Ultra-Processed Foods-Dietary Foe or Potential Ally?

The prevalence of non-communicable diseases (NCDs) has steadily increased in the United States. Health experts attribute the increasing prevalence of NCDs, in part, to the consumption of ultra-processed foods (UPFs) based on epidemiological observations. However, no definitive evidence of causality has been established. Consequently, there is an ongoing debate over whether adverse health outcomes may be due to the low nutrient density per kilocalorie, the processing techniques used during the production of UPFs, taste preference-driven overconsumption of calories, or unidentified factors. Recognizing that "the science is not settled," we propose an investigative process in this narrative review to move the field beyond current controversies and potentially identify the basis of causality. Since many consumers depend on UPFs due to their shelf stability, affordability, availability, ease of use, and safety from pathogens, we also suggest a paradigm for guiding both the formulation of UPFs by food designers and the selection of UPFs by consumers.

Complementarity between Microbiome and Immunity May Account for the Potentiating Effect of Quercetin on the Antitumor Action of Cyclophosphamide in a Triple-Negative Breast Cancer Model.

Immunotherapy targeting program cell death protein 1 (PD-1) in addition to chemotherapy has improved the survival of triple-negative breast cancer (TNBC) patients. However, the development of resistance and toxicity remain significant problems. Using the translationally relevant 4T1 mouse model of TNBC, we report here that dietary administration of the phytochemical quercetin enhanced the antitumor action of Cyclophosphamide, a cytotoxic drug with significant immunogenic effects that is part of the combination chemotherapy used in TNBC. We observed that quercetin favorably modified the host fecal microbiome by enriching species such as Akkermansia muciniphilia, which has been shown to improve response to anti-PD-1 therapy. We also show that quercetin and, to a greater extent, Cyclophosphamide increased the systemic frequency of T cells and NK cells. In addition, Cyclophosphamide alone and in combination with quercetin reduced the frequency of Treg, which is consistent with an antitumor immune response. On the other hand, Cyclophosphamide did not significantly alter the host microbiome, suggesting complementarity between microbiome- and immune-mediated mechanisms in potentiating the antitumor action of Cyclophosphamide by quercetin. Overall, these results support the potential for microbiota-centered dietary intervention to overcome resistance to chemoimmunotherapy in TNBC.

Consumption of Common Bean Suppresses the Obesogenic Increase in Adipose Depot Mass: Impact of Dose and Biological Sex.

Obesity prevention is stated as a simple objective in the public health guidelines of most countries: avoid adult weight gain. However, the success of the global population in accomplishing this goal is limited as reflected in the persisting pandemic of overweight and obesity. While many intervention strategies have been proposed, most are directed at mitigating the consequences of obesity. Efforts intended to prevent unintentional weight gain and associated adiposity are termed anti-obesogenic. Herein, evidence is presented that a neglected category of foods, pulses, i.e., grain legumes, have anti-obesogenic activity. Using a preclinical mouse model of obesity, a dose-response study design in animals of both biological sexes, and cooked, freeze-dried, and milled common bean as a representative pulse, data are presented showing that the rate of body weight gain is slowed, and fat accumulation is suppressed when 70% of the dietary protein is provided from common bean. These anti-obesogenic effects are reduced at lower amounts of common bean (17.5% or 35%). The anti-obesogenic responsiveness is greater in female than in male mice. RNA sequence analysis indicates that the sex-related differences extend to gene expression patterns, particularly those related to immune regulation within adipose tissue. In addition, our findings indicate the potential value of a precision nutrition approach for human intervention studies that identify "pulse anti-obesogenic responders". A precision approach may reduce the concentration of pulses required in the diet for benefits, but candidate biomarkers of responsivity to pulse consumption remain to be determined.

Dietary Oncopharmacognosy as a Crosswalk between Precision Oncology and Precision Nutrition.

