ArticleLiterature Review

Wong JMW, de Souza R, Kendall CWC, Emam A, Jenkins DJA.. Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol 40: 235-243

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Abstract

Interest has been recently rekindled in short chain fatty acids (SCFAs) with the emergence of prebiotics and probiotics aimed at improving colonic and systemic health. Dietary carbohydrates, specifically resistant starches and dietary fiber, are substrates for fermentation that produce SCFAs, primarily acetate, propionate, and butyrate, as end products. The rate and amount of SCFA production depends on the species and amounts of microflora present in the colon, the substrate source and gut transit time. SCFAs are readily absorbed. Butyrate is the major energy source for colonocytes. Propionate is largely taken up by the liver. Acetate enters the peripheral circulation to be metabolized by peripheral tissues. Specific SCFA may reduce the risk of developing gastrointestinal disorders, cancer, and cardiovascular disease. Acetate is the principal SCFA in the colon, and after absorption it has been shown to increase cholesterol synthesis. However, propionate, a gluconeogenerator, has been shown to inhibit cholesterol synthesis. Therefore, substrates that can decrease the acetate: propionate ratio may reduce serum lipids and possibly cardiovascular disease risk. Butyrate has been studied for its role in nourishing the colonic mucosa and in the prevention of cancer of the colon, by promoting cell differentiation, cell-cycle arrest and apoptosis of transformed colonocytes; inhibiting the enzyme histone deacetylase and decreasing the transformation of primary to secondary bile acids as a result of colonic acidification. Therefore, a greater increase in SCFA production and potentially a greater delivery of SCFA, specifically butyrate, to the distal colon may result in a protective effect. Butyrate irrigation (enema) has also been suggested in the treatment of colitis. More human studies are now needed, especially, given the diverse nature of carbohydrate substrates and the SCFA patterns resulting from their fermentation. Short-term and long-term human studies are particularly required on SCFAs in relation to markers of cancer risk. These studies will be key to the success of dietary recommendations to maximize colonic disease prevention.

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... SCFAs are a group of fatty acid compounds with an alkyl chain shorter than six carbons that includes butyrate, acetate, and propionate [18]. They are products of microbial fermentation of mainly undigested dietary fiber [18][19][20][21]. SCFAs are found in both small and large intestines, except for butyrate, which is mostly located in the colon and cecum [22]. ...
... Further evidence comes from the administration of oral butyrate: it has the potential to enhance the effectiveness of oral mesalazine in treating active UC disease [20], and implementing a diet that elevates SCFA levels in individuals with IBD can also alleviate colitis [38]. ...
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... This can be explained by the higher amount of fibers in prebiotic-enriched feed. Butyrate is known to decrease the permeability of the intestinal epithelial lining by increasing the expression of tight junction proteins and reinforcing colonic defense barriers by increasing antimicrobial peptide levels and mucin production (Cook and Sellin, 1998;Wong et al., 2006;Antharam et al., 2013). It can be speculated that the increase in butyrate production may prevent over-growth of pathogens after an acute dysbisosis event. ...
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... However, a diet rich in fiber can elevate endogenous organic acid production to levels of 84-98 mmol/kg DM (Rossi et al., 2010). The rate of production and distribution of SCFAs largely depends on the diversity and population of the colonic gut microbiota, as well as the nature of the substrate and the transit time within the intestine (Wong et al., 2006). The genera primarily responsible for SCFAs synthesis include Eubacterium, Roseburia, Clostridium anaerobes, Streptococcus, Bacteroides and Bifidobacterium (Layden et al., 2013;Ziegler et al., 2016;McNabney and Henagan, 2017;Mehta et al., 2022). ...
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... The hippocampus, primarily affected in AD, is particularly susceptible to the products of the MB such as short chain fatty acids (SCFAs) (Sharon et al., 2016) that can reach the brain through the circulation, cross the BBB, and target microglia to regulate their function. It has been shown that prebiotics (dietary fibres) can modulate the expression of bacterial proteins associated with SCFAs production (Wong et al., 2006). Furthermore, a diet with low content of fibres causes reduction of bacterial SCFAs products in mice (Sonnenburg et al., 2016) human primates (Nagpal et al., 2018) and humans (Duncan et al., 2007). ...
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Foods that help improve menopausal syndrome are being studied worldwide. Doenjang is a traditional Korean fermented soybean food with potential health benefits for menopausal women. In this clinical trial using Doenjang, we aimed to compare the effectiveness of traditional Doenjang and commercial Doenjang in menopausal women. Furthermore, we compared whether Doenjang has a better effect if the number of beneficial microbes is higher. The analyses included the following groups: traditional Doenjang containing either a high dose (HDC; n = 18) or low dose (LDC; n = 18) of beneficial microbes and commercial Doenjang (CD; n = 20). The Kupperman index and hematological changes were examined before and after the use of Doenjang pills. The effects of Doenjang on obesity and body composition were studied before and after ingestion. Lastly, the microorganisms and short-chain fatty acid changes in the stool were compared. The Kupperman index decreased after Doenjang consumption in all three groups, with the greatest decrease in the LDC group. Only the groups that took traditional Doenjang pills exhibited reduced LDL cholesterol. No changes in obesity and inflammation-related indicators were observed. The number of Firmicutes, associated with obesity, decreased in the CD group but the numbers of Bacteroidetes increased in the HDC and CD groups. Thus, traditional Doenjang is more effective in alleviating menopausal syndrome than commercial Doenjang. Further research on the anti-obesity effect or changes in microbiomes and short-chain fatty acids in feces is needed.
