ArticleLiterature Review

The Role of Diet Related Short-Chain Fatty Acids in Colorectal Cancer Metabolism and Survival: Prevention and Therapeutic Implications

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Abstract

Colorectal Cancer (CRC) is a major cause of cancer-related death worldwide. CRC increased risk has been associated with alterations in the intestinal microbiota, with decreased production of Short Chain Fatty Acids (SCFAs). SCFAs produced in the human colon are the major products of bacterial fermentation of undigested dietary fiber and starch. While colonocytes use the three major SCFAs, namely acetate, propionate and butyrate, as energy sources, transformed CRC cells primarily undergo aerobic glycolysis. Compared to normal colonocytes, CRC cells exhibit increased sensitivity to SCFAs, thus indicating they play an important role in cell homeostasis. Manipulation of SCFA levels in the intestine, through changes in microbiota, has therefore emerged as a potential preventive/therapeutic strategy for CRC. Interest in understanding SCFAs mechanism of action in CRC cells has increased in the last years. Several SCFA transporters like SMCT-1, MCT-1 and aquaporins have been identified as the main transmembrane transporters in intestinal cells. Recently, it was shown that acetate promotes plasma membrane re-localization of MCT-1 and triggers changes in the glucose metabolism. SCFAs induce apoptotic cell death in CRC cells, and further mechanisms have been discovered, including the involvement of lysosomal membrane permeabilization, associated with mitochondria dysfunction and degradation. In this review, we will discuss the current knowledge on the transport of SCFAs by CRC cells and their effects on CRC metabolism and survival. The impact of increasing SCFA production by manipulation of colon microbiota on the prevention/therapy of CRC will also be addressed.

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... Emerging studies have suggested that gut dysbiosis provokes the damage of intestinal mucosal barriers and enhances the intestinal permeability, thus, leading to the translocations of pathogenic bacteria and their metabolites (such as LPS) into the plasma via the gut-heart axis, for triggering blood vessel chronic inflammation (18). As crucial metabolites of gut microorganisms, short-chain fatty acids (SCFAs), with <6 carbon atoms (C1-C6) and mainly include acetate (C2), propionate (C3), and butyrate (C4), are essential for intestinal homeostasis (19). Importantly, a remarkable reduction of SCFAs led to a dysfunction of the gut mucosal barrier in AS (20). ...
... Additionally, the intracellular target of SCFAs via inhibiting the activity of histone deacetylase (HDACs) is involved in the regulation of expression of genes promoting pathogenesis in many diseases (57). Besides, the SCFAs promote the increase of intestinal TJP (tight junction protein) through intestinal mucosal receptors of monocarboxylate transporter 1 (MCT-1) and sodium-coupled monocarboxylate transporter 1 (SMCT-1), to block the LPS translocation into the blood circulation and to ultimately suppress the systemic inflammation (19). The accurate mechanisms of these different SCFAs metabolites via binding to multiple specific corresponding sensors in AS, with or without dietary FO treatment, still need to be separately determined. ...
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Atherosclerosis (AS) is closely associated with abnormally chronic low-grade inflammation and gut dysbiosis. Flaxseed oil (FO) rich in omega-3 polyunsaturated fatty acids (PUFAs), which are mainly composed of alpha-linolenic acid (ALA, 18:3 omega-3), has been demonstrated to exhibit pleiotropic benefits in chronic metabolic diseases. However, the impact of dietary ALA-rich FO on AS and its associated underlying mechanisms remain poorly understood. Thus, the present study was designed as two phases to investigate the effects in atherosclerotic Apolipoprotein E ( ApoE ) −/− mice. In the initial portion, the ApoE −/− mice were randomly allocated to three groups: control group (CON), model group (MOD), and FO-fed model group (MOD/FO) and were treated for 12 weeks. The second phase used antibiotic (AB)-treated ApoE −/− mice were divided into two groups: AB-treated model group (AB/MOD) and FO-fed AB-treated model group (AB/FO). In the results, the dietary ALA-rich FO administration ameliorated atherosclerotic lesion, as well as the parameters of AS (body weights (BWs) and the total bile acids (TBA). Chronic systemic/vascular inflammatory cytokines and in situ macrophages (Mψs) were reduced with FO intervention. In addition, the FO improved the gut integrity and permeability by decreasing the plasma lipopolysaccharide (LPS). Moreover, gut dysbiosis and metabolites [short-chain fatty acids (SCFAs) and bile acids (BAs)] in AS were modulated after FO treatment. Intriguingly, during an AB-treated condition, a significantly weakened amelioration of FO-treated on AS proposed that the intestinal microbiota contributed to the FO effects. A correlation analysis showed close relationships among gut bacteria, metabolites, and inflammation. Collectively, these results suggested that the dietary ALA-rich FO ameliorated the AS in ApoE −/− mice via the gut microbiota-inflammation-artery axis.
... Adherence to vegetarian and Mediterranean diets significantly lowers the risk of CRC (Orlich et al. 2015;Schwingshackl et al. 2017). The protective effects of fibers on CRC depend on their properties such as lowering the colonic pH to prevent the carcinogens formation; better weight control; promoting healthy gut microbiota; and increasing the production of SCFAs, supporting the normal colonic mucosa; exerting anticarcinogenic and anti-inflammatory activities (Gomes et al. 2019). ...
... However, the US Phoenix Colon Cancer Prevention Physicians' Network including 1429 subjects reported a significant reduction in risk of adenoma recurrence by 12% in the wheat bran-rich vs low-wheat bran fiber diets (Alberts et al. 2000). In addition, a pooled analysis of two large RCTs (Wheat Bran Fiber Trial and 2000 Polyp Prevention Trial) showed that dietary fibers remarkably lowered the risk of recurrent CRC by 19% in men, while no significant association was found for women explaining the disparity in RCT results (Gomes et al. 2019). The US Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial on 57,774 adults with mean age of 62 years found that consumption of !12.8 g fiber/1000 kcal is protective against the development of rectal or distal colorectal adenoma, reducing their risk by 24% compared with the intake of <9.9 g fiber/1000 kcal (Kunzmann et al. 2015). ...
Chapter
The significant rise in burden of age-related chronic degenerative disorders is increasing the need for products that support active and healthy aging. Today’s sedentary lifestyle enhances the propensity to aging related diseases and premature death. Accumulating data establishes a beneficial relationship between food and health. The modern consumer has become aware of the valuable impact of Mediterranean diet (MD) on healthy aging. MD is largely plant based and rich in sources of unsaturated fatty acids like nuts and extra virgin olive oil, legumes, whole grains, fish, and fresh vegetables and fruits and it discourages the use of red and processed meat, added sugars as well as refined grains, has been associated with decreased risk of developing various chronic degenerative age-related disorders and increased life expectancy. With the advent of modern medicine and technological advancements the life expectancy has increased in the past few decades but the gap between the healthy life years and the extra years added to the life still remains there. Aging is a process that increases the vulnerability of an organism to challenges. During this process the oxidative stress leads towards various degenerative cascades that result in functional decline in aging population that is mainly associated with under nutrition in older people. Cognitive function declines, reduced mobility and sensory alterations are seen, oral and GI functions and health become compromised, and chronic diseases and age-related illness like osteoarthritis, diabetes type II, cardiovascular diseases, and certain types of cancer are also exhibited. The active and healthy aging is a prerequisite in order to enhance the quality of life as people age. The MD has proven to be the best tool to counteract the degenerative processes and promote an active healthy aging. Major effectors of MD are reduced caloric intake, decreased consumption of saturated fatty acids, microbiota derived metabolites, less amino acid utilization, and an increase in phytochemical consumption. MD protects against oxidative damage, injury, and inflammation and platelet aggregation, lowers lipid levels, modifies the hormones as well as growth factors that are involved in cancer pathogenesis, and inhibits the nutrient sensing pathway via restriction of specific amino acid as well as produces certain metabolites by gut microbiota and it influences the metabolic health. Thus, the molecular and metabolic health is chiefly associated with what we eat. Restriction of the calories can enhance the life span as well as the health span only if it is coupled with sufficient intake of all the essential nutrients and the micronutrients.
... Adherence to vegetarian and Mediterranean diets significantly lowers the risk of CRC (Orlich et al. 2015;Schwingshackl et al. 2017). The protective effects of fibers on CRC depend on their properties such as lowering the colonic pH to prevent the carcinogens formation; better weight control; promoting healthy gut microbiota; and increasing the production of SCFAs, supporting the normal colonic mucosa; exerting anticarcinogenic and anti-inflammatory activities (Gomes et al. 2019). ...
... However, the US Phoenix Colon Cancer Prevention Physicians' Network including 1429 subjects reported a significant reduction in risk of adenoma recurrence by 12% in the wheat bran-rich vs low-wheat bran fiber diets (Alberts et al. 2000). In addition, a pooled analysis of two large RCTs (Wheat Bran Fiber Trial and 2000 Polyp Prevention Trial) showed that dietary fibers remarkably lowered the risk of recurrent CRC by 19% in men, while no significant association was found for women explaining the disparity in RCT results (Gomes et al. 2019). The US Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial on 57,774 adults with mean age of 62 years found that consumption of !12.8 g fiber/1000 kcal is protective against the development of rectal or distal colorectal adenoma, reducing their risk by 24% compared with the intake of <9.9 g fiber/1000 kcal (Kunzmann et al. 2015). ...
Chapter
Nutrition plays a strong role in aging. Therefore, the absorption and metabolism of nutrients along with diet are a strong risk factor for aging related diseases. The nutritional requirements for the elderly are different as compared to the younger adults due to factors like drug and nutrient interactions, aging associated conditions, socioeconomic factors, etc. The amount and dosage of minerals, vitamins, and macronutrients are different in the elder population. Assessment of proper nutritional diet is important because in this age group, many people are malnourished that leads to various age-related disorders. Different nutraceuticals like the phytochemicals, carotenoids, vitamin B, D, E, various plant extracts have been reported to have rejuvenating properties. The use of nutraceuticals has beneficial effect on the metabolic and immune systems as they possess anti-oxidant properties.
... Butyrate is a four-carbon member of the short-chain fatty acids, produced during the fermentation of dietary fibers and complex carbohydrates by gut bacteria in the intestine (Louis et al., 2014). Butyrate is not only a source of energy but also identified as an HDAC inhibitor (Louis et al., 2014;Gomes et al., 2020). For instance, butyrate mainly can inhibit NADdependent Class III HDACs (SIRT family) and have some effects in Class IIa HDACs like HDAC4, 5, and 7 but do not affect Class IIb members like HDAC6 and HDAC10 (Corfe, 2012;Schilderink et al., 2013). ...
... Butyrate has been reported to inhibit tumor cell growth in colon cancer, HCC, pancreatic, and lung cancer cells (Farrow et al., 2003;Chopin et al., 2004;Donohoe et al., 2014Donohoe et al., , 2014Pant et al., 2017aPant et al., , 2017b. In addition, butyrate has been reported as an anti-inflammatory and antiviral agent (Pant et al., 2019;Gomes et al., 2020;Salvi and Cowles, 2021). Restoration of cilia using HDAC inhibitors, including ACY1215, Tubastatin-A, and sirtinol has been utilized to inhibit HDAC6 and SIRT1, respectively (Gradilone et al., 2013;Peixoto et al., 2020a;Pant et al., 2021). ...
Article
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Cholangiocarcinoma (CCA) is a deadly form of liver cancer with limited therapeutic approaches. The pathogenesis of CCA involves the loss of primary cilia in cholangiocytes, an important organelle that regulates several key cellular functions including the regulation of cell polarity, growth, and differentiation, by a mechanism involving increased expression of deacetylases like HDAC6 and SIRT1. Therefore, cilia restoration may represent an alternative and novel therapeutic approach against CCA. Butyrate is produced by bacterial fermentation of fibers in the intestine and has been shown to inhibit SIRT1, showing antitumor effects on various cancers. Herein, we investigated the role of butyrate on CCA cell proliferation, migration, and EMT and evaluated the synergistic effects with specific HDAC6 inhibition. When CCA cells, including HuCCT1 and KMCH, were treated with butyrate, the cilia formation and acetylated-tubulin levels were increased, while no significant effects were observed in normal human cholangiocytes. Butyrate treatment also depicted reduced cell proliferation in HuCCT1 and KMCH cells, but on the other hand, it affected cell growth of the normal cholangiocytes only at high concentrations. In HuCCT1 cells, spheroid formation and cell migration were also halted by butyrate treatment. Furthermore, we found that butyrate augmented the previously described effects of HDAC6 inhibitors on CCA cell proliferation and migration by reducing the expression of CD44, cyclin D1, PCNA, Zeb1, and Vimentin. In summary, butyrate targets cancer cell growth and migration and enhances the anti-cancer effects of HDAC6 inhibitors in CCA cells, suggesting that butyrate may have therapeutic effects in CCA and other ciliopathies.
