RESUMO
Cancer cachexia, or the unintentional loss of body weight in patients with cancer, is a multiorgan and multifactorial syndrome with a complex and largely unknown etiology; however, metabolic dysfunction and inflammation remain hallmarks of cancer-associated wasting. Although cachexia manifests with muscle and adipose tissue loss, perturbations to the gastrointestinal tract may serve as the frontline for both impaired nutrient absorption and immune-activating gut dysbiosis. Investigations into the gut microbiota have exploded within the past two decades, demonstrating multiple gut-tissue axes; however, the link between adipose and skeletal muscle wasting and the gut microbiota with cancer is only beginning to be understood. Furthermore, the most used anticancer drugs (e.g. chemotherapy and immune checkpoint inhibitors) negatively impact gut homeostasis, potentially exacerbating wasting and contributing to poor patient outcomes and survival. In this review, we 1) highlight our current understanding of the microbial changes that occur with cachexia, 2) discuss how microbial changes may contribute to adipose and skeletal muscle wasting, and 3) outline study design considerations needed when examining the role of the microbiota in cancer-induced cachexia.
Assuntos
Caquexia , Microbioma Gastrointestinal , Músculo Esquelético , Neoplasias , Caquexia/metabolismo , Caquexia/microbiologia , Caquexia/etiologia , Humanos , Microbioma Gastrointestinal/fisiologia , Neoplasias/microbiologia , Neoplasias/complicações , Neoplasias/metabolismo , Animais , Músculo Esquelético/metabolismo , Músculo Esquelético/microbiologia , Disbiose/microbiologia , Tecido Adiposo/metabolismo , Tecido Adiposo/microbiologia , Tecido Adiposo/imunologiaRESUMO
Immune cell-driven pathways are linked to cancer cachexia. Tumor presence is associated with immune cell infiltration whereas cytotoxic chemotherapies reduce immune cell counts. Despite these paradoxical effects, both cancer and chemotherapy can cause cachexia; however, our understanding of immune responses in the cachexia condition with cancer and chemotherapy is largely unknown. We sought to advance our understanding of the immunology underlying cancer and cancer with chemotherapy-induced cachexia. CD2F1 mice were given 106 C26 cells, followed by five doses of 5-fluorouracil (5FU; 30 mg/kg LM, ip) or PBS. Indices of cachexia and tumor (TUM), skeletal muscle (SKM), and adipose tissue (AT) immune cell populations were examined using high-parameter flow cytometry. Although 5FU was able to stunt tumor growth, % body weight loss and muscle mass were not different between C26 and C26 + 5FU. C26 increased CD11b+Ly6g+ and CD11b+Ly6cInt inflammatory myeloid cells in SKM and AT; however, both populations were reduced with C26 + 5FU. tSNE analysis revealed 24 SKM macrophage subsets wherein 8 were changed with C26 or C26 + 5FU. C26 + 5FU increased SKM CD11b-CD11c+ dendritic cells, CD11b-NK1.1+ NK-cells, and CD11b-B220+ B-cells, and reduced Ly6cHiCX3CR1+CD206+CD163IntCD11c-MHCII- infiltrated macrophages and other CD11b+Ly6cHi myeloid cells compared with C26. Both C26 and C26 + 5FU had elevated CD11b+F480+CD206+MHCII- or more specifically Ly6cLoCX3CR1+CD206+CD163IntCD11c-MHCII- profibrotic macrophages. 5FU suppressed tumor growth and decreased SKM and AT inflammatory immune cells without protecting against cachexia suggesting that these cells are not required for wasting. However, profibrotic cells and muscle inflammatory/atrophic signaling appear consistent with cancer- and cancer with chemotherapy-induced wasting and remain potential therapeutic targets.NEW & NOTEWORTHY Despite being an immune-driven condition, our understanding of skeletal muscle and adipose tissue immune cells with cachexia is limited. Here, we identified immune cell populations in tumors, skeletal muscle, and adipose tissue in C26 tumor-bearing mice with/without 5-fluorouracil (5FU). C26 and C26 + 5FU had increased skeletal muscle profibrotic macrophages, but 5FU reduced inflammatory myeloid cells without sparing mass. Tumor presence and chemotherapy have contrasting effects on certain immune cells, which appeared not necessary for wasting.