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Background Cardiovascular diseases are the leading cause of death worldwide, significantly impacting public health. Atherosclerotic cardiovascular diseases account for the majority of these deaths, with atherosclerosis marking the initial and most critical phase of their pathophysiological progression. There is a complex relationship between atherosclerosis, the gut microbiome’s composition and function, and the potential mediating role of exercise. The adaptability of the gut microbiome and the feasibility of exercise interventions present novel opportunities for therapeutic and preventative approaches. Methodology We conducted a comprehensive literature review using professional databases such as PubMed and Web of Science. This review focuses on the application of meta-omics techniques, particularly metagenomics and metabolomics, in studying the effects of exercise interventions on the gut microbiome and atherosclerosis. Results Meta-omics technologies offer unparalleled capabilities to explore the intricate connections between exercise, the microbiome, the metabolome, and cardiometabolic health. This review highlights the advancements in metagenomics and metabolomics, their applications in research, and examines how exercise influences the gut microbiome. We delve into the mechanisms connecting these elements from a metabolic perspective. Metagenomics provides insight into changes in microbial strains post-exercise, while metabolomics sheds light on the shifts in metabolites. Together, these approaches offer a comprehensive understanding of how exercise impacts atherosclerosis through specific mechanisms. Conclusions Exercise significantly influences atherosclerosis, with the gut microbiome serving as a critical intermediary. Meta-omics technology holds substantial promise for investigating the gut microbiome; however, its methodologies require further refinement. Additionally, there is a pressing need for more extensive cohort studies to enhance our comprehension of the connection among these element.
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Background Gut microbiota has been associated with dermatological problems in earlier observational studies. However, it is unclear whether gut microbiota has a causal function in dermatological diseases. Methods Thirteen dermatological diseases were the subject of bidirectional Mendelian randomization (MR) research aimed at identifying potential causal links between gut microbiota and these diseases. Summary statistics for the Genome-Wide Association Study (GWAS) of gut microbiota and dermatological diseases were obtained from public datasets. With the goal of evaluating the causal estimates, five acknowledged MR approaches were utilized along with multiple testing corrections, with inverse variance weighted (IVW) regression serving as the main methodology. Regarding the taxa that were causally linked with dermatological diseases in the forward MR analysis, reverse MR was performed. A series of sensitivity analyses were conducted to test the robustness of the causal estimates. Results The combined results of the five MR methods and sensitivity analysis showed 94 suggestive and five significant causal relationships. In particular, the genus Eubacterium_fissicatena_group increased the risk of developing psoriasis vulgaris (odds ratio [OR] = 1.32, pFDR = 4.36 × 10⁻³), family Bacteroidaceae (OR = 2.25, pFDR = 4.39 × 10⁻³), genus Allisonella (OR = 1.42, pFDR = 1.29 × 10⁻²), and genus Bacteroides (OR = 2.25, pFDR = 1.29 × 10⁻²) increased the risk of developing acne; and the genus Intestinibacter increased the risk of urticaria (OR = 1.30, pFDR = 9.13 × 10⁻³). A reverse MR study revealed insufficient evidence for a significant causal relationship. In addition, there was no discernible horizontal pleiotropy or heterogeneity. Conclusion This study provides novel insights into the causality of gut microbiota in dermatological diseases and therapeutic or preventive paradigms for cutaneous conditions.
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Diet is one of the most important external factor shaping the composition and metabolic activities of the gut microbiome. The gut microbiome plays a crucial role in host health, including immune system development, nutrients metabolism, and the synthesis of bioactive molecules. In addition, the gut microbiome has been described as critical for the development of several mental disorders. Nutritional psychiatry is an emerging field of research that may provide a link between diet, microbial function, and brain health. In this study, we have reviewed the influence of different diet types, such as Western, Mediterranean, vegetarian, and ketogenic, on the gut microbiota composition and function, and their implication in various neuropsychiatric and psychological disorders.
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The intestinal microbiota has major influence on human physiology and modulates health and disease. Complex host–microbe interactions regulate various homeostatic processes, including metabolism and immune function, while disturbances in microbiota composition (dysbiosis) are associated with a plethora of human diseases and are believed to modulate disease initiation, progression and therapy response. The vast complexity of the human microbiota and its metabolic output represents a great challenge in unraveling the molecular basis of host–microbe interactions in specific physiological contexts. To increase our understanding of these interactions, functional microbiota research using animal models in a reductionistic setting are essential. In the dynamic landscape of gut microbiota research, the use of germ‐free and gnotobiotic mouse technology, in which causal disease‐driving mechanisms can be dissected, represents a pivotal investigative tool for functional microbiota research in health and disease, in which causal disease‐driving mechanisms can be dissected. A better understanding of the health‐modulating functions of the microbiota opens perspectives for improved therapies in many diseases. In this review, we discuss practical considerations for the design and execution of germ‐free and gnotobiotic experiments, including considerations around germ‐free rederivation and housing conditions, route and timing of microbial administration, and dosing protocols. This comprehensive overview aims to provide researchers with valuable insights for improved experimental design in the field of functional microbiota research.