... Weak organic acids (also strong acids such as hydrochloride (HCl)) are sensed to be sour as follows; (1) protons in the acid permeate through otopetrin 1 (OTOP1) and/or transient receptor potential vanilloid 4 (TRPV4) channels; (2) the proton influx (a decrease in the cytosolic pH) blocks Kir2.1K + channels depolarizing the taste receptor cells; (3) the depolarization activates voltage-gated Na + channels inducing an increase in Na + influx, which generates the action potential via more depolarization; (4) the generated action potential activates voltage-gated Ca 2+ channels inducing Ca 2+ influx, which elevates the cytosolic Ca 2+ concentration ([Ca 2+ ] c ); (5) the elevated [Ca 2+ ] c induces translocation of neurotransmitter-containing vesicles to the presynaptic terminal membrane and the membrane of neurotransmitter-containing vesicles merges the presynaptic terminal membrane releasing neurotransmitters into the synaptic cleft; (6) the released neurotransmitters into the synaptic cleft bind to their receptors located at the postsynaptic nerve membrane; (7) the neurotransmitter-binding neuron receives the signal generated by the influx of protons contained in weak organic acids via OTOP1 and/or TRPV4 channels, and then transmits the sour-sense to the brain. carboxylate transporters (NaDCT) such as NaDCT1 (SLC13A2) primarily found on the apical membrane of epithelial cells in the intestine/colon and renal proximal tubules [82][83][84][85][86] (see the mechanism shown in Figure 3). Other types of Na + -coupled citrate transporters are also found: NaDCT3 (SLC13A3) is a transporter widely expressed in the kidney and the liver with higher substrate affinity compared with NaDCT1 [86], and NaCT (SLC13A5) primarily transports citrate in the liver, neurons, and astrocytes [87,88]. ...
... The drug-induced reduction in blood glucose level is useful for prevention from the development of heart and blood vessel damages [97], heart failure [95,98], and A weak organic 'acid', in general, consists of carboxyl part (R-COO − ) and proton (H + , a resource of sour teste). Only the carboxyl group (R-COO − ) but not proton in weak organic acids is absorbed into the epithelial cells of the intestine and/or colon via sodium-coupled carboxylate transporters (SCT) such as SMCT1 [89,90] and/or di-,tri-carboxylate transporters such as NaDCT1 [82][83][84][85][86]. Absorbed carboxyl groups are transported from the intracellular space of epithelial cells of intestine and/or colon via H + -coupled carboxylate transporters (HCT) to the interstitial space. ...
Article
Type 2 diabetes mellitus (T2DM) is one of the most common lifestyle-related diseases (metabolic disorders) due to hyperphagia and/or hypokinesia. Hyperglycemia is the most well-known symptom occurring in T2DM patients. Insulin resistance is also one of the most important symptoms, however it is still unclear how insulin resistance develops in T2DM. Detailed understandings of the pathogenesis primarily causing insulin resistance is essentially required for developing new therapies for T2DM. Insulin receptors are located at the plasma membrane of the insulin-targeted cells such as myocytes, adipocytes etc., and insulin binds to the extracellular site of its receptor facing the interstitial fluid. Thus, changes in interstitial fluid microenvironments, specially pH, affect the insulin-binding affinity to its receptor. The most well-known clinical condition regarding pH is systemic acidosis (arterial blood pH<7.35) frequently observed in severe T2DM associated with insulin resistance. Based on the fact that the insulin-binding site of its receptor faces the interstitial fluid, we should recognize the interstitial fluid pH value, one of the most important factors influencing the insulin-binding affinity. It is notable that the interstitial fluid pH is unstable compared with the arterial blood pH even under conditions that the arterial blood pH stays within the normal range, 7.35~7.45. This review article introduces molecular mechanisms on unstable interstitial fluid pH value influencing the insulin action via changes in insulin-binding affinity and ameliorating actions of weak organic acids on insulin resistance via their characteristics as bases after absorption into the body even with sour taste at the tongue.
... Acetate is also a potential chemopreventive agent against CRC by inhibiting cell proliferation and inducing apoptosis [72]. However, others reported that acetate promoted plasma membrane relocalization of MCT-1 and triggered increased glucose consumption and lactate production, thus increasing the glycolytic phenotype in cancer cells [73]. ...
Article
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Colorectal cancer (CRC) is one of the leading cancers that cause cancer-related deaths worldwide. The gut microbiota has been proved to show relevance with colorectal tumorigenesis through microbial metabolites. By decomposing various dietary residues in the intestinal tract, gut microbiota harvest energy and produce a variety of metabolites to affect the host physiology. However, some of these metabolites are oncogenic factors for CRC. With the advent of metabolomics technology, studies profiling microbiota-derived metabolites have greatly accelerated the progress in our understanding of the host-microbiota metabolism interactions in CRC. In this review, we briefly summarize the present metabolomics techniques in microbial metabolites researches and the mechanisms of microbial metabolites in CRC pathogenesis, furthermore, we discuss the potential clinical applications of microbial metabolites in cancer diagnosis and treatment.
... As validation for such an approach we focused on SCFAs. Several papers have identified SCFAs as the products of bacterial metabolism 45,46 ; the role these metabolites play in disease has been extensively studied in the gastrointestinal microbiota 20,21,23,24 and thought to be beneficial in inflammatory bowel disease and bowel cancer [47][48][49][50] . Within the lower airways, we have described that levels of these metabolites are associated with oral commensal enrichment (as defined by 16S rRNA gene sequencing) and have significant immunomodulatory effects on T cells 13 . ...
Article
Rationale Microbiome studies of the lower airway based on bacterial 16S rRNA gene sequencing assess microbial community structure but can only infer functional characteristics. Microbial products, such as short chain fatty acids (SCFAs), in the lower airways have significant impact on the host's immune tone. Thus, functional approaches to the analyses of the microbiome are necessary. Methods Here we used upper and lower airway samples from a research bronchoscopy smoker cohort. In addition, we validated our results in an experimental mouse model. Measurements We extended our microbiota characterisation beyond 16S rRNA gene sequencing with the use of whole genome (WGS) and RNA metatranscriptome sequencing. Short chain fatty acids (SCFA) were also measured in lower airway samples and correlated with each of the sequencing datasets. In the mouse model, 16S rRNA gene and RNA metatranscriptome sequencing were performed. Main Results Functional evaluations of the lower airway microbiota using inferred metagenome, WGS and metatranscriptome were dissimilar. Comparison with measured levels of SCFAs shows that the inferred metagenome from the 16S rRNA gene sequencing data was poorly correlated, while better correlations were noted when SCFAs levels were compared with WGS and metatranscriptome. Modelling lower airway aspiration with oral commensals in a mouse model showed that the metatranscriptome most efficiently captures transient active microbial metabolism, which was overestimated by 16S rRNA gene sequencing. Conclusions Functional characterisation of the lower airway microbiota through metatranscriptome identify metabolically active organisms capable of producing metabolites with immunomodulatory capacity such as SCFAs.
... Moreover, gut microbiome dysbiosis also has a strong effect on disease development, and alterations in the intestinal microbiota and decreased production of short chain fatty acids (SCFAs) appear to be relevant risk factors (Figure 4). Gomes et al. suggested that increasing the level of SCFAs by manipulating the colon microbiota has the potential to prevent or potentially treat CRC [123]. Another population-based cohort study (n = 68,860) identified non-modifiable risk factors in early-onset CRC development, such as family or personal history of polyps and rectal bleeding at the time of diagnosis [124]. ...
Article
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The most commonly mutated isoform of RAS among all cancer subtypes is KRAS. In this review, we focus on the special role of KRAS mutations in colorectal cancer (CRC), aiming to collect recent data on KRAS-driven enhanced cell signalling, in vitro and in vivo research models, and CRC development-related processes such as metastasis and cancer stem cell formation. We attempt to cover the diverse nature of the effects of KRAS mutations on age-related CRC development. As the incidence of CRC is rising in young adults, we have reviewed the driving forces of ageing-dependent CRC.
... The main reasons are as follows: (1) SCFAs can regulate TLRs and NLRP3 inflammasomes to prevent the occurrence of excessive inflammatory responses; (2) SCFAs can promote the expression of IL10 and inhibit the expression of IL17. They can effectively prevent cancer due to repeated damage-repair on top of the treatment of IBD; (3) the ability of SCFAs to promote apoptosis and inhibit the activity of cancer cells has been reviewed in many studies [126,127]; (4) in addition, no side effects have been observed with SCFAs for the treatment of IBD. ...
Article
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Inflammatory bowel disease (IBD) comprises a group of chronic inflammatory disorders of the gastrointestinal tract. Accumulating evidence shows that the development of IBD is always accompanied by the dysbiosis of the gut microbiota (GM), causing a decrease in prebiotic levels and an increase in harmful metabolite levels. This leads to persistent immune response and inflammation in the intestine, greatly impairing the physiological function of the gastrointestinal tract. Short-chain fatty acids (SCFAs) are produced by probiotic gut bacteria from a fiber-rich diet that cannot be digested directly. SCFAs with significant anti-inflammatory functions regulate immune function and prevent an excessive immune response, thereby delaying the clinical progression of IBD. In this review, we summarize the generation of SCFAs and their potential therapeutic effects on IBD. Furthermore, we suggest that SCFAs may modulate innate immune recognition and cytokine production to intervene in the progression of IBD. Additional randomized controlled trials and prospective cohort studies should also investigate the clinical impact of SCFA.
... SCFA-producing bacteria abundance is closely negatively related to the degree of malignancy, and it has recently emerged that the manipulation of intestinal SCFA levels could be a preventive/therapeutic strategy for CRC because of their anti-inflammatory and anti-tumorigenesis properties [40,41]. ...
Article
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Altered circulating levels of free fatty acids (FFAs), namely short chain fatty acids (SCFAs), medium chain fatty acids (MCFAs), and long chain fatty acids (LCFAs), are associated with metabolic, gastrointestinal, and malignant diseases. Hence, we compared the serum FFA profile of patients with celiac disease (CD), adenomatous polyposis (AP), and colorectal cancer (CRC) to healthy controls (HC). We enrolled 44 patients (19 CRC, 9 AP, 16 CD) and 16 HC. We performed a quantitative FFA evaluation with the gas chromatography–mass spectrometry method (GC–MS), and we performed Dirichlet-multinomial regression in order to highlight disease-specific FFA signature. HC showed a different composition of FFAs than CRC, AP, and CD patients. Furthermore, the partial least squares discriminant analysis (PLS-DA) confirmed perfect overlap between the CRC and AP patients and separation of HC from the diseased groups. The Dirichlet-multinomial regression identified only strong positive association between CD and butyric acid. Moreover, CD patients showed significant interactions with age, BMI, and gender. In addition, among patients with the same age and BMI, being male compared to being female implies a decrease of the CD effect on the (log) prevalence of butyric acid in FFA composition. Our data support GC–MS as a suitable method for the concurrent analysis of circulating SCFAs, MCFAs, and LCFAs in different gastrointestinal diseases. Furthermore, and notably, we suggest for the first time that butyric acid could represent a potential biomarker for CD screening.
... These microbial metabolites play a role in modulating host metabolic and immune responses 35 . The current study demonstrated that diet-related SCFAs prevent disease and provide therapeutic implications for CRC 36 , as these bacterial metabolites are restricted to CRC patients and not present in healthy controls. In the present study, we observed EVs with metagenomic profiles similar to those from previous studies utilizing stool-based metagenome analyses of CRC patients. ...
Article
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Colorectal cancer (CRC) is the most common type cancers in the world. CRC occurs sporadically in the majority of cases, indicating the predominant cause of the disease are environmental factors. Diet-induced changes in gut-microbiome are recently supposed to contribute on epidemics of CRC. This study was aimed to investigate the association of metagenomics and metabolomics in gut extracellular vesicles (EVs) of CRC and healthy subjects. A total of 40 healthy volunteers and 32 patients with CRC were enrolled in this study. Metagenomic profiling by sequencing 16 S rDNA was performed for assessing microbial codiversity. We explored the small molecule metabolites using gas chromatography-time-of-flight mass spectrometry. In total, stool EVs were prepared from 40 healthy volunteers and 32 patients with CRC. Metagenomic profiling demonstrated that bacterial phyla, particularly of Firmicutes and Proteobacteria, were significantly altered in patients with colorectal cancer. Through metabolomics profiling, we determined seven amino acids, four carboxylic acids, and four fatty acids; including short-chain to long chain fatty acids that altered in the disease group. Binary logistic regression was further tested to evaluate the diagnostic performance. In summary, the present findings suggest that gut flora dysbiosis may result in alternation of amino acid metabolism, which may be correlated with the pathogenesis of CRC.
... These compounds are formed as the by-products of gut microbes during fermentation of non-digestible polysaccharides and can be used as a fuel source for the host [21,22]. Changes in SCFA composition following consumption of fermentable carbohydrates were shown to be well associated with improved health conditions in the context of glucose homeostasis, blood lipid profile, reduction of body weight and colon cancer risk [23][24][25][26]. Therefore the faecal SCFAs level could provide crucial information about the composition, metabolism and function of gut microbiota within certain gut environment responding to a particular dietary modulation. ...
... Although it is a major product of beneficial probiotics [90], lactic acid can also fuel cancer cells [91]. Increased levels of SCFA, namely, acetate, butyrate, and propionate in CRC are usually linked with lower risk and improved prevention or therapy [92], so microbial-derived butyrate rather counteracts tumor development [93]. Butyrate suppresses proinflammatory genes and tumor growth, the latter via histone deacetylase inhibition, which downregulates oncogenic signaling pathways [94]. ...