While diet and nutrition are modifiable risk factors for many chronic and infectious diseases, their role in cancer prevention and control remains under investigation. The lack of clarity of some diet-cancer relationships reflects the ongoing debate about the relative contribution of genetic factors, environmental exposures, and replicative errors in stem cell division as determinate drivers of cancer risk. In addition, dietary guidance has often been based upon research assuming that the effects of diet and nutrition on carcinogenesis would be uniform across populations and for various tumor types arising in a specific organ, i.e., that one size fits all. Herein, we present a paradigm for investigating precision dietary patterns that leverages the approaches that led to successful small-molecule inhibitors in cancer treatment, namely understanding the pharmacokinetics and pharmacodynamics of small molecules for targeting carcinogenic mechanisms. We challenge the scientific community to refine the paradigm presented and to conduct proof-in-concept experiments that integrate existing knowledge (drug development, natural products, and the food metabolome) with developments in artificial intelligence to design and then test dietary patterns predicted to elicit drug-like effects on target tissues for cancer prevention and control. We refer to this precision approach as dietary oncopharmacognosy and envision it as the crosswalk between the currently defined fields of precision oncology and precision nutrition with the goal of reducing cancer deaths.

Natural Products in Precision Oncology: Plant-Based Small Molecule Inhibitors of Protein Kinases for Cancer Chemoprevention.

Striking progress is being made in cancer treatment by using small molecule inhibitors of specific protein kinases that are products of genes recognized as drivers for a specific type of cancer. However, the cost of newly developed drugs is high, and these pharmaceuticals are neither affordable nor accessible in most parts of the world. Accordingly, this narrative review aims to probe how these recent successes in cancer treatment can be reverse-engineered into affordable and accessible approaches for the global community. This challenge is addressed through the lens of cancer chemoprevention, defined as using pharmacological agents of natural or synthetic origin to impede, arrest, or reverse carcinogenesis at any stage in the disease process. In this regard, prevention refers to reducing cancer-related deaths. Recognizing the clinical successes and limitations of protein kinase inhibitor treatment strategies, the disciplines of pharmacognosy and chemotaxonomy are juxtaposed with current efforts to exploit the cancer kinome to describe a conceptual framework for developing a natural product-based approach for precision oncology.

Thwarting Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) with Common Bean: Dose- and Sex-Dependent Protection against Hepatic Steatosis.

Hepatic steatosis signifies onset of metabolic dysfunction-associated fatty liver disease (MAFLD) caused by disrupted metabolic homeostasis compromising liver function. Regular consumption of common beans reduces the risk of metabolic impairment, but its effective dose, the impact of biological sex, and underlying mechanisms of action are unknown. We fed female and male C57BL6/J mice with obesogenic yet isocaloric diets containing 0%, 17.5%, 35%, and 70% of total dietary protein derived from cooked whole common beans. Liver tissue was collected for histopathology, lipid quantification, and RNA-seq analyses. Beans qualitatively and quantitatively diminished hepatic fat deposition at the 35% dose in female and 70% dose in male mice. Bean-induced differentially expressed genes (DEGs) most significantly mapped to hepatic steatosis and revealed dose-responsive inhibition of de novo lipogenesis markers (Acly, Acaca, Fasn, Elovl6, Scd1, etc.) and triacylglycerol biosynthesis, activation of triacylglycerol degradation, and downregulation of sterol regulatory element-binding transcription factor 1 (SREBF1) signaling. Upregulated fatty acid ß-oxidation was more prominent in females, while suppression of Cd36-mediated fatty acid uptake-in males. Sex-dependent bean effects also involved DEGs patterns downstream of peroxisome proliferator-activated receptor α (PPARα) and MLX-interacting protein-like (MLXIPL). Therefore, biological sex determines amount of common bean in the diet required to prevent hepatic lipid accumulation.

Relandscaping the Gut Microbiota with a Whole Food: Dose-Response Effects to Common Bean.