Assuntos
Antineoplásicos , Fluoruracila , Camundongos , Animais , Fluoruracila/efeitos adversos , Caquexia/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/patologia , Antineoplásicos/farmacologiaRESUMO
Cancer cachexia, the unintentional loss of lean mass, contributes to functional dependency, poor treatment outcomes, and decreased survival. While its pathogenicity is multifactorial, metabolic dysfunction remains a hallmark of cachexia. However, significant knowledge gaps exist in understanding the role of skeletal muscle lipid metabolism and dynamics in this condition. We examined skeletal muscle metabolic dysfunction, intramyocellular LD content, LD morphology and subcellular distribution, and LD-mitochondrial interactions using the Lewis Lung Carcinoma (LLC) murine model of cachexia. C57/BL6 male mice (n=20) were implanted with LLC cells [106] in the right flank or underwent PBS sham injections. Skeletal muscle was excised for transmission electron microscopy (TEM; soleus), oil red o/lipid staining (tibialis anterior), and protein (gastrocnemius). LLC mice had a greater number (232%; p=0.006) and size (130%; p=0.023) of intramyocellular LDs further supported by increased oil-red O positive (87%; p=0.0109) and 'very high' oil-red O positive (178%; p=0.0002) fibers compared to controls and this was inversely correlated with fiber size (R2=0.5294; p<0.0001). Morphological analyses of LDs show increased elongation and complexity (aspect ratio: IMF: 9%, p=0.046) with decreases in circularity (circularity: SS: 6%, p=0.042) or roundness (roundness: Whole: 10%, p=0.033; IMF: 8%, p=0.038) as well as decreased LD-mitochondria touch (-15%; p=0.006), contact length (-38%; p=0.036), and relative contact (86%; p=0.004). Further, dysregulation in lipid metabolism (adiponectin, CPT-1b) and LD-associated proteins, perilipin-2 and perilipin-5, in cachectic muscle (p<0.05) were observed. Collectively, we provide evidence that skeletal muscle myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in a preclinical model of cancer cachexia.
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Merriam-Webster and Oxford define a xenobiotic as any substance foreign to living systems. Allura Red AC (a.k.a., E129; FD&C Red No. 40), a synthetic food dye extensively used in manufacturing ultra-processed foods and therefore highly prevalent in our food supply, falls under this category. The surge in synthetic food dye consumption during the 70s, and 80s was followed by an epidemic of metabolic diseases and the emergence of early onset colorectal cancer (EOCRC) in the 1990s. This temporal association raises significant concerns, particularly given the widespread inclusion of synthetic food dyes in ultra-processed products, notably those marketed towards children. Given its interactions with key contributors to colorectal carcinogenesis such as inflammatory mediators, the microbiome, and DNA damage, there is growing interest in understanding Allura Red AC's potential impact on colon health as a putative carcinogen. This review discusses the history of Allura Red AC, current research on its effects on the colon and rectum, potential mechanisms underlying its impact on colon health, and provides future considerations. Indeed, although no governing agencies classify Allura Red AC as a carcinogen, its' interaction with key guardians of carcinogenesis makes it suspect and worthy of further molecular investigation. The goal of this review is to inspire research into the impact of synthetic food dyes on colon health.