Article
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Mounting evidence from metagenomic analyses suggests that a state of pathological microbial imbalance or dysbiosis is prevalent in the gut of patients with colorectal cancer. Several bacterial taxa have been identified of which representative isolate cultures interact with human cancer cells in vitro and trigger disease pathways in animal models. However, how the complex interrelationships in dysbiotic communities may be involved in cancer pathogenesis remains a crucial question. Here, we provide a survey of current knowledge of the gut microbiome in colorectal cancer. Moving beyond observational studies, we outline new experimental approaches for gaining ecosystem-level mechanistic understanding of the gut microbiome’s role in cancer pathogenesis.
... It is also an important regulator of the growth and differentiation of intestinal cells (Gibson et al. 2004;Teng and Kim 2018) and may improve barrier function and intestinal structure (Scheppach 1994;Donohoe et al. 2011;Peixoto et al. 2018). Other potential roles of butyrate are the maintenance of a normal cell phenotype, reduced risk of colonic carcinomas, and reduction of mucosal inflammation (Scheppach 1994;De Theodoro et al. 2019;Gomes et al. 2020). ...
Article
Fermentable fibres are used in commercial dog food to promote intestinal health by providing substrates for better metabolic activity of the gut microbiota. Brazil is the world’s largest producer of oranges, from which it is possible to obtain fibre with a relevant soluble fraction. The present study compared the effects of two inclusions of orange fibre (1% and 3%, on as fed basis) with a negative control (without addition of fibre source) and two positive controls, beet pulp (3%) and purified inulin (1%), totalling five extruded diets for dogs. The experiment followed a randomised block design with 4 blocks of 10 dogs, 2 dogs per food in each block, totalling 8 dogs per diet. The apparent total tract nutrient digestibility was determined by total faecal collection. Faecal pH and fermentation product content were also measured. The digesta mean retention time (DMRT) was evaluated using plastic markers. The inclusion of a 3% fibre source in diets with 3% orange fibre and beet pulp reduced DM, OM, and energy digestibility (p < 0.05). Diets with 3% orange fibre, beet pulp and 1% inulin presented lower crude protein digestibility than the control (p < 0.05). Dietary fibre digestibility was higher for orange fibre-supplemented diets than inulin (p < 0.05). Beet pulp and 3% orange fibre inclusions resulted in increased moisture content in the faeces of dogs (p < 0.05) but did not alter DMRT. Total short-chain fatty acids were higher than the control in the faeces of dogs fed both orange fibre levels and the beet pulp-supplemented diet (p < 0.05), and the inulin diet-fed dogs presented intermediate values. Butyrate was higher in the faeces of dogs fed the diets supplemented with 1% and 3% orange fibre (p < 0.05), and similar values to the control were observed for beet pulp- and inulin-fed animals. Thus, it was concluded that orange fibre presented higher apparent total tract dietary fibre digestibility than beet pulp and had a fermentation profile in the colon that promoted the generation of butyrate, an effect not observed for inulin and beet pulp.
... Aside from DM, cancer ranks as the second main cause of death in the developed world and the third cause for death in developing nations (3). DM and cancer share several common characteristics, such as microbial imbalance and bacterial translocation (4)(5)(6). Unfortunately, these two diseases are frequently coexistent and can affect each other, worsening the prognosis of patients. ...
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Converging evidences showed that people with diabetes mellitus (DM) have significantly higher risk for different cancers, of which the exact mechanism underlying the association has not been fully realized. Short-chain fatty acids (SCFAs), the fermentation products of the intestinal microbiota, are an essential source for energy supply in gut epithelial cells. They have been reported to improve intestinal barrier integrity, prevent microbial translocation, and further dampen inflammation. Gut dysbiosis and reduction in SCFA-producing bacteria as well as SCFAs production in the intestine are commonly seen in metabolic disorders including DM and obesity. Moreover, inflammation can contribute to tumor initiation and progression through multiple pathways, such as enhancing DNA damage, accumulating mutations in tumor suppressor genes Tp53, and activating nuclear factor-kappa B (NF-κB) signaling pathways. Based on these facts, we hypothesize that lower levels of microbial SCFAs resulted from gut dysbiosis in diabetic individuals, enhance microbial translocation, and increase the inflammatory responses, inducing tumorigenesis ulteriorly. To this end, we will discuss protective properties of microbial SCFAs and explore the pivotal roles SCFAs played in the link of DM with cancer, so as to take early precautions to reduce the risk of cancer in patients with DM.
... In fact, the lower abundance of beneficial bacteria SCFAs producers have been associated with CRC [8]. Therefore, the manipulation of SCFA levels in the intestine, through changes in microbiota, could be a potential preventive/therapeutic strategy for CRC [102]. However, at present, only preclinical evidence is available, and the effects have not been achieved in human studies yet. ...
Article
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Colorectal cancer (CRC) is the third most diagnosed type of cancer worldwide. Dietary features play an important role in its development, and the involvement of human microbial communities in this pathology has also recently been recognized. Individuals with CRC display alterations in gut bacterial composition and a notably higher abundance of putative oral bacteria in colonic tumors. Many experimental studies and preclinical evidence propose that dietary polyphenols have a relevant role in CRC development and progression, mainly attributed to their immunomodulatory activities. Furthermore, polyphenols can modulate oral and gut microbiota, and in turn, intestinal microbes catabolize polyphenols to release metabolites that are often more active and better absorbed than the original phenolic compounds. The current study aimed to review and summarize current knowledge on the role of microbiota and the interactions between dietary polyphenols and microbiota in relation to CRC development. We have highlighted the mechanisms by which dietary polyphenols and/or their microbial metabolites exert their action on the pathogenesis and prevention of CRC as modulators of the composition and/or activity of oral and intestinal microbiota, including novel screening biomarkers and possible nutritional therapeutic implications.
... Several bacterial species (e.g., Fusobacterium nucleatum, Streptococcus bovis, Bacteroides fragilis, Escherichia coli, Enterococcus faecalis, and Peptostreptococcus anaerobius) have been strongly related with colorectal carcinogenesis (Cheng et al., 2020;Janney et al., 2020). In addition, an increased risk of CRC was associated with the decreased production of SCFAs (Gomes et al., 2018). FFAR2, an important regulator of colonic inflammation, was proposed as a tumor suppressor; however, the exact role is still under investigation (Cosín-Roger et al., 2020). ...
Article
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Short-chain fatty acids (SCFAs) are the main metabolites produced by the bacterial fermentation of dietary fiber, and they play a critical role in the maintenance of intestinal health. SCFAs are also essential for modulating different processes, and they have anti-inflammatory properties and immunomodulatory effects. As the inflammatory process predisposes the development of cancer and promotes all stages of tumorigenesis, an antitumor effect has also been associated with SCFAs. This is strongly supported by epidemiological studies showing that a diet rich in fiber is linked to a reduced risk of colon cancer and has significant clinical benefits in patients with inflammatory bowel disease (IBD). SCFAs may signal through the metabolite-sensing G protein-coupled receptors free fatty acid receptor 3 [FFAR3 or G protein-coupled receptor 41 (GPR41)], FFAR2 (GPR43), and GPR109A (also known as hydroxycarboxylic acid receptor 2 or HCAR2) expressed in the gut epithelium and immune cells. This review summarizes the existing knowledge regarding the SCFA-mediated suppression of inflammation and carcinogenesis in IBD and colon cancer.
... These bacteria belong to SCFAs-producing bacteria [38,42] and correspond to higher levels of SCFAs in the MXJ32 group (Fig. 5). SCFAs have been shown to play an important role in preventing intestinal diseases, such as IBD and CRC [43]. Previous literature reported that SCFAs could inhibit the growth of some pathogens in the host intestinal microenvironment [44]. ...
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PurposeGut microbiota has been reported to contribute to either prevent or promote colorectal cancer (CRC), and treatment with probiotics might be a promising intervention method. The present study aimed to evaluate the potential anti-CRC effects of Lactobacillus coryniformis MXJ32 on a colitis-associated (CA)-CRC mouse model.Methods The CA-CRC mouse model was induced by a single intraperitoneal injection of 10 mg/kg azoxymethane and followed by three 7-day cycles of 2% dextran sulfate sodium in drinking water with a 14-day recovery period. Mice were supplemented with L. coryniformis MXJ32 by oral gavage (1 × 109 CFU/day/mouse). The CA-CRC attenuating effects of this probiotic were assessed via intestinal barrier integrity, inflammation, and gut microenvironment.ResultsTreatment with L. coryniformis MXJ32 could significantly inhibit the total number of tumors and the average tumor diameter. This probiotic administration prevented the damage of intestinal barrier function by enhancing the expression of tight junction proteins (Occludin, Claudin-1, and ZO-1) and recovering the loss of goblet cells. Moreover, L. coryniformis MXJ32 alleviated intestinal inflammation via down-regulating the expression of inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-γ, and IL-17a) and chemokines (Cxcl1, Cxcl2, Cxcl3, Cxcl5, and Ccl7). In addition, L. coryniformis MXJ32 supplementation increased the abundance of some beneficial bacteria (such as SCFAs-producing bacteria, Lactobacillus, Bifidobacterium, Akkermansia, and Faecalibaculum) and decreased the abundance of some harmful bacteria (such as pro-inflammatory bacteria, Desulfovibrio and Helicobacter), which in turn attenuated the overexpression of inflammation.Conclusion Lactobacillus coryniformis MXJ32 could effectively ameliorate CA-CRC via regulating intestinal microenvironment, alleviating inflammation, and intestinal barrier damage, which further suggested that L. coryniformis MXJ32 could be considered as a functional food ingredient for the alleviation of CA-CRC.Graphic abstract
... SCFAs also play a beneficial role in CRC clinically [137]. Mechanically, SCFAs inhibited cell growth and differentiation, promoted cell-cycle arrest and apoptosis, and regulated histone acetylation to protect against CRC [138]. Given the potential benefits of SCFAs, they are also considered as useful probiotics to prevent CRC. ...
Article
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The incidence of obesity and colorectal cancer (CRC) has risen rapidly in recent decades. More than 650 million obese and 2 billion overweight individuals are currently living in the world. CRC is the third most common cancer. Obesity is regarded as one of the key environmental risk factors for the pathogenesis of CRC. In the present review, we mainly focus on the epidemiology of obesity and CRC in the world, the United States, and China. We also summarize the molecular mechanisms linking obesity to CRC in different aspects, including nutriology, adipokines and hormones, inflammation, gut microbiota, and bile acids. The unmet medical needs for obesity-related CRC are still remarkable. Understanding the molecular basis of these associations will help develop novel therapeutic targets and approaches for the treatment of obesity-related CRC.
... These metabolites have been shown to play important roles in host physiology, by modulating metabolism, gut permeability, inflammatory responses, and immune function (12)(13)(14)(15). SCFAs also protect the host from several diseases, including colorectal cancer, inflammatory bowel disease, and diabetes (16)(17)(18). Bacteroidetes and Firmicutes are the most abundant phyla in the human gut, accounting for over 85% of microbial composition (19). In the human gut, Bacteroidetes members mainly produce acetate and propionate, while Firmicutes populations mostly produce butyrate (20). ...
Article
In humans, aging is characterized by the progressive decline in biological, physiological, and psychological functions, and is a major risk factor in the development of chronic diseases. Therefore, the development of strategies aimed at attenuating aging-related disorders and promoting healthy aging is critical. In a previous study, we have demonstrated that Lactobacillus plantarum TWK10 (TWK10), a probiotic strain isolated from Taiwanese pickled cabbage, improved muscle strength, exercise endurance, and overall body composition in healthy humans. In this study, the effect of TWK10 on the progression of age-related impairments was investigated in mice. We found that TWK10 not only enhanced muscle strength in young mice, but also prevented the aging-related loss of muscle strength in aged mice, which was accompanied by elevated muscle glycogen levels. Furthermore, TWK10 attenuated the aging-associated decline in learning and memory abilities, as well as bone mass. Further analyses of gut microbiota using next-generation sequencing (NGS) of the 16S rRNA gene showed that the pattern of gut microbial composition was clearly altered following 8 weeks of TWK10 administration. TWK10-treated mice also experienced an increase in short-chain fatty acid (SCFA)-producing bacteria and higher overall levels of gut SCFA. Furthermore, TWK10 administration to some extent reversed the aging-associated accumulation of pathogenic bacterial taxa. In conclusion, TWK10 could be viewed as a potential therapeutic agent that attenuates aging-related disorders and provides health benefits by modulating the imbalance of gut microbiota.
... SCFAs inhibit calcineurin/NFATc3 activation and thus contribute to control protein acetylation and tumor cell proliferation (79). SCFAs induce apoptotic cell death in CRC cells by pathways involving lysosomal membrane permeabilization, which is linked to mitochondrial malfunction and degradation (98). Moreover, C. butyricum can suppress the growth of intestinal tumors by regulating Wnt/b-catenin signaling, lowering proliferation, and promoting apoptosis (78). ...