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Background Due to their complexity and to the presence of common clinical features, differentiation between asthma and chronic obstructive pulmonary disease (COPD) can be a challenging task, complicated in such cases also by asthma–COPD overlap syndrome. The distinct immune/inflammatory and structural substrates of COPD and asthma are responsible for significant differences in the responses to standard pharmacologic treatments. Therefore, an accurate diagnosis is of central relevance to assure the appropriate therapeutic intervention in order to achieve safe and effective patient care. Induced sputum (IS) accurately mirrors inflammation in the airways, providing a more direct picture of lung cell metabolism in comparison to those specimen that reflect analytes in the systemic circulation. Methods An integrated untargeted metabolomics and lipidomics analysis was performed in IS of asthmatic (n = 15) and COPD (n = 22) patients based on Ultra-High-Pressure Liquid Chromatography-Mass Spectrometry (UHPLC-MS) and UHPLC–tandem MS (UHPLC-MS/MS). Partial Least Squares-Discriminant Analysis (PLS-DA) was applied to resulting dataset. The analysis of main enriched metabolic pathways and the association of the preliminary metabolites/lipids pattern identified to clinical parameters of asthma/COPD differentiation were explored. Multivariate ROC analysis was performed in order to determine the discriminatory power and the reliability of the putative biomarkers for diagnosis between COPD and asthma. Results PLS-DA indicated a clear separation between COPD and asthmatic patients. Among the 15 selected candidate biomarkers based on Variable Importance in Projection scores, putrescine showed the highest score. A differential IS bio-signature of 22 metabolites and lipids was found, which showed statistically significant variations between asthma and COPD. Of these 22 compounds, 18 were decreased and 4 increased in COPD compared to asthmatic patients. The IS levels of Phosphatidylethanolamine (PE) (34:1), Phosphatidylglycerol (PG) (18:1;18:2) and spermine were significantly higher in asthmatic subjects compared to COPD. Conclusions This is the first pilot study to analyse the IS metabolomics/lipidomics signatures relevant in discriminating asthma vs COPD. The role of polyamines, of 6-Hydroxykynurenic acid and of d-rhamnose as well as of other important players related to the alteration of glycerophospholipid, aminoacid/biotin and energy metabolism provided the construction of a diagnostic model that, if validated on a larger prospective cohort, might be used to rapidly and accurately discriminate asthma from COPD. Graphical Abstract
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Introduction Cerebral ischaemic stroke is a common disease that poses a serious threat to human health. Butyrate is an important metabolite of intestinal microorganisms. Recent studies have shown that butyrate has a significant protective effect in animal models of cerebral ischaemic injury. Objective The aim of this study was to evaluate the protective effect of butyrate on cerebral ischaemic stroke by meta-analysis, aiming to provide a scientific basis for the clinical application of butyrate in patients with cerebral ischaemia. Materials and methods A systematic search was conducted for all relevant studies published before 23 January 2024, in PubMed, Web of Science, Cochrane Library, and Embase. Methodological quality was assessed using Syrcle’s risk of bias tool for animal studies. Data were analysed using Rev Man 5.3 software. Results A total of nine studies were included, and compared with controls, butyrate significantly increased BDNF levels in the brain (SMD = 2.33, 95%CI = [1.20, 3.47], p < 0.005) and P-Akt expression (SMD = 3.53, 95% CI = [0.97, 6.10], p < 0.05). Butyrate also decreased IL-β levels in the brain (SMD = −2.02, 95% CI = [−3.22, −0.81], p < 0.005), TNF-α levels (SMD = −0.86, 95% CI = [−1.60, −0.12], p < 0.05), and peripheral vascular IL-1β levels (SMD = −2.10, 95%CI = [−3.59, −0.61], p < 0.05). In addition, butyrate reduced cerebral infarct volume (MD = −11.29, 95%CI = [−17.03, −5.54], p < 0.05), mNSS score (MD = −2.86, 95%CI = [−4.12, −1.60], p < 0.005), foot fault score (MD = −7.59, 95%CI = [−9.83, −5, 35], p < 0.005), and Morris water maze time (SMD = −2.49, 95%CI = [−4.42, −0.55], p < 0.05). Conclusion The results of this study indicate that butyrate has a protective effect on cerebral ischaemic stroke in animal models, and the mechanism is related to reducing inflammation and inhibiting apoptosis. It provides an evidence-based basis for the future clinical development of butyrate in the treatment of ischaemic stroke. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/, CRD42023482844.
