSI) consisting of additional twice-daily access to a small amount (4 ml) of either 3% or 30% sucrose drink, or water (controls) for 2 weeks. Rats then received an acute restraint stress challenge, with collection of tail blood samples for measurement of plasma corticosterone. WD-fed rats had increased caloric intake, body weight and adiposity, as expected. Rats offered LSI (3% or 30%) readily drank the maximal amount allowed (8 ml/day) and reduced their dietary intake to compensate for the sucrose calories, such that LSI did not alter body weight regardless of diet type. In chow-fed lean rats, LSI with either 3% or 30% sucrose reduced the plasma corticosterone response to restraint stress, but this effect was absent in WD-fed DIO rats. Together, these data support the hypothesis that obesity attenuates stress blunting by palatable foods and suggest the possibility that consequently, individuals with obesity may need to consume larger amounts of palatable food to obtain adequate stress relief.

Association between Dietary Indices and Dietary Patterns and Mortality and Cancer Recurrence among Cancer Survivors: An Updated Systematic Review and Meta-Analysis of Cohort Studies.

The number of cancer survivors is growing rapidly; however, specific lifestyle recommendations for these patients are still sparse, including dietary approaches. Thus, the aim of the present systematic review and meta-analysis was to examine the associations between adherence to diet-quality indices and dietary patterns on overall mortality, cancer-specific mortality, and cancer recurrence among cancer survivors. The literature search was conducted in PubMed and Web of Science between 18 May 2016 and 22 May 2022 with no language restrictions. Thirty-nine studies were included for quantitative analysis, providing data from 77,412 participants. Adherence to both diet-quality indices and a healthy/prudent dietary pattern was inversely associated with overall mortality (RR, 0.81; 95% CI, 0.77-0.86; RR, 0.80; 95% CI, 0.70-0.92, respectively) and with cancer-specific mortality (RR, 0.86; 95% CI, 0.79-0.94; RR, 0.79; 95% CI, 0.64-0.97, respectively). These associations could be observed following assessment of dietary patterns either pre- and/or postdiagnosis. For unhealthy/western dietary patterns, high adherence was associated with overall mortality (RR, 1.26; 95% CI, 1.08-1.47). Although the certainty of evidence was rated as low, we conclude that there are no reservations against high adherence to healthy dietary patterns or indices in cancer survivors.

Western Diet-induced Transcriptional Changes in Anastomotic Tissue Is Associated With Early Local Recurrence in a Mouse Model of Colorectal Surgery.

OBJECTIVE: To determine the timeframe and associated changes in the microenvironment that promote the development of a diet-induced local-regional recurrence in a mouse model of colorectal surgery. BACKGROUND: Postoperative recurrence and metastasis occur in up to 30% of patients undergoing attempted resection for colorectal cancer (CRC). The underlying mechanisms that drive the development of postoperative recurrences are poorly understood. Preclinical studies have demonstrated a diet and microbial-driven pathogenesis of local-regional recurrence, yet the precise mechanisms remain undefined. METHODS: BALB/C mice were fed a western diet (WD) or standard diet (SD), underwent a colon resection and anastomosis, given an Enterococcus faecalis enema on postoperative day (POD) 1, and subjected to a CT26 cancer cell enema (mimicking shed cancer cells) on POD2. Mice were sacrificed between POD3 and POD7 and cancer cell migration was tracked. Dynamic changes in gene expression of anastomotic tissue that were associated with cancer cell migration was assessed. RESULTS: Tumor cells were identified in mice fed either a SD or WD in both anastomotic and lymphatic tissue as early as on POD3. Histology demonstrated that these tumor cells were viable and replicating. In WD-fed mice, the number of tumor cells increased over the early perioperative period and was significantly higher than in mice fed a SD. Microarray analysis of anastomotic tissue found that WD-fed mice had 11 dysregulated genes associated with tumorigenesis. CONCLUSIONS: A WD promotes cancer cells to permeate a healing anastomosis and migrate into anastomotic and lymphatic tissue forming viable tumor nodules. These data offer a novel recurrence pathogenesis by which the intestinal microenvironment promotes a CRC local-regional recurrence.

Adherence to a "Western-type" dietary pattern is positively associated with the Apnea-Hypopnea Index in adults with obstructive sleep apnea.

Dietary habits have been associated with obstructive sleep apnea (OSA); however, the underlying mechanisms remain unclear. We hypothesized that adherence to dietary patterns may be associated with Apnea-Hypopnea Index (AHI) and OSA severity and that insulin resistance, oxidative stress, and inflammation may act as potential mediators of these associations. This was a cross-sectional study among 269 adult participants with polysomnography-diagnosed moderate-to-severe OSA. Dietary and physical activity habits were assessed through validated questionnaires, and biochemical, inflammatory, and oxidative stress markers were measured for all volunteers. Dietary patterns were identified using principal component analysis, and mediation analyses was also performed. A "Western-type" dietary pattern (characterized by high intakes of full-fat dairy, refined grains, potatoes, red meat, sweets, salty snacks, and soft drinks and low intakes of low-fat dairy and whole grains) was positively associated with AHI. Mediation analyses also revealed that insulin resistance partially explained this association. In multivariable models controlling for age, sex, smoking, socioeconomic status, obesity presence, energy intake, and physical activity level, participants in the highest quartile of adherence to the Western-type dietary pattern had ∼3.5 times higher likelihood of suffering from severe OSA, compared with participants in the lowest quartile of adherence (odds ratio [95% confidence interval]: 3.45 [1.21-9.94], P trend across quartiles: 0.024). After further adjustment for Homeostasis Model of Assessment-Insulin Resistance and high-sensitivity C-reactive protein, this association lost significance. Higher adherence to a less healthy, Western-type dietary pattern is positively associated with AHI and OSA severity, which may partially be mediated through insulin resistance.