Article
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Colorectal cancer (CRC) is a leading cause of cancer morbidity and mortality worldwide. The etiology and pathogenesis of CRC remain unclear. A growing body of evidence suggests dysbiosis of gut bacteria can contribute to the occurrence and development of CRC by generating harmful metabolites and changing host physiological processes. Metabolomics, a systems biology method, will systematically study the changes in metabolites in the physiological processes of the body, eventually playing a significant role in the detection of metabolic biomarkers and improving disease diagnosis and treatment. Metabolomics, in particular, has been highly beneficial in tracking microbially derived metabolites, which has substantially advanced our comprehension of host-microbiota metabolic interactions in CRC. This paper has briefly compiled recent research progress of the alterations of intestinal flora and its metabolites associated with CRC and the application of association analysis of metabolomics and gut microbiome in the diagnosis, prevention, and treatment of CRC; furthermore, we discuss the prospects for the problems and development direction of this association analysis in the study of CRC. Gut microbiota and their metabolites influence the progression and causation of CRC, and the association analysis of metabolomics and gut microbiome will provide novel strategies for the prevention, diagnosis, and therapy of CRC.
... Generally, Lachnospiraceae are associated with the promotion of resistance to intestinal pathogen colonization and the production of short chain fatty acids and bile acid metabolism [35,36]. Short chain fatty acids are also reported to exert a tumor-suppressing effect [37]. However, in the present study, cecal short chain fatty acids were not found to differ between control, AOM/DSS, and AOM/DSS + lactulose groups. ...
Article
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Lactulose, a galactose-fructose disaccharide, is made from the milk sugar lactose by heating or isomerization processes. Lactulose is proposed to modulate gut microbiota and thus expected to be beneficial in treating inflammatory bowel disease. In the present study, we investigated the therapeutic effect of lactulose on gastrointestinal inflammation and inflammation-related tumorigenesis in a mouse model of colorectal cancer as well as its effect on gut microbiota composition. Azoxymethane (AOM)/dextran sulfate sodium (DSS) model was used in this study. Lactulose treatment was performed by feeding 2% lactulose for 14 weeks. Stool samples collected at 4 time points were used for metagenomic analysis of the microbiota. Pathological analysis was performed 21 weeks after AOM injection. AOM/DSS increased the macrophage counts, inflammatory cytokine expression, colorectal tumorigenesis, and imbalance in gut microbiota composition, as evidenced by increased pathogen abundance (e.g., Escherichia and Clostridium). Lactulose significantly inhibited the inflammatory events, and ameliorated inflammation and tumorigenesis. The composition of the intestinal microbiota was also restored upon lactulose treatment, and lactulose reduced pathogen abundance and increased the abundance of Muribaculum and Lachnospiraceae. Meanwhile, the pathways related to Crohn’s disease were downregulated after lactulose treatment. Our findings suggest that lactulose restores the structure and composition of the intestinal microbiota, mitigates inflammation, and suppresses inflammatory tumorigenesis.
... Moreover, upon butyrate (one of the most produced SCFAs) stimulation, the CD4 + effector T cells increase T-bet and IFN-γ expression, being able to exert either beneficial or detrimental effects on the mucosal immune system depending on its concentration and immunological milieu [73] . The presence of CTLs and IFN-γ- producing Th1 cells has been associated with prolonged survival [74,75] , making some SCFAs, including butyrate, propionate, and acetate, potential therapeutic tools to modulate inflammatory responses [76,77] , including for CRC treatment [78] . Nevertheless, it is important to consider that SCFAs interact with the receptor GPR43 of colonic Tregs, as well as act as histone deacetylase (HDAC) inhibitors in mucosal peripheral Tregs, which under healthy conditions, helps to maintain intestinal immune homeostasis [79][80][81] . ...
Article
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers, and it is characterized by genetic and epigenetic alterations, as well as by inflammatory cell infiltration among malignant and stromal cells. However, this dynamic infiltration can be influenced by the microenvironment to promote tumor proliferation, survival and metastasis or cancer inhibition. In particular, the cancer microenvironment metabolites can regulate the inflammatory cells to induce a chronic inflammatory response that can be a predisposing condition for CRC retention. In addition, some nutritional components might contribute to a chronic inflammatory condition by regulating various immune and inflammatory pathways. Besides that, diet strongly modulates the gut microbiota composition, which has a key role in maintaining gut homeostasis and is associated with the modulation of host inflammatory and immune responses. Therefore, diet has a fundamental role in CRC initiation, progression and prevention. In particular, functional foods such as probiotics, prebiotics and symbiotics can have a potentially positive effect on health beyond basic nutrition and have antiinflammatory effects. In this review, we discuss the influence of diet on gut microbiota composition, focusing on its role on gut inflammation and immunity. Finally, we describe the potential benefits of using probiotics and prebiotics to modulate the host inflammatory response, as well as its application in CRC prevention and treatment. © The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
... Given the facts that the increased risk of certain gastroenteric tumors is linked to alterations of gut microbiota species and reduced production of SCFAs, efforts have been made to elucidate the relation between dietary pattern and gut microbiota. Dietary interventions like high-fiber diets and the supplementation with polyunsaturated fatty acids, polyphenols and probiotics, which are known to regulate gut microbiota and generate SCFAs, have emerged as potential therapeutical strategy to prevent or to be used as adjuvants to conventional therapy (189). Of note, there is not a simple linear relationship between gut SCFA levels and individual dietary components or bacterial strains. ...
Article
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Metabolic reprogramming is one of the emerging hallmarks of cancer and is driven by both the oncogenic mutations and challenging microenvironment. To satisfy the demands of energy and biomass for rapid proliferation, the metabolism of various nutrients in tumor cells undergoes important changes, among which the aberrant lipid metabolism has gained increasing attention in facilitating tumor development and metastasis in the past few years. Obstacles emerged in the aspect of application of targeting lipid metabolism for tumor therapy, due to lacking of comprehensive understanding on its regulating mechanism. Tumor cells closely interact with stromal niche, which highly contributes to metabolic rewiring of critical nutrients in cancer cells. This fact makes the impact of microenvironment on tumor lipid metabolism a topic of renewed interest. Abundant evidence has shown that many factors existing in the tumor microenvironment can rewire multiple signaling pathways and proteins involved in lipid metabolic pathways of cancer cells. Hence in this review, we summarized the recent progress on the understanding of microenvironmental factors regulating tumor lipid metabolism, and discuss the potential of modulating lipid metabolism as an anticancer approach.
... As a SCFA mostly derived from carbohydrates, butyrate has long been known to exert beneficial effects. Mounting evidence implicated that it plays a vital role in maintaining intestinal and immune homeostasis [2,3], preventing the metabolic syndrome [4], cancer [5], and cardiovascular disease [6]. Meanwhile, other SCFAs such as valerate has drawn much interests in their multiple physiological effects, such as inhibiting the histone deacetylases [7], lowering intraocular pressure and arterial blood pressure [8], and suppressing autoimmunity [9]. ...
Article
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Background Short-chain fatty acids (SCFAs) are a group of microbial metabolites of undigested dietary fiber, protein and unabsorbed amino acids in the colon, well-known for their gut health promoting benefits. A relatively high intestinal level of valerate was found in the healthy human subjects. However, the intestinal protection effects and the underlying mechanism of valerate are waiting to be verified and elucidated.Methods and ResultsIn the present study, valerate, a SCFAs mainly converted from proteins or amino acids, was demonstrated to promote intestinal barrier function at its physiological concentrations of 0–4 mM in the Caco-2 cell monolayer model of intestinal barrier using transepithelial electrical resistance (TEER) assay and paracellular permeability assay. Valerate achieved the maximum increase in the TEER at 2 mM and reduced the paracellular permeability. Its intestinal barrier function promoting activity is similar to that of butyrate, with a broader range of effective concentrations than the later. Through western blot analysis, this activity is linked to the valerate-induced AMPK activation and tight junctions (TJs) assembly, but not to the reinforced expression of TJs related proteins.Conclusions It provides direct experimental evidence supporting valerate’s function in intestinal health, implying the once under-valued function of valerate and its amino acid precursors. The valerate’s role in regulating intestine homeostasis and its possible synergetic effects with other SCFAs warranted to be further investigated.
... Short-chain fatty acids (SCFAs) trigger cell death in colorectal cancer associated with lysosomal membrane permeabilization and mitochondrial dysfunction [58]. SCFAs are normally produced in colon cells by bacterial fermentation [59]. ...
Article
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Cancer is a global health and economic issue. The majority of anticancer therapies become ineffective due to frequent genomic turnover and chemoresistance. Furthermore, chemotherapy and radiation are non-specific, killing all rapidly dividing cells including healthy cells. In this review, we examine the ability of some natural products to induce lysosomal-mediated cell death in neoplastic cells as a way to kill them more specifically than conventional therapies. This list is by no means exhaustive. We postulate mechanisms to explain lysosomal membrane permeabilization and its role in triggering cell death in cancer cells.
... These metabolites have been shown to play important roles in host physiology, by modulating metabolism, gut permeability, inflammatory responses, and immune function (12)(13)(14)(15). SCFAs also protect the host from several diseases, including colorectal cancer, inflammatory bowel disease, and diabetes (16)(17)(18). Bacteroidetes and Firmicutes are the most abundant phyla in the human gut, accounting for over 85% of microbial composition (19). In the human gut, Bacteroidetes members mainly produce acetate and propionate, while Firmicutes populations mostly produce butyrate (20). ...
Article
Full-text available
In humans, aging is characterized by the progressive decline in biological, physiological, and psychological functions, and is a major risk factor in the development of chronic diseases. Therefore, the development of strategies aimed at attenuating aging-related disorders and promoting healthy aging is critical. In a previous study, we have demonstrated that Lactobacillus plantarum TWK10 (TWK10), a probiotic strain isolated from Taiwanese pickled cabbage, improved muscle strength, exercise endurance, and overall body composition in healthy humans. In this study, the effect of TWK10 on the progression of age-related impairments was investigated in mice. We found that TWK10 not only enhanced muscle strength in young mice, but also prevented the aging-related loss of muscle strength in aged mice, which was accompanied by elevated muscle glycogen levels. Furthermore, TWK10 attenuated the aging-associated decline in learning and memory abilities, as well as bone mass. Further analyses of gut microbiota using next-generation sequencing (NGS) of the 16S rRNA gene showed that the pattern of gut microbial composition was clearly altered following 8 weeks of TWK10 administration. TWK10-treated mice also experienced an increase in short-chain fatty acid (SCFA)-producing bacteria and higher overall levels of gut SCFA. Furthermore, TWK10 administration to some extent reversed the aging-associated accumulation of pathogenic bacterial taxa. In conclusion, TWK10 could be viewed as a potential therapeutic agent that attenuates aging-related disorders and provides health benefits by modulating the imbalance of gut microbiota.
... Even when tumorigenesis is not linked to intestinal flora, particular bacteria may interact with the tumor via oncometabolites (e.g., l-2-hydroxyglutarate, succinate, fumarate) which enhance cancer progression [38]. The latter is a double-edged sword, given that other bacterial metabolites such as acetate, butyrate, and propionate have been shown to downsize tumor growth [39]. On these grounds, the microbiome is now regarded as an additional CRC tool regarding the armamentarium of potential biomarkers [40], with guaiac-based fecal occult blood tests (gFOBTs), fecal immuno-chemical tests (FITs) and multitarget stool DNA (sDNA) testing being integrated into state of the art diagnostic testing protocols [41]. ...
Article
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Metastatic colorectal cancer (mCRC) remains a highly lethal malignancy, although considerable progress has resulted from molecular alterations in guiding optimal use of available treatments. CRC recurrence remains a great barrier in the disease management. Hence, the spotlight turns to newly mapped fields concerning recurrence risk factors in patients with resectable CRC with a focus on genetic mutations, microbiota remodeling and liquid biopsies. There is an urgent need for novel biomarkers to address disease recurrence since specific genetic signatures can identify a higher or lower recurrence risk (RR) and, thus, be used both as biomarkers and treatment targets. To a large extent, CRC is mediated by the immune and inflammatory interplay of microbiota, through intestinal dysbiosis. Clarification of these mechanisms will yield new opportunities, leading not only to the appropriate stratification policies, but also to more precise, personalized monitoring and treatment navigation. Under this perspective, early detection of post-operative CRC recurrence is of utmost importance. Ongoing trials, focusing on circulating tumor cells (CTCs) and, even more, circulating tumor DNA (ctDNA), seem to pave the way to a promising, minimally invasive but accurate and life-saving monitoring, not only supporting personalized treatment but favoring patients’ quality of life, as well.
... Additionally, the optimisation of SCFA levels in the gut by increased dietary fibre intake and microbiome manipulation, needs further study as a potential prevention or treatment strategy for CRC [52,53]. As it has been shown that SCFAs in the colon are reduced compare to controls, the increase of SCFA intake through diet and probiotics might be protective against CRC [54]. ...
Article
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Background & aims Short chain fatty acid (SCFAs) are bacterially derived metabolites suggested to have protective roles against colorectal cancer (CRC) development. However, there is sparse evidence from epidemiological studies in this context. Here, we assessed whether circulating SCFA concentrations varied in patients with colorectal adenomas (CRA) and CRC. Methods Levels of seven SCFAs were extracted from plasma samples and determined by gas chromatography for 213 individuals from Ireland and the Czech Republic (CRC, n = 84; CRA, n = 66; controls, n = 63). Results In the Irish CRA/CRC cohort, only levels of 2-MethylButyric acid were significantly higher in cancers compared to the adenoma and control groups (p = 0.016 and 0.043). Using regression analysis, we observed that levels of Acetic and Propionic acid were associated with an increased CRC risk in the Czech cohort (Odd Ratio (OR): 1.02; 95% Confidence interval (CI): 1.00-1.03; OR: 1.29; 95% CI: 1.05-1.59, respectively), while i-Valeric and Valeric acid levels were associated with a decreased cancer risk (OR: 0.92; 95% CI: 0.86-0.99; OR: 0.67; 95% CI: 0.44-1.00). In the Irish cohort, levels of SCFAs were not associated with CRC risk. Conclusions The association with colorectal neoplasia varied between the studied SCFAs. Future studies need to confirm these findings and address the mechanism of how these acids may promote or prevent colorectal carcinogenesis.