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The eubiotic state of the gut microbiota is primarily brought about by various probiotic species that colonize the gut. It is becoming very clear that the probiotic-metabolite mixtures in the gut luminal milieu is central in establishing cross-kingdom signalling networks to maintain gut-multi-organ axes health. Culturally, different fermented foods and beverages have been regional staples since ancient times, and are known to be enriched with probiotics. However, regional variations including the environment, the staple food source (prebiotics), and fermentation methods, among other factors, influence the fermenting probiotic species. Fermented rice water (FRW), an economical, easy to make, simple beverage is a rich source of synbiotics. Therefore, consumption of fermented rice water allows for the intake of a variety of region-specific live probiotics. The secondary metabolites (postbiotics) present in such symbiotic mixtures may also contribute toward maintaining normal intestinal cellular functions. In this study, we highlight that regional staples such as rice consumed in their fermented form may hold promise in alleviating gut-related diseases. Our results show that simple overnight fermentation of cooked edible rice enables the growth of probiotic bacterial species belonging to the Lactic Acid Bacteria group (Leuconostoc lactis, Weisella confusa, Weisella cibacria, Lactococcus lactis, lactococcus taiwanensis, Lactobacillus fermentum, Lactobacillus nagelii, and Lactobacillus delbrueckii ssp. indicus). Metabolomic analysis of the overnight fermented and over two-nights fermented rice water identified more than 200 postbiotic metabolites. Our results show that postbiotics contributing to energy metabolism, gut-multiorgan axes, and microbial paraprobiotics are enriched in the overnight (~10 h) fermented rice water as compared to the over two-nights fermented rice water. Functional analysis via gene expression studies for nutrient absorption (mct-1 and mct-2) and barrier integrity (occludin and zo-1) reveals significant upregulation of these genes upon FRW treatment of HT29 colon cells. This study is a first-of-its-kind to demonstrate the proof-of-principle that postbiotics of naturally fermented rice water positively modulates colonocyte health.
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Feeding the type 4 resistant starch, Versafibe 1490™ (VF), alters the microbiome, SCFA production and gene expression in the cecum and colon in mice.
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Scope : Dietary proteins and essential amino acids (EAAs) are the major nutritional supplements that support the growth and activity of gut microbes contributing to the wellbeing of their host. This study hypothesizes that daily supplementation of the diet with either EAAs or whey protein for 12 weeks would improve the gut microbiome of older adults. Methods and results : The stool samples are processed and subjected to Illumina‐based 16S ribosomal ribonucleic acid (rRNA) gene amplicon sequencing. In both groups, the most abundant families are found in order of relative abundance included: Bacteroidaceae , Lachnospiraceae , Ruminococcaceae , Prevotellaceae , Rikenellaceae , Enterobacteriaceae , Oscillospiraceae , Tannerellaceae , and Akkermansiaceae , which indicate that these subjects are able to maintain a same healthy microbial diversity in their guts. A significant finding is a reduction of proinflammatory cytokine, interleukin‐18 (IL‐18) in the EAAs group. It also uses the standard 6‐min walking test (6MWT) as a measure of cardiopulmonary fitness. At the end of the study, the subjects in the EAAs group perform significantly better in the 6MWT as compared to the whey group. Conclusion : It seems plausible that the improved physical performance and reduced proinflammatory cytokine, IL‐18 seen in the EAAs group, are independent of changes in gut microbiota.
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Consumption of fructo- (FOS) and galacto-oligosaccharides (GOS) has health benefits which have been linked in part to short-chain fatty acids (SCFA) production by the gut microbiota. However, detailed knowledge of this process in the human intestine is lacking. We aimed to determine the acute fermentation kinetics of a FOS:GOS mixture in healthy males using a naso-intestinal catheter for sampling directly in the ileum or colon. We studied the fate of SCFA as substrates for glucose and lipid metabolism by the host after infusion of 13C-SCFA. In the human distal ileum, no fermentation of FOS:GOS, nor SCFA production, or bacterial cross-feeding was observed. The relative composition of intestinal microbiota changed rapidly during the test day, which demonstrates the relevance of postprandial intestinal sampling to track acute responses of the microbial community toward interventions. SCFA were vividly taken up and metabolized by the host as shown by incorporation of 13C in various host metabolites.
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Objectives Alcohol consumption is not uncommon among people with HIV (PWH) and may exacerbate HIV-induced intestinal damage, and further lead to dysbiosis and increased intestinal permeability. This study aimed to determine the changes in the fecal microbiota and its association with alcohol consumption in HIV-infected patients. Methods A cross-sectional survey was conducted between November 2021 and May 2022, and 93 participants were recruited. To investigate the alterations of alcohol misuse on fecal microbiology in HIV-infected individuals, we performed 16s rDNA gene sequencing on fecal samples from the low-to-moderate drinking (n = 21) and non-drinking (n = 72) groups. Results Comparison between groups using alpha and beta diversity showed that the diversity of stool microbiota in the low-to-moderate drinking group did not differ from that of the non-drinking group (all p > 0.05). The Linear discriminant Analysis effect size (LEfSe) algorithm was used to determine the bacterial taxa associated with alcohol consumption, and the results showed altered fecal bacterial composition in HIV-infected patients who consumed alcohol; Coprobacillus, Pseudobutyrivibrio, and Peptostreptococcaceae were enriched, and Pasteurellaceae and Xanthomonadaceae were depleted. In addition, by using the Kyoto Encyclopedia of Genes and Genomes (KEGG), functional microbiome features were also found to be altered in the low-to-moderate drinking group compared to the control group, showing a reduction in metabolic pathways (p = 0.036) and cardiovascular disease pathways (p = 0.006). Conclusion Low-to-moderate drinking will change the composition, metabolism, and cardiovascular disease pathways of the gut microbiota of HIV-infected patients.