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Ulcerative colitis (UC) is an idiopathic inflammatory disease of the large intestine, which impacts millions worldwide. Current interventions aimed at treating UC symptoms can have off-target effects, invoking the need for alternatives that may provide similar benefits with less unintended consequences. This study builds on our initial data, which showed that panaxynol-a novel, potent, bioavailable compound found in American ginseng-can suppress disease severity in murine colitis. Here we explore the underlying mechanisms by which panaxynol improves both chronic and acute murine colitis. Fourteen-week-old C57BL/6 female mice were either given three rounds of dextran sulfate sodium (DSS) in drinking water to induce chronic colitis or one round to induce acute colitis. Vehicle or panaxynol (2.5 mg/kg) was administered via oral gavage three times per week for the study duration. Consistent with our previous findings, panaxynol significantly (P < 0.05) improved the disease activity index and endoscopic scores in both models. Using the acute model to examine potential mechanisms, we show that panaxynol significantly (P < 0.05) reduced DSS-induced crypt distortion, goblet cell loss, and mucus loss in the colon. 16S Sequencing revealed panaxynol altered microbial composition to suppress colitis-enriched genera (i.e., Enterococcus, Eubacterium, and Ruminococcus). In addition, panaxynol significantly (P < 0.05) suppressed macrophages and induced regulatory T-cells in the colonic lamina propria. The beneficial effects of panaxynol on mucosal and crypt architecture, combined with its microbial and immune-mediated effects, provide insight into the mechanisms by which panaxynol suppresses murine colitis. Overall, this data is promising for the use of panaxynol to improve colitis in the clinic.NEW & NOTEWORTHY In the current study, we report that panaxynol ameliorates chemically induced murine colitis by improving colonic crypt and mucosal architecture, suppressing colitis-enriched microbes, reducing macrophages, and promoting the differentiation of regulatory T-cells in the colonic lamina propria. This study suggests that this novel natural compound may serve as a safe and effective treatment option for colitis patients.
Assuntos
Colite , Sulfato de Dextrana , Microbioma Gastrointestinal , Mucosa Intestinal , Camundongos Endogâmicos C57BL , Animais , Feminino , Camundongos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/imunologia , Microbioma Gastrointestinal/efeitos dos fármacos , Colite/tratamento farmacológico , Colite/induzido quimicamente , Colite/patologia , Colite/imunologia , Colite/microbiologia , Álcoois Graxos/farmacologia , Di-Inos/farmacologia , Modelos Animais de Doenças , Colo/efeitos dos fármacos , Colo/patologia , Colo/imunologia , Colo/microbiologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/imunologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Colite Ulcerativa/microbiologiaRESUMO
Background People living with HIV continue to face laws, policies, and practices that impact their potential for travel and migration. These laws include: mandatory HIV testing and involuntary disclosure of HIV; lack of access to affordable HIV-related health care, treatment and counselling during the migration process; deportation of foreign nationals living with HIV; and restrictions on the length of stays. Methods HIV migration laws were the topic of a half-day community forum held as part of the 12th International AIDS Society Conference on HIV Science held in Brisbane, Australia, in July 2023. Over 150 delegates attended and, after a series of presentations, delegates were invited to participate in structured, facilitated conversations about issues related to policy, health and law concerning migration of people living with HIV. In this paper, we report on key themes from those discussions and identify areas for ongoing investigation. Results Advocates recommended the removal of unfair and unjust migration laws and policies that contribute to HIV stigma and discrimination; updated migration policies that reflect the current context and cost of biomedical approaches to HIV management and prevention; expanded and equitable access to HIV-related care regardless of migration or residency status; and the development of advocacy networks to promote changes to migration policies. Conclusions Laws limiting the migration of people living with HIV actively discourage individuals from seeking HIV testing, treatment and care. Ultimately, restrictive migration laws and policies undermine global efforts to end AIDS as a public health concern and to virtually eliminate HIV transmission by 2030.
Assuntos
Infecções por HIV , Equidade em Saúde , Acessibilidade aos Serviços de Saúde , Humanos , Emigração e Imigração/legislação & jurisprudência , Estigma Social , Austrália , Saúde Global , Política de Saúde/legislação & jurisprudênciaRESUMO
Increased production of extracellular matrix is a necessary response to tissue damage and stress. In a normal healing process, the increase in extracellular matrix is transient. In some instances; however, the increase in extracellular matrix can persist as fibrosis, leading to deleterious alterations in organ structure, biomechanical properties, and function. Indeed, fibrosis is now appreciated to be an important cause of mortality and morbidity. Extensive research has illustrated that fibrosis can be slowed, arrested or even reversed; however, few drugs have been approved specifically for anti-fibrotic treatment. This is in part due to the complex pathways responsible for fibrogenesis and the undesirable side effects of drugs targeting these pathways. Natural products have been utilized for thousands of years as a major component of traditional medicine and currently account for almost one-third of drugs used clinically worldwide. A variety of plant-derived compounds have been demonstrated to have preventative or even reversal effects on fibrosis. This review will discuss the effects and the underlying mechanisms of some of the major plant-derived compounds that have been identified to impact fibrosis.