... In addition to the induction of IL-18 by IEC, which is also crucial for intestinal immune homeostasis since IL-18 helps maintaining the balance between T helper 17 cells (T h 17) and regulatory T cells (T reg ) (88, 89), SCFA also interact directly with innate mechanisms of defense. In neutrophils, SCFA modulate recruitment, effector function, and cell survival (90). Phagocytes including dendritic cells and macrophages also respond to SCFA, which regulates pro-inflammatory cytokine production (91,92). ...
Article
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The hypothesis that links the increase in the intake of plant-source foods to a decrease in colorectal cancer (CRC) risk has almost 50 years. Nowadays, systematic reviews and meta-analysis of case-control and cohort studies confirmed the association between dietary patterns and CRC risk, in which the non-digestible carbohydrates (NDC) from plant-source foods are known to play beneficial effects. However, the mechanisms behind the physicochemical properties and biological effects induced by NDC on the decrease of CRC development and progression remain not fully understood. NDC from plant-source foods consist mainly of complex carbohydrates from plant cell wall including pectin and hemicellulose, which vary among foods in structure and in composition, therefore in both physicochemical properties and biological effects. In the present review, we highlighted the mechanisms and described the recent findings showing how these complex NDC from plant-source foods are related to a decrease in CRC risk through induction of both physicochemical effects in the gastrointestinal tract, fermentation-related effects, and direct effects resulting from the interaction between NDC and cellular components including toll-like receptors and galectin-3. Studies support that the definition of the structure-function relationship—especially regarding the fermentation-related effects of NDC, as well as the direct effects of these complex carbohydrates in cells—is crucial for understanding the possible NDC anticancer effects. The dietary recommendations for the intake of NDC are usually quantitative, describing a defined amount of intake per day. However, as NDC from plant-source foods can exert effects that vary widely according to the NDC structure, the dietary recommendations for the intake of NDC plant-source foods are expected to change from a quantitative to a qualitative perspective in the next few years, as occurred for lipid recommendations. Thus, further studies are necessary to define whether specific and well-characterized NDC from plant-source foods induce beneficial effects related to a decrease in CRC risk, thereby improving nutritional recommendations of healthy individuals and CRC patients.
... SCFAs are taken up inside cells by a variety of transporters/carriers [84][85][86] and once inside inhibit histone deacetylases (HDAC). However, this action may be limited to butyrate in the intestine. ...
Article
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The microbiota regulates immunological development during early human life, with long- term effects on health and disease. Microbial products include short-chain fatty acids (SCFAs), formyl peptides (FPs), polysaccharide A (PSA), polyamines (PAs), sphingolipids (SLPs) and aryl hydrocarbon receptor (AhR) ligands. Anti-inflammatory SCFAs are produced by Actinobacteria, Bacteroidetes, Firmicutes, Spirochaetes and Verrucomicrobia by undigested-carbohydrate fermentation. Thus, fiber amount and type determine their occurrence. FPs bind receptors from the pattern recognition family, those from commensal bacteria induce a different response than those from pathogens. PSA is a capsular polysaccharide from B. fragilis stimulating immunoregulatory protein expression, promoting IL-2, STAT1 and STAT4 gene expression, affecting cytokine production and response modulation. PAs interact with neonatal immunity, contribute to gut maturation, modulate the gut– brain axis and regulate host immunity. SLPs are composed of a sphingoid attached to a fatty acid. Prokaryotic SLPs are mostly found in anaerobes. SLPs are involved in proliferation, apoptosis and immune regulation as signaling molecules. The AhR is a transcription factor regulating development, reproduction and metabolism. AhR binds many ligands due to its promiscuous binding site. It participates in immune tolerance, involving lymphocytes and antigen-presenting cells during early development in exposed humans.
... Colonocytes use the three major SCFAs, namely, acetate, propionate and butyrate, as energy sources, while transformed CRC cells primarily undergo aerobic glycolysis. Compared to normal colonocytes, CRC cells exhibit an increased sensitivity to SCFAs, demonstrating that they likely have a vital role in cell homeostasis [30]. Manipulation of SCFA levels in the gut, through changes in the GM, has therefore emerged as a potential preventive/therapeutic strategy for CRC. ...
Article
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The gut microbiome (GM) has been implicated in a vast number of human pathologies and has become a focus of oncology research over the past 5 years. The normal gut microbiota imparts specific function in host nutrient metabolism, xenobiotic and drug metabolism, maintenance of structural integrity of the gut mucosal barrier, immunomodulation and protection against pathogens. Strong evidence is emerging to support the effects of the GM on the development of some malignancies but also on responses to cancer therapies, most notably, immune checkpoint inhibition. Tools for manipulating the GM including dietary modification, probiotics and faecal microbiota transfer (FMT) are in development. Current understandings of the many complex interrelationships between the GM, cancer, the immune system, nutrition and medication are ultimately based on a combination of short‐term clinical trials and observational studies, paired with an ever-evolving understanding of cancer biology. The next generation of personalised cancer therapies focusses on molecular and phenotypic heterogeneity, tumour evolution and immune status; it is distinctly possible that the GM will become an increasingly central focus amongst them. The aim of this review is to provide clinicians with an overview of microbiome science and our current understanding of the role the GM plays in cancer.
... Moreover, supplementation of nanoparticle curcumin and resveratrol increased fecal/cecal butyrate concentration (89,94), and salvianolic acid B elevated serum SCFAs in mice with colitis (103). These results indicate that polyphenol-mediated modulation of gut microbial functions, including suppression of epithelial invasion and increase in SCFA production, may contribute to the mitigation of colitis by these compounds (36,105). ...
Article
Accumulating evidence indicates that the gut microbiota can promote or inhibit colonic inflammation and carcinogenesis. Promotion of beneficial gut bacteria is considered a promising strategy to alleviate colonic diseases including colitis and colorectal cancer. Interestingly, dietary polyphenols, which have been shown to attenuate colitis and inhibit colorectal cancer in animal models and some human studies, appear to reach relatively high concentrations in the large intestine and to interact with the gut microbial community. This review summarizes the modulatory effects of polyphenols on the gut microbiota in humans and animals under healthy and diseased conditions including colitis and colitis-associated colorectal cancer (CAC). Existing human and animal studies indicate that polyphenols and polyphenol-rich whole foods are capable of elevating butyrate producers and probiotics that alleviate colitis and inhibit CAC, such as Lactobacillus and Bifidobacterium. Studies in colitis and CAC models indicate that polyphenols decrease opportunistic pathogenic or proinflammatory microbes and counteract disease-induced dysbiosis. Consistently, polyphenols also change microbial functions, including increasing butyrate formation. Moreover, polyphenol metabolites produced by the gut microbiota appear to have anticancer and anti-inflammatory activities, protect gut barrier integrity, and mitigate inflammatory conditions in cells and animal models. Based on these results, we conclude that polyphenol-mediated alteration of microbial composition and functions, together with polyphenol metabolites produced by the gut microbiota, likely contribute to the protective effects of polyphenols on colitis and CAC. Future research is needed to validate the causal role of the polyphenol-gut microbiota interaction in polyphenols' anti-colitis and anti-CAC effects, and to further elucidate mechanisms underlying such interaction.
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In animals, the gastrointestinal microbiota is reported to play a major role in digestion, nutrient absorption and the release of energy through metabolism of food. Therefore, the microbiota may be a factor in the links between diet and enteric diseases and oxidative stress. The gut microbial composition and concentration are affected by diet throughout the lifetime of an animal, and respond rapidly and efficiently to dietary alterations, in particular to the use of prebiotics. Prebiotics, which play an important role in mammalian nutrition, are defined as dietary ingredients that lead to specific changes in both the composition and activity of the gastrointestinal microbiota through suppressing the proliferation of pathogens and in modifying the growth of beneficial microorganisms in the host intestine. A review of the evidence suggests possible beneficial effects of prebiotics on host intestinal health, including immune stimulation, gut barrier enhancement and the alteration of the gastrointestinal microbiota, and these effects appear to be dependent on alteration of the bacterial composition and short-chain fatty acid (SCFA) production. The production of SCFAs depends on the microbes available in the gut and the type of prebiotics available. The SCFAs most abundantly generated by gastrointestinal microbiota are acetate, butyrate and propionate, which are reported to have physiological effects on the health of the host. Nowadays, prebiotics are widely used in a range of food products to improve the intestinal microbiome and stimulate significant changes to the immune system. Thus, a diet with prebiotic supplements may help prevent enteric disease and oxidative stress by promoting a microbiome associated with better growth performance. This paper provides an overview of the hypothesis that a combination of ingestible prebiotics, chitosan, fructooligosaccharides and inulin will help relieve the dysbiosis of the gut and the oxidative stress of the host.
Article
Increased risk of colorectal cancer (CRC) is associated with altered intestinal microbiota as well as short‐chain fatty acids (SCFAs) reduction of output The energy source of colon cells relies mainly on three SCFAs, namely butyrate (BT), propionate, and acetate, while CRC transformed cells rely mainly on aerobic glycolysis to provide energy. This review summarizes recent research results for dysregulated glucose metabolism of SCFAs, which could be initiated by gut microbiome of CRC. Moreover, the relationship between SCFA transporters and glycolysis, which may correlate with the initiation and progression of CRC, are also discussed. Additionally, this review explores the linkage of BT to transport of SCFAs expressions between normal and cancerous colonocyte cell growth for tumorigenesis inhibition in CRC. Furthermore, the link between gut microbiota and SCFAs in the metabolism of CRC, in addition, the proteins and genes related to SCFAs‐mediated signaling pathways, coupled with their correlation with the initiation and progression of CRC are also discussed. Therefore, targeting the SCFA transporters to regulate lactate generation and export of BT, as well as applying SCFAs or gut microbiota and natural compounds for chemoprevention may be clinically useful for CRCs treatment. Future research should focus on the combination these therapeutic agents with metabolic inhibitors to effectively target the tumor SCFAs and regulate the bacterial ecology for activation of potent anticancer effect, which may provide more effective application prospect for CRC therapy.
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There is convincing evidence that consuming whole grains (WGs) may decrease the risk of colorectal cancer (CRC). Wheat bran (WB) is a rich source of dietary fiber and phytochemicals with health-promoting properties. However, the active components especially the interaction between different components in WG wheat have not been fully explored. Here, we investigated whether one of the major WB phytochemicals, alkylresorcinol (AR) C21, and the major active intestinal microbial metabolite of fiber, butyrate, could synergistically suppress human colon cancer cells. Our results demonstrated for the first time that the combination of C21 and butyrate synergistically inhibited the growth of human colon cancer cells and induced apoptosis. Further mechanistic studies demonstrated that the co-treatment of C21 and butyrate induced significant up-regulations in cleaved Poly (ADP-ribose) polymerase (PARP), cleaved caspase 3, p53 upregulated modulator of apoptosis (PUMA), cytochrome C, lipid-conjugated membrane-bound form of microtubule-associated protein 1A/1B-light chain 3 (LC3-II) and C/EBP homologous protein (CHOP) expressions, indicating the synergistic anti-cancer effects of C21 and butyrate were associated with induction of apoptosis, autophagy and ER stress pathways. Notably, the C21 concentrations in the large intestinal tract of mice treated with human relevant doses of C21, were from 0.86-1.78 µmol/g, suggesting the C21 doses used in vitro may be achievable after daily WG wheat intake. These results provide novel insights into the dietary prevention of CRC regarding the potential interaction of bioactive WG wheat phytochemicals and the microbial metabolites of fiber.
Article
Gut microbiota dysbiosis may promote the process of colorectal cancer (CRC). Lacticaseibacillus rhamnosus LS8 (LRL) is a potential gut microbiota regulating strain because it can produce a novel antimicrobial substance (like cycloalanopine). In addition, this probiotic had an inflammation-ameliorating effect on the dextran sulfate sodium (DSS)–induced colitis mice. However, it is not known whether treatment with this probiotic could ameliorate colitis-associated CRC via regulating gut microbiota. In this study, a CRC mouse model was induced by a single intraperitoneal injection of azoxymethane (AOM, 10 mg/kg) and followed by three 7-day cycles of 2% DSS administration. Results showed that LRL could inhibit tumor formation. Moreover, LRL enhanced the gut barrier by preventing goblet cell loss and promoting the expression of ZO-1, occludin, and claudin-1. Furthermore, LRL ameliorated gut microbiota dysbiosis, which was conducive to the growth of beneficial bacteria (e.g., Faecalibaculum and Akkermansia), and further led to an increase in SCFAs and a decrease in LPS. In addition, LRL alleviated colonic inflammation by inhibiting the overexpression of TLR4/NF-κB, pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-γ, and IL-17a), and chemokines (Cxcl1, Cxcl2, Cxcl3, Cxcl5, and Cxcl7). In conclusion, LRL could alleviate CRC by regulating gut microbiota and preventing gut barrier damage and inflammation.