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Background Gut microbiome is a community of microorganisms that lives in the human intestine and exerts various functions on the host, including metabolic, immunoregulatory, and control over cell proliferation. Gut microbiome alterations have been associated with various pathological conditions, such as diabetes mellitus, obesity, and cardiovascular diseases. Gut‐prostate axis is explained by the association between gut microbiome quantitative and functional alterations along with increased intestinal epithelial permeability with prostatediseases. However, the pathophysiological mechanisms and clinical importance of this association are not completely clarified yet. Methods We conducted a narrative review of the most relevant articles in the Medline (US National Library of Medicine, Bethesda, MD, USA), Scopus (Elsevier, Amsterdam, The Netherlands) and Web of Science Core Collection (Thomson Reuters, Toronto, ON, Canada) databases. No chronological restrictions were applied, and the most related papers published until December 2023 were included. Results Gut microbiota (GM) and its metabolites are capable of modifying host androgen level, as well as prostate cancer (PCa) therapy response. Moreover, patients with inflammatory bowel disease have higher rates of prostatitis‐like symptoms and a potential risk of developing PCa. Conclusions There is evidence that interventions on the GM and its metabolites have a high potential to serve as diagnostic and therapeutic tools for prostate diseases, including PCa.
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Epidemiological studies have shown associations between whole-grain intake and lowered disease risk. A sufficient level of whole-grain intake to reach the health benefits has not been established, and there is limited knowledge about the impact of whole-grain intake on metabolite levels. In this clinical intervention study, we aimed to identify plasma and urine metabolites associated with two different intake levels of whole-grain wheat and rye and to correlate them with clinical plasma biomarkers. Healthy volunteers ( N = 68) were divided into two groups receiving either whole-grain wheat or whole-grain rye in two four-week interventions with 48 and 96 g/d of whole grains consumed. The metabolomics of the plasma samples was performed with UPLC–QTOF-MS. Plasma alkylresorcinols were quantified with GC-MS and plasma and urinary mammalian lignans with HPLC-ECD. The high-dose intervention impacted the metabolite profile, including microbial metabolites, more in the rye-enriched diet compared with wheat. Among the increased metabolites were alkylresorcinol glucuronides, sinapyl alcohol, and pipecolic acid betaine, while the decreased metabolites included acylcarnitines and ether lipids. Plasma alkylresorcinols, urinary enterolactone, and total mammalian lignans reflected the study diets in a dose-dependent manner. Several key metabolites linked with whole-grain consumption and gut microbial metabolism increased in a linear manner between the two interventions. The results reveal that an increase in whole-grain intake, particularly rye, is strongly reflected in the metabolite profile, is correlated with clinical variables, and suggests that a diet rich in whole grains promotes the growth and/or metabolism of microbes producing potentially beneficial microbial metabolites.
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Necrotising enterocolitis (NEC) is a devastating condition that poses a significant risk of morbidity and mortality, particularly among preterm babies. Extensive research efforts have been directed at identifying optimal treatment and diagnostic strategies but results from such studies remain unclear and controversial. Among the most promising candidates are prebiotics, probiotics and their metabolites, including short chain fatty acids (SCFAs). Such metabolites have been widely explored as possible biomarkers of gut health for different clinical conditions, with overall positive effects on the host observed. This review aims to describe the role of gut microbiome derived SCFAs in necrotising enterocolitis. Until now, information has been conflicting, with the primary focus on the main three SCFAs (acetic acid, propionic acid, and butyric acid). While numerous studies have indicated the relationship between SCFAs and NEC, the current evidence is insufficient to draw definitive conclusions about the use of these metabolites as NEC biomarkers or their potential in treatment strategies. Ongoing research in this area will help enhance both our understanding of SCFAs as valuable indicators of NEC and their practical application in clinical settings.
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Male pigs were fed a low fiber beef diet (control) or that diet with additionalfiber either as wheat bran, oat bran or baked beans. Total large bowel digesta and volatile fatty acid (VFA) pools were highest in pigs fed the diet with baked beans, intermediate in those fed the diets with oat bran and wheat bran and lowest in those fed the control diet. In all groups digesta mass and total VFA pools rose from the cecum and then fell to the distal colon, and incremental effects of diet were the same at all sampling sites. For acetate and propionate pools there was a significant interaction between diet and anatomical site, but data conversion to logarithms abolished this interaction, indicating that all dietary ef fects were proportionately the same across sections. Consumption of the diets with wheat bran, oat bran and baked beans increased the total large bowel butyrate pool compared with consumption of the control diet. Digesta H+ concentrations fell along the large bowel and correlated positively with VFA concentrations in the median colon. Portal venous VFA concentrations cor related with VFA in the proximal colon only. Plasma cholesterol and biliary steroids were unrelated to portal venous propionate concentrations. J. Nutr. 123: 133-143, 1993.