Underconsumption of dietary fiber and the milieu of chemicals with which it is associated is a health concern linked to the increasing global burden of chronic diseases. The benefits of fiber are partially attributed to modulation of the gut microbiota, whose composition and function depend on the amount and quality of microbiota-accessible substrates in the diet. However, not all types of fiber are equally accessible to the gut microbiota. Phaseolus vulgaris L., or common bean, is a food type rich in fiber as well as other prebiotics posing a great potential to positively impact diet-microbiota-host interactions. To elucidate the magnitude of bean's effects on the gut microbiota, increasing doses of common bean were administered in macronutrient-matched diet formulations. The microbial communities in the ceca of female and male mice were evaluated via 16S rRNA gene sequencing. As the bean dose increased, the Bacillota:Bacteroidota ratio (formerly referred to as the Firmicutes:Bacteroidetes ratio) was reduced and α-diversity decreased, whereas the community composition was distinctly different between the diet groups according to ß-diversity. These effects were more pronounced in female mice compared to male mice. Compositional analyses identified a dose-responsive bean-induced shift in microbial composition. With an increasing bean dose, Rikenellaceae, Bacteroides, and RF39, which are associated with health benefits, were enhanced. More taxa, however, were suppressed, among which were Allobaculum, Oscillospira, Dorea, and Ruminococcus, which are predominantly associated with chronic disease risk. Investigation of the origins of the dose dependent and biological sex differences in response to common bean consumption may provide insights into bean-gut microbiota-host interactions important to developing food-based precision approaches to chronic disease prevention and control.

Compositional Changes of the High-Fat Diet-Induced Gut Microbiota upon Consumption of Common Pulses.

The gut microbiome is involved in the host's metabolism, development, and immunity, which translates to measurable impacts on disease risk and overall health. Emerging evidence supports pulses, i.e., grain legumes, as underutilized nutrient-dense, culinarily versatile, and sustainable staple foods that promote health benefits through modulating the gut microbiota. Herein, the effects of pulse consumption on microbial composition in the cecal content of mice were assessed. Male mice were fed an obesogenic diet formulation with or without 35% of the protein component comprised by each of four commonly consumed pulses-lentil (Lens culinaris L.), chickpea (Cicer arietinum L.), common bean (Phaseolus vulgaris L.), or dry pea (Pisum sativum L.). Mice consuming pulses had distinct microbial communities from animals on the pulse-free diet, as evidenced by ß-diversity ordinations. At the phylum level, animals consuming pulses showed an increase in Bacteroidetes and decreases in Proteobacteria and Firmicutes. Furthermore, α-diversity was significantly higher in pulse-fed animals. An ecosystem of the common bacteria that were enhanced, suppressed, or unaffected by most of the pulses was identified. These compositional changes are accompanied by shifts in predicted metagenome functions and are concurrent with previously reported anti-obesogenic physiologic outcomes, suggestive of microbiota-associated benefits of pulse consumption.

Cell Signaling Pathways in Mammary Carcinoma Induced in Rats with Low versus High Inherent Aerobic Capacity.

An inverse association exists between physical activity and breast cancer incidence and outcomes. An objective indicator of an individual's recent physical activity exposure is aerobic capacity. We took advantage of the fact that there is an inherited as well as inducible component of aerobic capacity to show that experimentally induced mammary cancer is inversely related to inherent aerobic capacity (IAC). The objective of this study was to determine whether cell signaling pathways involved in the development of mammary cancer differed in rats with low inherent aerobic capacity (LIAC, n = 55) versus high inherent aerobic capacity (HIAC, n = 57). Cancer burden was 0.21 ± 0.16 g/rat in HIAC versus 1.14 ± 0.45 in LIAC, p < 0.001. Based on protein expression, cancer in LIAC animals was associated with upregulated glucose utilization, and protein and fatty acid synthesis. Signaling in cancers from HIAC rats was associated with energy sensing, fatty acid oxidation and cell cycle arrest. These findings support the thesis that pro-glycolytic, metabolic inflexibility in LIAC favors not only insulin resistance and obesity but also tumor development and growth. This provides an unappreciated framework for understanding how obesity and low aerobic fitness, hallmarks of physical inactivity, are associated with higher cancer risk and poorer prognosis.