Chapter
Currently, healthy aging is a major public concern. In between, nutritional interventions and dietary patterns are supposed to play crucial roles in regulation/delaying the aging process. High intake of dietary fiber is inversely associated with reduced risk of several age-related diseases. A bulk of evidence indicated that consumption of dietary fiber is implicated with lower concentrations of inflammatory and oxidative stress markers, resulting in improving health status during aging and extending the life span. Even, it was proven that inadequate amounts of dietary fiber are accelerating the aging process. Significant intake of dietary fiber is an essential parameter of a healthy aging. The current chapter reviews the specific roles of dietary fiber in conjunction with age-associated-gastrointestinal system, age-associated-metabolic status, age-associated cardiovascular diseases, age-associated neurodegenerative diseases, cancer, immune system, and allergic disorders.
Chapter
Carbon is the most important biobased material that forms the backbone of life as we know it. Based on this fundamental fact, it is no surprise that carbon-based materials have played an integral role in the development of medical materials. Biobased materials will continue to play an even greater role in medicine as we uncover more of the nuanced mechanisms that determine the multiple roles that carbon plays in biological systems. The purpose of this chapter is to introduce biobased materials and the unique roles that they play in medical products. The important role of carbon will be highlighted while focusing on the role of biobased materials in healthcare and medical products including high surface area adsorbents, recycling of biowaste products, and tailored gut microbiome-based products and therapies that can proactively prevent health challenges.
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Short-chain fatty acids (SCFA), as end products of indigestible-fiber-fermentation by gut-bacteria, affect inflammatory disease and cancer. SCFA are quickly absorbed in the colon through their transporters categorized as SMCT1/SLC5a8, MCT1/SLAC16a, and SCFA-HCO3⁻ exchangers. These compounds have anti-inflammatory and anticancer properties by activating FFR2/GPR43, FFR3/GPR41, GPR109, olfactory receptor 78, and inhibiting histone deacetylases (HDAC). SCFA suppresses inflammation by influencing chemotaxis, immune cells' differentiation, and the production of cytokines from different cell types. In addition to autophagy induction ability of SCFA in cancer cells, they can also induce apoptosis in tumoral cells. SCFA has not shown significant effects on normal cells' propagation. On the other hand, previous reports showed their preventive impacts on cancer cell proliferation, which has been named the “Butyrate paradox” and discussed in terms of the “Warburg effect."
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The dietary role of macronutrients and their metabolites in cancer has been evident for many decades. Dietary ingestion of fat, carbohydrates, protein, and fiber, as well as probiotics that influence gut microbiota, have all been linked to gastrointestinal (GI) tract health and disease, particularly in the colon, where it has long been known that fat and fiber can regulate inflammation and carcinogenesis. Short-chained fatty acids (SCFA), including acetate, propionate, and butyrate, which are biosynthesized by microbiota-mediated metabolism of dietary fiber, have previously been shown to play important roles in colorectal health, including decreasing inflammation and oxidative stress. Since the 1980’s, a growing number of studies have also demonstrated a link between SCFA and colon epithelial cell carcinogenesis and prevention of colorectal cancers (CRC). While the effects of SCFA have historically been associated with their intracellular metabolism and function, the discovery of a family of G protein-coupled free-fatty acid receptors in the early 2000’s suggests that many effects of SCFA are cell-surface receptor mediated. Indeed, the SCFA GPCRs FFA2 (previously termed GPR43), FFA3 (previously termed GPR41), and GPR109A are now well established to be expressed within the GI tract, where they modulate a variety of functions in response to luminal SCFA. While the role of SCFA in cancers, including CRC, has been reviewed in detail elsewhere, the goal of this report is to provide a review on the current body of evidence in regard to the effects of SCFA on FFA2, FFA3, and GPR109A in colon cancers.
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This study investigated the effects of water-soluble polysaccharide extracted from the sporoderm-removed spores of Ganoderma lucidum (GLP) against AOM/DSS-induced inflammation, tumorigenesis, and gut microbiota modification, which has never been reported before. Our data revealed that GLP (200 and 300 mg/kg) decreased AOM/DSS-induced colitis and tumorigenesis, manifested by significantly reduced disease activity index score, and total number and size of tumors. Furthermore, GLP ameliorated AOM/DSS-induced microbiota dysbiosis, increased short-chain fatty acid production, and alleviated endotoxemia by inhibiting TLR4/MyD88/NF-κB signaling. Besides, GLP profoundly improved gut barrier function as evidenced by increased numbers of goblet cells, MUC2 secretion, and tight junction protein expressions. GLP treatment inhibited macrophage infiltration and downregulated IL-1β, iNOS, and COX-2 expressions. Additionally, GLP inhibited lipopolysaccharides (LPS)-induced inflammation markers and MAPK (JNK and ERK) activation in macrophage RAW264.7, intestinal HT-29, and NCM460 cells. In conclusion, these results indicate that GLP is a promising prebiotic for the treatment of colorectal cancer.
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Supplementation of probiotics is a promising method to alleviate colorectal cancer (CRC) via modulating the intestinal microenvironment. This study aimed to assess the potential anti-CRC effect of Companilactobacillus crustorum MN047 on an azoxymethane and dextran sulfate sodium-induced colitis-associated (CA)-CRC mouse model. Mice were gavaged with C. crustorum MN047 once daily (∼1 × 109 CFU per mouse). The CA-CRC ameliorating effect of this strain was investigated based on the gut microbiota, inflammation and intestinal barrier integrity. Results showed that C. crustorum MN047 could significantly attenuate tumorigenesis and inflammation via suppressing the TLR4/NF-κB pathway. Moreover, this probiotic could improve the intestinal barrier integrity by increasing the mRNA level of some tight junction-related proteins and reducing goblet cell loss. In addition, C. crustorum MN047 administration led to an increase in beneficial bacteria and a decrease in harmful bacteria, thereby increasing SCFAs and reducing LPS levels. These results suggested that C. crustorum MN047 could partially ameliorate the formation of CA-CRC by modulating the gut microbiota, attenuating inflammation and enhancing the intestinal barrier integrity. Therefore, C. crustorum MN047 was a promising probiotic supplement for attenuating CA-CRC.
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The short-chain fatty acids (SCFAs) acetate, propionate, butyrate, isovalerate, and valerate are end products of intestinal bacterial fermentation and important mediators in the interplay between the intestine and peripheral organs. To unravel the transorgan fluxes and mass balance comparisons of SCFAs, we measured their net fluxes across several organs in a translational pig model. In multi-catheterized conscious pigs (n=12, 25.6 (95% CI [24.2, 26.9]) kg, 8-12 weeks old), SCFA fluxes across portal drained viscera (PDV), liver, kidneys, and hindquarter (muscle compartment) were measured after an overnight fast and in the postprandial state, 4 h after administration of a fiber-free, mixed meal. PDV was the main releasing compartment of acetate, propionate, butyrate, isovalerate, and valerate during fasting and in the postprandial state (all P=0.001). Splanchnic acetate release was high due to the absence of hepatic clearance. All other SCFAs were extensively taken up by the liver (all P<0.05). Even though only 7% [4, 10] (propionate), 42% [23, 60] (butyrate), 26% [12, 39] (isovalerate), and 3% [0.4, 5] (valerate) of PDV release were excreted from the splanchnic area in the fasted state, splanchnic release of all SCFAs was significant (all P≤0.01). Splanchnic propionate, butyrate, isovalerate and valerate release remained low but significant in the postprandial state (all P<0.01). We identified muscle and kidneys as main peripheral SCFA metabolizing organs, taking up the majority of all splanchnically released SCFAs in the fasted state and in the postprandial state. We conclude that the PDV is the main SCFA releasing and the liver the main SCFA metabolizing organ. Splanchnically released SCFAs appear to be important energy substrates to peripheral organs not only in the fasted but also in the postprandial state.
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In the last years, the scientific community has recognized that specific microbial strains resident in the intestinal ecosystem play a key role in human health, participating in several functions beneficial to the host. Such microorganisms have been termed as next-generation probiotics and they are presently considered as food/nutraceutical supplements and biotherapeutic products. However, most of the next-generation probiotic candidates are nutritionally demanding and highly sensitive to aerobic conditions, which translates into several technological challenges concerning large-scale production and appeals to the development of suitable delivery systems able to promote viability and functionality of such probiotic strains. In this chapter, we will present an overall perspective of next-generation probiotics candidates in terms of their health beneficial effects, the delivery systems developed and employed to protect them, and related regulation framework and risk assessment targeting relevant criteria for commercialization in food and pharmaceutical markets.
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Gut microbiota and their major metabolites, short-chain fatty acids (SCFAs), are recognized as important players in gut homeostasis and metabolic disease occurance. A convenient and sensitive detection method is needed to profile SCFAs in limited and complex biological samples. The gas chromatography/mass spectrometry (GC/MS) is the most common method for SCFAs profiling in biological samples. Trimethylsilyl (TMS) derivatization reagents such as N, O-bis(trimethyl-silyl)-trifluoroacetamide (BSTFA) are commonly used in GC/MS analysis to improve sensitivity and accuracy, but they were barely used in SCFA analysis due to their sensitivity to moisture and the volatility of SCFAs. Here, we developed a rapid, convenient and reliable method for SCFAs profiling in small amounts of fecal and serum samples by GC/MS using BSTFA in combination with sodium sulfate dehydration pretreatment. SCFAs were extracted with anhydrous ether from acidified fecal water extract or serum samples, followed by dehydration with sodium sulfate and BSTFA derivatization at a reduced temperature. Select ion monitoring mode was used for highly sensitive quantification of SCFAs by GC/MS. The derivation with BSTFA at 37 °C or 22 °C showed an excellent linearity (R² > 0.999), good recoveries (81.27–128.42%), high repeatability (RSD < 2%) and low limit of detections (LODs) of different SCFAs ranging from 0.064 to 0.067 µM. All major SCFAs including acetic acid, propionic acid, isobutyric acid, butyric acid, isovaleric acid and valeric acid were identified and quantified accurately in fecal and serum samples. In conclusions, a reliable, convenient and sensitive method wasdeveloped for the measurement of SCFA and other volatile compounds in small biological samples using sodium sulfate dehydration pretreatment and BSTFA derivatization-based GC/MS analyses.
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Propionibacterium freudenreichii is a commercially relevant bacterium with probiotic potential. This bacterium can exert protective effects particularly against colorectal cancer (CRC), via the production of short chain fatty acids (SCFA), namely acetate and propionate. In this work, we aimed to evaluate the performance and adaptation capacity of P. freudenreichii to a simulated digestive stress using different culture media, namely YEL, Basal medium, Mimicking the Content of the Human Colon medium (MCHC) and DMEM. The effect of the fermented culture broth on CRC cells survival and of CRC cells conditioned media on the bacteria performance was also evaluated. Basal medium was found to be the best for P. freudenreichii to produce SCFA. MCHC medium, despite being the medium in which lower amounts of acetate and propionate were produced, showed higher acetate and propionate yields as compared to other media. We also observed that the presence of lactate in CRC cells conditioned growth medium resulting from cell metabolism, leads to an increased production of SCFA by the bacteria. The bacterial fermented broth successfully inhibited CRC cells proliferation and increased cell death. Our results showed for the first time that P. freudenreichii performance might be stimulated by extracellular lactate produced by CRC metabolic switch also known as “Warburg effect,” where cancer cells “ferment” glucose into lactate. Additionally, our results suggest that P. freudenreichii could be potentially used as a probiotic in CRC prevention at early stages of the carcinogenesis process and might help in CRC therapeutic approaches.
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Colorectal cancers (CRCs) are the third leading cause of cancer-related mortality worldwide. Rather than being a single, uniform disease type, accumulating evidence suggests that CRCs comprise a group of molecularly heterogeneous diseases that are characterized by a range of genomic and epigenomic alterations. This heterogeneity slows the development of molecular-targeted therapy as a form of precision medicine. Recent data regarding comprehensive molecular characterizations and molecular pathological examinations of CRCs have increased our understanding of the genomic and epigenomic landscapes of CRCs, which has enabled CRCs to be reclassified into biologically and clinically meaningful subtypes. The increased knowledge of the molecular pathological epidemiology of CRCs has permitted their evolution from a vaguely understood, heterogeneous group of diseases with variable clinical courses to characteristic molecular subtypes, a development that will allow the implementation of personalized therapies and better management of patients with CRC. This review provides a perspective regarding recent developments in our knowledge of the molecular and epidemiological landscapes of CRCs, including results of comprehensive molecular characterizations obtained from high-throughput analyses and the latest developments regarding their molecular pathologies, immunological biomarkers, and associated gut microbiome. Advances in our understanding of potential personalized therapies for molecularly specific subtypes are also reviewed.