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Butyrate, a short chain fatty acid produced in the colon, induces apoptosis in cancer cell lines by a sequential process involving inhibition of histone deacetylase, de novo protein synthesis and activation of DEVD-caspase, a major effector of apoptotic DNA fragmentation and membrane blebbing, We now show in LIM 1215 colorectal cancer cells, that butyrate, in addition to activating DEVD-caspase and inducing apoptosis, also increases expression and cleavage of the universal cyclin-dependent kinase inhibitor p21(Waf1/Cip1) and leads to hypo-phosphorylation of retinoblastoma protein. Accompanying these molecular changes was a progressive loss of G(0)/G(1) and S phase cells. Expression of p21 had similar kinetics to that of the essential protein required for DEVD-caspase activation, indicating parallel effects of butyrate on anti-apoptotic and pro-apoptotic mechanisms. LIM 1215 cells, which were resistant to butyrate-induced apoptosis, were selected by three cycles of exposure to butyrate and removal of floating apoptotic cells. These cells showed markedly enhanced p21 expression and were in cell cycle arrest as determined by flow cytometry. On the other hand, subsequent culture of these cells for 2-3 days in the absence of butyrate resulted in downregulation of p21 and restoration of sensitivity to apoptosis by butyrate, Western blots of butyrate-treated cells undergoing apoptosis consistently demonstrated a 15 kDa band (p15) that was not present in control cultures. This band became apparent immediately after the onset of DEVD-caspase activation, was enriched in the floating apoptotic cell population when compared with the adherent, non-apoptotic cells and was absent in butyrate-resistant cells lacking DEVD-caspase activity. Peptide caspase inhibitors partially blocked appearance of p15, Here we show, for the first time, that p21 is a target of effector caspases in colorectal cancer cells and that the resistance to butyrate-induced apoptosis is characterized by failure of p21 cleavage.
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The uptake of propionate by the isolated perfused rat liver is not influenced by oleate or glucagon. However, glucagon does stimulate glucose production in the presence of 10 mm propionate and increases the incorporation of isotope from [14C]propionate into glucose. These observations have been interpreted to indicate a sparing of the metabolism of propionate in the citric acid cycle by endogenous materials. As others have noted, propionate inhibits gluconeogenesis from lactate in the perfused liver. Studies of the influence of glucagon and oleate on glucose production from a mixture of propionate and lactate suggest that glucagon is acting at some point in common with the metabolism of propionate and lactate, whereas oleate selectively stimulates gluconeogenesis from lactate.
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Plasma cholesterol concentration is reduced by feeding some dietary fibers but the mechanism is not fully understood. We examined whether cecal fermentation products are involved in lowering plasma cholesterol by feeding rats a highly fermentable sugar-beet fiber (SBF) in four separate experiments. These were designed to investigate the effects on plasma cholesterol of oral ingestion of fermentation products on plasma cholesterol, the effects of the products in comparison with that of a short-chain fatty acid (SCFA) mixture, effects of individual SCFA and effects of alteration of energy and nitrogen ratio in the diet by the addition of the SCFA mixture. Cecal contents of rats were cultured with SBF by using a jar fermenter under anaerobic conditions, and the supernatant from the culture medium, containing fermentation products of SBF, was collected and freeze-dried before feeding to rats. Yield of fermentation products as dry weight from the fiber was 80-90%. In rats fed a diet containing fermentation products (80 g/kg diet), plasma cholesterol concentrations were lower than in rats of the fiber-free group 3, 7 and 14 d after feeding the test diet. Major SCFA in the fermentation products were sodium salts of acetic, propionic and butyric acids. Plasma cholesterol concentration in rats fed the diet containing a mixture of equal amounts of the three SCFA salts (66 g/kg diet) as the fermentation products diet was also lower than that in the fiber-free group and was not different from those in rats fed SBF (100 g/kg diet) and the fermentation products. In rats fed an acetate-containing diet but not in rats fed diets without acetate, plasma cholesterol was significantly lower than in the fiber-free group. In conclusion, absorption of SCFA from cecal fermentation products lowers plasma cholesterol. Acetate, and not propionate, may be responsible for lowering plasma cholesterol concentration.
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Short chain fatty acid absorption from the human rectum has been studied in 46 subjects attending an obesity clinic, using a dialysis bag technique. From a mixed electrolyte solution, acetate concentrations fell from 97.0 to 64.2 mmol/l, and sodium from 97.8 to 85.1 mmol/l with respective net absorption rates of 8.1 and 5.2 mumol/cm2/h. From a solution with mixed short chain fatty acids acetate concentration fell from 62.3 to 37.6 mmol/l, propionate from 20.2 to 11.5 mmol/l, and butyrate from 25.7 to 17.3 mmol/l with absorption rates of 5.2, 1.8, and 1.9 mumol/cm2/h. Lowering pH from 7.2 to 5.5, to test the possibility that absorption occurred by passive non-ionic diffusion, had no effect on absorption rates, although pH rose rapidly in the dialysis fluid. These results are comparable with rates of acetate absorption from the animal large intestine. The hypothesis that short chain fatty acids are not absorbed from the large gut and therefore contribute to faecal bulk by retaining water in the bowel lumen may need revision.