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Purpose of Review In this review, we describe molecular pathological epidemiology (MPE) studies from around the world that have studied diet and/or lifestyle factors in relation to molecular markers of (epi)genetic pathways in colorectal cancer (CRC), and explore future perspectives in this realm of research. The main focus of this review is diet and lifestyle factors for which there is evidence for an association with CRC as identified by the World Cancer Research Fund reports. In addition, we review promising hypotheses, that warrant consideration in future studies. Recent Findings Associations between molecular characteristics of CRC have been published in relation to smoking, alcohol consumption; body mass index (BMI); waist:hip ratio; adult attained height; physical activity; early life energy restriction; dietary acrylamide, fiber, fat, methyl donors, omega 3 fatty acids; meat, including total protein, processed meat, and heme iron; and fruit and vegetable intake. Summary MPE studies help identify where associations between diet, lifestyle, and CRC risk may otherwise be masked and also shed light on how timing of exposure can influence etiology. Sample size is often an issue, but this may be addressed in the future by pooling data.
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[USE HYPERLINK PROVIDED IN THE COMMENTS TO READ THE FULL TEXT] Red and processed meat is an established risk factor for colorectal cancer (CRC). However, exact mechanisms to explain the associations remain unclear. Few studies have investigated the association with CRC by molecular tumor features, which could provide relevant information on associated molecular pathways. In this population-based case-control study from Germany (DACHS), 2449 cases and 2479 controls provided information on risk factors of CRC and completed a food frequency questionnaire. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the associations between meat intake and risk of CRC by molecular pathologic features and specific subtypes. Red and processed meat intake was associated with increased risk of colorectal (>1 time/day vs ≤1 time/week OR 1.66, 95% CI 1.34-2.07), colon and rectal cancer. Among the single molecular tumor features investigated, the results were similar for associations of red and processed meat with CRC risk by microsatellite instability, CpG island methylator phenotype, BRAF, oestrogen receptor-β and p53 status. Red and processed meat intake was associated less strongly with risk of KRAS-mutated CRC (OR >1 time/day vs ≤1 time/week: 1.49, 95% CI 1.09-2.03) than with risk of KRAS-wildtype CRC (OR 1.82, 95% CI 1.42-2.34; p heterogeneity 0.04). These results support an association between red and processed meat and CRC risk similar for subsites of CRC and most of the investigated major molecular pathological features. Potential differences were observed in more specific subtype analyses. Further large studies are needed to confirm these results and to help further elucidate potential underlying mechanisms.
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Acetate, together with other short chain fatty acids has been implicated in colorectal cancer (CRC) prevention/therapy. Acetate was shown to induce apoptosis in CRC cells. The precise mechanism underlying acetate transport across CRC cells membrane, that may be implicated in its selectivity towards CRC cells, is not fully understood and was addressed here. We also assessed the effect of acetate in CRC glycolytic metabolism and explored its use in combination with the glycolytic inhibitor 3-bromopyruvate (3BP). We provide evidence that acetate enters CRC cells by the secondary active transporters MCT1 and/or MCT2 and SMCT1 as well as by facilitated diffusion via aquaporins. CRC cell exposure to acetate upregulates the expression of MCT1, MCT4 and CD147, while promoting MCT1 plasma membrane localization. We also observed that acetate increases CRC cell glycolytic phenotype and that acetate-induced apoptosis and anti-proliferative effect was potentiated by 3BP. Our data suggest that acetate selectivity towards CRC cells might be explained by the fact that aquaporins and MCTs are found overexpressed in CRC clinical cases. Our work highlights the importance that acetate transport regulation has in the use of drugs such as 3BP as a new therapeutic strategy for CRC.
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Highlights: Fermentation of the dietary fiber by intestinal microflora results in production of butyrate.Butyrate possesses anticarcinogenic effect at the colonic level.Three transporters (MCT1, SMCT1 and BCRP) regulate the intracellular concentration of BT in colonic epithelial cells.Changes in the expression of these transporters occur in colorectal cancer. Abstract: Colorectal cancer (CRC) is one of the most common solid tumors worldwide. Consumption of dietary fiber is associated with a low risk of developing CRC. The fermentation of the dietary fiber by intestinal microflora results in production of butyrate (BT). This short-chain fatty acid is an important metabolic substrate in normal colonic epithelial cells and has important homeostatic functions at the colonic level. Because the cellular effects of BT (e.g. inhibition of histone deacetylases) are dependent on its intracellular concentration, knowledge on the mechanisms involved in BT membrane transport and its regulation seems particularly relevant. In this review, we will present the carrier-mediated mechanisms involved in BT membrane transport at the colonic epithelial level and their regulation, with an emphasis on CRC. Several xenobiotics known to modulate the risk for developing CRC are able to interfere with BT transport at the intestinal level. Thus, interference with BT transport certainly contributes to the anticarcinogenic or procarcinogenic effect of these compounds and these compounds may interfere with the anticarcinogenic effect of BT. Finally, we suggest that differences in BT transport between normal colonocytes and tumoral cells contribute to the "BT paradox" (the apparent opposing effect of BT in CRC cells and normal colonocytes).
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Malignant transformation of cells leads to enhanced glucose uptake and the conversion of a larger fraction of pyruvate into lactate, even under normoxic conditions; this phenomenon of aerobic glycolysis is largely known as the Warburg effect. This metabolic reprograming serves to generate biosynthetic precursors, thus facilitating the survival of rapidly proliferating malignant cells. Extracellular lactate directs the metabolic reprograming of tumor cells, thereby serving as an additional selective pressure. Besides tumor cells, stromal cells are another source of lactate production in the tumor microenvironment, whose role in both tumor growth and the antitumor immune response is the subject of intense research. In this review, we provide an integral perspective of the relationship between lactate and the overall tumor microenvironment, from lactate structure to metabolic pathways for its synthesis, receptors, signaling pathways, lactate-producing cells, lactate-responding cells, and how all contribute to the tumor outcome. We discuss the role of lactate as an immunosuppressor molecule that contributes to tumor evasion and we explore the possibility of targeting lactate metabolism for cancer treatment, as well as of using lactate as a prognostic biomarker.
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An investigation of interactive effects of exogenous and endogenous factors and tumor molecular changes can lead to a better understanding of tumor molecular signatures in colorectal cancer. We here report a molecular pathological epidemiology study in a large cohort of 945 colorectal cancer patients. Mutations of KRAS (36.6%) and BRAF (3.46%) were nearly mutually exclusive. KRAS-mutated tumors were more common in female patients (odds ratio [OR] = 1.68; P = 0.0001) and never smokers (OR = 1.60; P = 0.001). Whereas BRAF-mutated tumors demonstrated no discrepancy in aspects of gender and smoking status compared with wild-type tumors. In addition, tumors with BRAF or KRAS mutations were in correlation with elevated serum level of carbohydrate antigen (CA19-9) and carcinoma embryonic antigen (CEA) and the combination of serum biomarkers and molecular mutation status may enhance the more precise risk stratification of CRC patients. Further studies are needed to define the mechanism brought about by the aforementioned epidemiologic and clinicopathologic characteristics that may help optimize cancer prevention and precision therapy.
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The gastrointestinal tract, in particular the colon, holds a complex community of microorganisms, which are essential for maintaining homeostasis. However, in recent years, many studies have implicated microbiota in the development of colorectal cancer (CRC), with this disease considered a major cause of death in the western world. The mechanisms underlying bacterial contribution in its development are complex and are not yet fully understood. However, there is increasing evidence showing a connection between intestinal microbiota and CRC. Intestinal microorganisms cause the onset and progression of CRC using different mechanisms, such as the induction of a chronic inflammation state, the biosynthesis of genotoxins that interfere with cell cycle regulation, the production of toxic metabolites, or heterocyclic amine activation of pro-diet carcinogenic compounds. Despite these advances, additional studies in humans and animal models will further decipher the relationship between microbiota and CRC, and aid in developing alternate therapies based on microbiota manipulation.
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Short chain fatty acids (SCFA), including acetate, propionate, and butyrate, are produced during bacterial fermentation of undigested carbohydrates in the human colon. In this study, we applied a stable-isotope dilution method to quantify the in vivo colonic production of SCFA in healthy humans after consumption of inulin. Twelve healthy subjects performed a test day during which a primed continuous intravenous infusion with [1-13C]acetate, [1-13C]propionate and [1-13C]butyrate (12, 1.2 and 0.6 μmol•kg-1•min-1, respectively) was applied. They consumed 15 g of inulin with a standard breakfast. Breath and blood samples were collected at regular times during the day over a 12 h period. The endogenous rate of appearance of acetate, propionate, and butyrate was 13.3 ± 4.8, 0.27 ± 0.09, and 0.28 ± 0.12 μmol•kg-1•min-1, respectively. Colonic inulin fermentation was estimated to be 137 ± 75 mmol acetate, 11 ± 9 mmol propionate, and 20 ± 17 mmol butyrate over 12 h, assuming that 40%, 10%, and 5% of colonic derived acetate, propionate, and butyrate enter the systemic circulation. In conclusion, inulin is mainly fermented into acetate and, to lesser extents, into butyrate and propionate. Stable isotope technology allows quantifying the production of the three main SCFA in vivo and proved to be a practical tool to investigate the extent and pattern of SCFA production.
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Acetate is a short-chain fatty acid secreted by Propionibacteria from the human intestine, known to induce mitochondrial apoptotic death in colorectal cancer (CRC) cells. We previously established that acetate also induces lysosome membrane permeabilization in CRC cells, associated with release of the lysosomal protease cathepsin D (CatD), which has a well-established role in the mitochondrial apoptotic cascade. Unexpectedly, we showed that CatD has an antiapoptotic role in this process, as pepstatin A (a CatD inhibitor) increased acetate-induced apoptosis. These results mimicked our previous data in the yeast system showing that acetic acid activates a mitochondria-dependent apoptosis process associated with vacuolar membrane permeabilization and release of the vacuolar protease Pep4p, ortholog of mammalian CatD. Indeed, this protease was required for cell survival in a manner dependent on its catalytic activity and for efficient mitochondrial degradation independently of autophagy. In this study, we therefore assessed the role of CatD in acetate-induced mitochondrial alterations. We found that, similar to acetic acid in yeast, acetate-induced apoptosis is not associated with autophagy induction in CRC cells. Moreover, inhibition of CatD with small interfering RNA or pepstatin A enhanced apoptosis associated with higher mitochondrial dysfunction and increased mitochondrial mass. This effect seems to be specific, as inhibition of CatB and CatL with E-64d had no effect, nor were these proteases significantly released to the cytosol during acetate-induced apoptosis. Using yeast cells, we further show that the role of Pep4p in mitochondrial degradation depends on its protease activity and is complemented by CatD, indicating that this mechanism is conserved. In summary, the clues provided by the yeast model unveiled a novel CatD function in the degradation of damaged mitochondria when autophagy is impaired, which protects CRC cells from acetate-induced apoptosis. CatD inhibitors could therefore enhance acetate-mediated cancer cell death, presenting a novel strategy for prevention or therapy of CRC.
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During feeding, the gut microbiota contributes to the host energy acquisition and metabolic regulation thereby influencing the development of metabolic disorders such as obesity and diabetes. Short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate, which are produced by gut microbial fermentation of dietary fiber, are recognized as essential host energy sources and act as signal transduction molecules via G-protein coupled receptors (FFAR2, FFAR3, OLFR78, GPR109A) and as epigenetic regulators of gene expression by the inhibition of histone deacetylase (HDAC). Recent evidence suggests that dietary fiber and the gut microbial-derived SCFAs exert multiple beneficial effects on the host energy metabolism not only by improving the intestinal environment, but also by directly affecting various host peripheral tissues. In this review, we summarize the roles of gut microbial SCFAs in the host energy regulation and present an overview of the current understanding of its physiological functions.
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The dysbiosis of the human intestinal microbiota is linked to sporadic colorectal carcinoma (CRC). The present study was designed to investigate the gut microbiota distribution features in CRC patients. We performed pyrosequencing based analysis of the 16S rRNA gene V3 region to investigate microbiota of the cancerous tissue and adjacent non-cancerous normal tissue in proximal and distal CRC samples. The results revealed that the microbial structures of the CRC patients and healthy individuals differed significantly. Firmicutes and Fusobacteria were over-represented whereas Proteobacteria was under-represented in CRC patients. In addition, Lactococcus and Fusobacterium exhibited a relatively higher abundance while Pseudomonas and Escherichia-Shigella was reduced in cancerous tissues compared to adjacent non-cancerous tissues. Meanwhile, the overall microbial structures of proximal and distal colon cancerous tissues were similar; but certain potential pro-oncogenic pathogens were different. These results suggested that the mucosa-associated microbiota is dynamically associated with CRC, which may provide evidences for microbiota-associated diagnostic, prognostic, preventive, and therapeutic strategies for CRC.
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T cells are central players in the regulation of adaptive immunity and immune tolerance. In the periphery, T cell differentiation for maturation and effector function is regulated by a number of factors. Various factors such as antigens, co-stimulation signals, and cytokines regulate T cell differentiation into functionally specialized effector and regulatory T cells. Other factors such as nutrients, micronutrients, nuclear hormones and microbial products provide important environmental cues for T cell differentiation. A mounting body of evidence indicates that the microbial metabolites short-chain fatty acids (SCFAs) have profound effects on T cells and directly and indirectly regulate their differentiation. We review the current status of our understanding of SCFA functions in regulation of peripheral T cell activity and discuss their impact on tissue inflammation.