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Most nonsporing anaerobes of the intestinal tract use the Embden-Meyerhof-Parnas scheme to ferment carbohydrates. Almost all of them oxidize pyruvate, the key fermentation intermediate, to acetyl coenzyme A and CO2 with reduction of a low-potential electron acceptor. H2 is formed from the low potential acceptor or from NADH. Pyruvate is a precursor of lactate, and phosphoenolpyruvate is a precursor of succinate and propionate. Ethanol, acetate, and butyrate are formed from acetyl coenzyme A. Formate is produced by reduction of CO2 by Ruminococcus albus. Heme is required by human Bacteroides for the formation of succinate and, in the presence of vitamin B12, propionate. A fermentation equation derived from the concentration of volatile acids found in human feces suggests that the fermentation in the large intestine is similar to the rumen fermentation.
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There are elevated fatty acid levels in non-insulin-dependent diabetes mellitus that are due to diminished insulin action in inhibiting fatty acid release from adipocytes. Insulin therapy and other inhibitors of fatty acid release from adipocytes (e.g., nicotinic acid) suppress these elevated fatty acid levels and bring about a reduction in hyperglycemia. One mechanism by which fatty acids may be causal in hyperglycemia is in stimulating gluconeogenesis in the liver in the postabsorptive state. Another mechanism is in attenuating glucose disposal in skeletal muscle in the fed state. Potential nonglycemia-related effects of fatty acids are in substrate utilization in the heart and lipid synthesis in the liver. Inhibition of fatty acid oxidation is useful in reducing hyperglycemia by inhibiting glucose production in humans. However, there is less evidence that such inhibition can be useful in increasing glucose utilization in muscle, as predicted by the Randle hypothesis. This, coupled with potential adverse effects on heart muscle, make liver targeting of fatty acid oxidation inhibitors an important factor in their potential for development. Although such agents have advantageous effects on lipid metabolism, overdosing can lead to adverse liver lipid effects via the same mechanism. These adverse liver lipid effects could be minimized by development of reversible inhibitors that allow fatty acid oxidation to occur only during the overnight fast. The potential usefulness of such agents is evident; however, no drug that meets these objectives has been developed.
Article
Young male pigs were fed a diet formulated from human foods including either boiled white rice plus rice bran or heat-stabilized brown rice at equivalent levels of fiber for 3 wk. Stool and starch excretion were low in pigs fed white rice during the first 2 wk of the experiment. In pigs fed brown rice, their excretion was high during wk 1 but declined in wk 2 while short-chain fatty acid (SCFA) excretion was higher at both times. Large bowel digesta mass, measured during wk 3, was higher in pigs fed brown rice but only in the proximal colon. Large bowel and fecal starch concentrations were higher in pigs fed brown rice but the difference was insufficient to explain the increase in large bowel digesta mass. In pigs with a cecal cannula, digesta starch concentrations were equally higher when white or brown rice was fed compared with the corresponding rice which had been finely milled, indicating that particle size was a determinant of ileal digestibility. Concentrations and pools of total and individual SCFA were higher in all regions of the colon but not the cecum of pigs fed brown rice. Large bowel Ca²⁺ concentrations were lower in pigs fed brown rice, suggesting greater absorption. The data confirm earlier findings that brown rice raises large bowel digesta mass and SCFA through greater fermentation of starch but show that starch itself makes a relatively small contribution to digesta and stool mass. Apparently, the rate of passage of digesta is a determinant of the concentrations and pools of SCFA in the distal colon and in feces.
Chapter
Short-chain fatty acids (SCFAs) are produced when undigested dietary constituents are fermented by anaerobic bacteria in the intestine (Bancroft et al., 1944). Dietary fiber has been suggested to be the main substrate for the production of SCFAs. The SCFAs are readily absorbed and play significant physiological roles in the host. For example, butyrate is proposed to be a preferable fuel to glucose, glutamate, or ketone bodies for colonocytes (Roediger, 1982), whereas acetate and propionate are mainly converted to fatty acids and glucose, respectively, in the liver (Demigne et al., 1986). In addition, SCFAs are involved in the maintenance of secretory and absorptive functions in the large intestine by affecting movement of water and electrolytes (Argenzio et al., 1975). Therefore, investigation of the production of SCFAs through the fermentation of dietary fiber and evaluation of the mechanisms involved in the absorption are of interest. In this chapter we focus on absorption of SCFAs with a brief overview of production.
Chapter
The principal sources of carbon and energy for bacteria growing in the human large intestine are resistant starches, plant cell wall polysaccharides, and host mucopolysaccharides, together with various proteins, peptides, and other lower-molecular-weight carbohydrates that escape digestion and absorption in the small bowel (Cummings and Macfarlane 1991, Macfarlane and Cummings 1991). These complex polymers are degraded by a wide range of bacterial polysaccharidases, glycosidases, proteases, and peptidases to smaller oligomers and their component sugars and amino acids. Intestinal bacteria are then able to ferment these substances to short chain fatty acids (SCFAs), hydroxy and dicarboxylic organic acids, H2, CO2, and other neutral, acidic, and basic end products. Carbohydrate metabolism is quantitatively more important than amino acid fermentation in the human large intestine, particularly in the proximal colon, where substrate availability is greatest. The hydrolysis and metabolism of carbohydrates in the large intestine are influenced by a variety of physical, chemical, biological, and environmental factors, some of which are shown in Table 9.1.