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The human gut is home to a complex and diverse microbiota that contributes to the overall homeostasis of the host. Increasingly, the intestinal microbiota is recognized as an important player in human illness such as colorectal cancer (CRC), inflammatory bowel diseases, and obesity. CRC in itself is one of the major causes of cancer mortality in the Western World. The mechanisms by which bacteria contribute to CRC are complex and not fully understood, but increasing evidence suggests a link between the intestinal microbiota and CRC as well as diet and inflammation which are believed to play a role in carcinogenesis.. It is thought that the gut microbiota interact with dietary factors to promote chronic inflammation and CRC through direct influence on host cell physiology, cellular homeostasis, energy regulation, and/or metabolism of xenobiotics. This review provides an overview on the role of commensal gut microbiota in the development of human colorectal cancer and explores its association with diet and inflammation. Copyright © 2012, American Journal of Physiology- Gastrointestinal and Liver Physiology.
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Microbiome analysis has identified a state of microbial imbalance (dysbiosis) in patients with chronic intestinal inflammation and colorectal cancer. The bacterial phylum Proteobacteria is often overrepresented in these individuals, with Escherichia coli being the most prevalent species. It is clear that a complex interplay between the host, bacteria and bacterial genes is implicated in the development of these intestinal diseases. Understanding the basic elements of these interactions could have important implications for disease detection and management. Recent studies have revealed that E. coli utilizes a complex arsenal of virulence factors to colonize and persist in the intestine. Some of these virulence factors, such as the genotoxin colibactin, were found to promote colorectal cancer in experimental models. In this Review, we summarize key features of the dysbiotic states associated with chronic intestinal inflammation and colorectal cancer, and discuss how the dysregulated interplay between host and bacteria could favor the emergence of E. coli with pathological traits implicated in these pathologies.
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The gastrointestinal (GI) tract is separated from the body's internal environment by a single layer of epithelial cells, through which nutrients must pass for their absorption into the bloodstream. Besides food and drink, the GI lumen is also exposed to bioactive chemicals and bacterial products including short-chain fatty acids (SCFAs). Therefore, the GI tract has to monitor the composition of its contents continuously to discriminate between necessary and unnecessary compounds. Recent molecular identification of epithelial membrane receptor proteins has revealed the sensory roles of intestinal epithelial cells in the gut chemosensory system. Malfunctioning of these receptors may be responsible for a variety of metabolic dysfunctions associated with obesity and related disorders. Recent studies suggest that SCFAs produced by microbiota fermentation act as signaling molecules and influence the host's metabolism; uncovering the sensory mechanisms of such bacterial metabolites would help us understand the interactions between the host and microbiota in host energy homeostasis. In this review, the contribution of colonic SCFA receptors in energy metabolism and our recent findings concerning the possible link between SCFA receptors and host energy homeostasis are discussed.
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Monocarboxylate transporters (MCTs) belong to a family of transporters, encoded by the SLC16 gene family, which is presently composed by 14 members, but only MCT1 to 4 have been biochemically characterized. They have important functions in healthy tissues, being involved in the transmembrane transport of lactic acid and other monocarboxylic acids in human cells. One of the recently recognized hallmarks of cancer is altered metabolism, with high rates of glucose consumption and consequent lactate production. To maintain this metabolic phenotype, cancer cells upregulate a series of plasma membrane proteins, including MCTs. MCT1 and MCT4, in particular, play a dual role in the maintenance of the metabolic phenotype of tumour cells. On one hand, they facilitate the efflux of lactate and, on the other hand, they contribute to the preservation of the intracellular pH, by co-transporting a proton. Thus, MCTs are attractive targets in cancer therapy, especially in cancers with a hyper-glycolytic and acid-resistant phenotype. Recent evidence demonstrates that MCTs are involved in cancer cell uptake of chemotherapeutic agents, including 3-bromopyruvate. In this way MCTs can act as "Trojan horses", as their elevated expression in cancer cells can mediate the entry of this chemotherapeutic agent into the cells and selectively kill cancer cells. As a result, MCTs will be mediators of chemotherapeutic response, and their expression can be used as a molecular marker to predict response to chemotherapy.
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Many epidemiological and experimental studies have suggested that dietary fiber plays an important role in colon cancer prevention. These findings may relate to the ability of fiber to reduce the contact time of carcinogens within the intestinal lumen and to promote healthy gut microbiota, which modifies the host's metabolism in various ways. Elucidation of the mechanisms by which dietary fiber-dependent changes in gut microbiota enhance bile acid deconjugation, produce short chain fatty acids, and modulate inflammatory bioactive substances can lead to a better understanding of the beneficial role of dietary fiber. This article reviews the current knowledge concerning the mechanisms via which dietary fiber protects against colon cancer.
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Foxp3 expression and regulatory T cell (Treg) development are critical for maintaining dominant tolerance and preventing autoimmune diseases. Human MST1 deficiency causes a novel primary immunodeficiency syndrome accompanied by autoimmune manifestations. However, the mechanism by which Mst1 controls immune regulation is unknown. In this article, we report that Mst1 regulates Foxp3 expression and Treg development/function and inhibits autoimmunity through modulating Foxo1 and Foxo3 (Foxo1/3) stability. We have found that Mst1 deficiency impairs Foxp3 expression and Treg development and function in mice. Mechanistic studies reveal that Mst1 enhances Foxo1/3 stability directly by phosphorylating Foxo1/3 and indirectly by attenuating TCR-induced Akt activation in peripheral T cells. Our studies have also shown that Mst1 deficiency does not affect Foxo1/3 cellular localization in CD4 T cells. In addition, we show that Mst1(-/-) mice are prone to autoimmune disease, and mutant phenotypes, such as overactivation of naive T cells, splenomegaly, and autoimmune pathological changes, are suppressed in Mst1(-/-) bone marrow chimera by cotransplanted wt Tregs. Finally, we demonstrate that Mst1 and Mst2 play a partially redundant role in Treg development and autoimmunity. Our findings not only identify Mst kinases as the long-searched-for factors that simultaneously activate Foxo1/3 and inhibit TCR-stimulated Akt downstream of TCR signaling to promote Foxp3 expression and Treg development, but also shed new light on understanding and designing better therapeutic strategies for MST1 deficiency-mediated human immunodeficiency syndrome.
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Colorectal cancer (CRC) is one of the most common solid tumors worldwide. A diet rich in dietary fiber is associated with a reduction in its risk. Butyrate (BT) is one of the main end products of anaerobic bacterial fermentation of dietary fiber in the human colon. This short-chain fatty acid is an important metabolic substrate in normal colonic epithelial cells and has important homeostatic functions at this level, including the ability to prevent/inhibit carcinogenesis. BT is transported into colonic epithelial cells by two specific carrier-mediated transport systems, the monocarboxylate transporter 1 (MCT1) and the sodium-coupled monocarboxylate transporter 1 (SMCT1). In normal colonic epithelial cells, BT is the main energy source for normal colonocytes and it is effluxed by BCRP. Colonic epithelial tumoral cells show a reduction in BT uptake (through a reduction in MCT1 and SMCT1 protein expression), an increase in the rate of glucose uptake and glycolysis becomes their primary energy source. BT presents an anticarcinogenic effect (induction of cell differentiation and apoptosis and inhibition of cell proliferation) but has an apparent opposing effect upon growth of normal colonocytes (the "BT paradox"). Because the cellular effects of BT (e.g. inhibition of histone deacetylases) are dependent on its intracellular concentration, knowledge on the mechanisms involved in BT membrane transport and its regulation seem particularly relevant in the context of the physiological and pharmacological benefits of this compound. This review discusses the mechanisms of BT transport and integrates this knowledge with the effects of BT in tumoral and normal colonocytes.
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Background & aims: Nearly 20% of the global cancer burden can be linked to infectious agents. Fusobacterium nucleatum promotes tumor formation by epithelial cells via unclear mechanisms. We aimed to identify microRNAs (miRNAs) induced by F nucleatum and evaluate their ability to promote colorectal carcinogenesis in mice. Methods: Colorectal cancer (CRC) cell lines were incubated with F nucleatum or control reagents and analyzed in proliferation and would healing assays. HCT116, HT29, LoVo, and SW480 CRC cell lines were incubated with F nucleatum or phosphate buffer saline (PBS control) and analyzed for miRNA expression patterns and in chromatin immunoprecipitation assays. Cells were incubated with miRNAs mimics, control sequences, or small interfering (si) RNAs; expression of reporter constructs was measured in luciferase assays. CRC cells were incubated with F nucleatum or PBS and injected into BALB/C nude mice; growth of xenograft tumors was measured. C57BL APC(min/+), C57BL miR21a(-/-), and C57BL mice with full-length miR21a (controls) were given F nucleatum by gavage; some mice were given azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce colitis and colon tumors. Intestinal tissues were collected and tumors were counted. Serum samples from mice were analyzed for cytokine levels by ELISAs. We performed in situ hybridization analyses to detect enrichment of F nucleatum in CRC cells. F nucleatum DNA in 90 tumor and matched non-tumor tissues from patients in China were explored for the expression correlation analysis; levels in 125 tumor tissues from patients in Japan were compared with their survival times. Results: F nucleatum increased proliferation and invasive activities of CRC cell lines, compared with control cells. CRC cell lines infected with F nucleatum formed larger tumors, more rapidly, in nude mice than uninfected cells. APC(min/+) mice gavaged with F nucleatum developed significantly more colorectal tumors than mice given PBS and had shorter survival times. We found several inflammatory factors to be significantly increased in serum from mice given F nucleatum (interleukin 17F [IL17F], IL21, IL22, and MIP3A). We found 50 miRNAs to be significantly upregulated and 52 miRNAs to be significantly downregulated in CRCs incubated with F nucleatum vs PBS; levels of miR21 increased by the greatest amount (more than 4-fold). Inhibitors of miR21 prevented F nucleatum from inducing cell proliferation and invasion in culture. miR21a(-/-) mice had a later appearance of fecal blood and diarrhea after administration of AOM and DSS, and had longer survival times, compared with control mice. The colorectum of miR21a(-/-) mice had fewer tumors, of smaller size, and the miR21a(-/-) mice survived longer than control mice. We found RASA1, which encodes a RAS GTPase, to be one of the target genes consistently downregulated in cells that overexpressed miR21 and upregulated in cells exposed to miR21 inhibitors. Infection of cells with F nucleatum increased expression of miR21 by activating TLR4 signaling to MYD88, leading to activation of the nuclear factor NFκB. Levels of F nucleatum DNA and miR21 were increased in tumor tissues (and even more so in advanced tumor tissues), compared with non-tumor colon tissues from patients. Patients whose tumors had high amounts of F nucleatum DNA and miR21 had shorter survival times than patients whose tumors had lower amounts. Conclusions: We found infection of CRC cells with F nucleatum to increase their proliferation, invasive activity, and ability to form xenograft tumors in mice. F nucleatum activates TLR4 signaling to MYD88, leading to activation of the nuclear factor NFκB and increased expression of miR21; this miRNA reduces levels of the RAS GTPase RASA1. Patients with both high amount of tissue F nucleatum DNA and miR21 demonstrated a higher risk for poor outcomes.
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Molecular pathological epidemiology (MPE) is an integrative field that utilizes molecular pathology to incorporate interpersonal heterogeneity of a disease process into epidemiology. In each individual, the development and progression of a disease are determined by a unique combination of exogenous and endogenous factors, resulting in different molecular and pathological subtypes of the disease. Based on “the unique disease principle,” the primary aim of MPE is to uncover an interactive relationship between a specific environmental exposure and disease subtypes in determining disease incidence and mortality. This MPE approach can provide etiologic and pathogenic insights, potentially contributing to precision medicine for personalized prevention and treatment. Although breast, prostate, lung, and colorectal cancers have been among the most commonly studied diseases, the MPE approach can be used to study any disease. In addition to molecular features, host immune status and microbiome profile likely affect a disease process, and thus serve as informative biomarkers. As such, further integration of several disciplines into MPE has been achieved (e.g., pharmaco-MPE, immuno-MPE, and microbial MPE), to provide novel insights into underlying etiologic mechanisms. With the advent of high-throughput sequencing technologies, available genomic and epigenomic data have expanded dramatically. The MPE approach can also provide a specific risk estimate for each disease subgroup, thereby enhancing the impact of genome-wide association studies on public health. In this article, we present recent progress of MPE, and discuss the importance of accounting for the disease heterogeneity in the era of big-data health science and precision medicine.
Chapter
In the colon, short chain fatty acids are absorbed at the same time as sodium and water absorption. Two mechanisms of absorption have been proposed. During diffusion of protonated SCFAs, luminal protons (Na⁺/H⁺ exchange, K⁺ H⁺-ATPase or bacterial metabolic activity) acidify the colonic lumen. This creates a pH between the colonic lumen compared to the systemic circulation. This pH gradient can promote the diffusive movement of SCFAs. With anion exchange, a family of anion exchangers mediates SCFAs and HCO3 exchange and entry across the membrane[3]. Once absorbed, SCFAs are used preferentially as fuel for colonic epithelial cells [4]. Butyrate is used preferentially over propionate and acetate. Those SCFAs are later transported to the liver. There, propionate acts as a substrate for gluconeogenesis and inhibits cholesterol synthesis in hepatic tissue. Acetate is utilized in the synthesis of long chain fatty acids, glutamine, glutamate and beta-hydroxybutyrate [2, 4]. Over the last a fe