Article
BACKGROUND Sodium butyrate, a product of colonic bacterial fermentation, is able to inhibit cell proliferation and to stimulate cell differentiation of colonic epithelial cell lines. It has been proposed that these cellular effects could be linked to its ability to cause hyperacetylation of histone through the inhibition of histone deacetylase. AIM To analyse the molecular mechanisms of butyrate action on cell proliferation/differentiation and to compare them with those of trichostatin A, a well known inhibitor of histone deacetylase. METHODS HT-29 cells were grown in the absence or presence of butyrate or trichostatin A. Cell proliferation and cell cycle distribution were studied after DNA staining by crystal violet and propidium iodide respectively. Cell cycle regulatory proteins were studied by western blot and reverse transcription-polymerase chain reaction. Cell differentiation was followed by measuring brush border enzyme activities. Histone acetylation was studied by acid/urea/Triton acrylamide gel electrophoresis. RESULTS Butyrate blocked cells mainly in the G1 phase of the cell cycle, whereas trichostatin A was inhibitory in both G1 and G2 phases. Butyrate inhibited the mRNA expression of cyclin D1 without affecting its protein expression and stimulated the protein expression of cyclin D3 without affecting its mRNA expression. Trichostatin A showed similar effects on cyclin D1 and D3. Butyrate and trichostatin A stimulated p21 expression both at the mRNA and protein levels, whereas their effects on the expression of cyclin dependent kinases were slightly different. Moreover, butyrate strongly stimulated the activity of alkaline phosphatase and dipeptidyl peptidase IV, whereas trichostatin A had no effect. Finally, a six hour exposure to butyrate or trichostatin A induced histone H4 hyperacetylation. At 15 and 24 hours, histone H4 remained hyperacetylated in the presence of butyrate, whereas it returned to control levels in the presence of trichostatin A. CONCLUSIONS The data may explain how butyrate acts on cell proliferation/differentiation, and they show that trichostatin A does not reproduce every effect of butyrate, mainly because of its shorter half life.
Article
Psyllium hydrophilic mucilloid was examined for its ability to lower serum cholesterol levels in hypercholesterolemic patients. Seventy-five patients with mild to moderate hypercholesterolemia were evaluated in this randomized, double-blind, placebo-controlled parallel study. Patients were treated with a Step I diet for 12 weeks before receiving placebo or 3.4 g of psyllium (equivalent to 1 teaspoon) three times per day for 8 weeks. Compared with placebo, psyllium achieved an additional 4.8% reduction in total cholesterol level, 8.2% reduction in low-density lipoprotein cholesterol level, and 8.8% reduction in apolipoprotein B level. Psyllium did not significantly affect blood pressure or levels of high-density cholesterol, triglycerides, serum glucose, or iron. Reported adherence to diet and treatment was excellent, and no significant adverse side effects were noted. These results indicate psyllium hydrophilic mucilloid is an effective and well-tolerated adjunct to diet in the management of mild to moderate hypercholesterolemia. (JAMA. 1989;261:3419-3423)
Article
• The effect of psyllium hydrophilic mucilloid on serum cholesterol levels was investigated in 26 men with mild to moderate hypercholesterolemia (range of cholesterol level, 4.86 to 8.12 mmol/L [188 to 314 mg/dL]) in a double-blind, placebo-controlled parallel study. Following a two-week baseline period, subjects were treated for eight weeks with 3.4 g of psyllium or cellulose placebo at mealtimes (three doses per day). All subjects maintained their usual diets, which provided less than 300 mg of cholesterol per day and approximately 20% of energy from protein, 40% from carbohydrate, and 40% from fat. Eight weeks of treatment with psyllium reduced serum total cholesterol levels by 14.8%, low-density lipoprotein (LDL) cholesterol by 20.2%, and the ratio of LDL cholesterol to high-density lipoprotein cholesterol by 14.8% relative to baseline values. The reductions in total cholesterol and LDL cholesterol became progressively larger with time, and this trend appeared to be continuing at the eighth week. Psyllium treatment did not affect body weight, blood pressure, or serum levels of high-density lipoprotein cholesterol, triglycerides, glucose, iron, or zinc. No significant changes in serum lipid levels, body weight, blood pressure, or other serum parameters were observed with placebo treatment. Subject adherence to psyllium treatment was excellent, and no adverse effects were observed. Results of this study show that psyllium is an effective and well-tolerated therapy for mild to moderate hypercholesterolemia. (Arch Intern Med 1988;148:292-296)
Article
Evidence for the occurrence of microbial breakdown of carbohydrate in the human colon has been sought by measuring short chain fatty acid (SCFA) concentrations in the contents of all regions of the large intestine and in portal, hepatic and peripheral venous blood obtained at autopsy of sudden death victims within four hours of death. Total SCFA concentration (mmol/kg) was low in the terminal ileum at 13 +/- 6 but high in all regions of the colon ranging from 131 +/- 9 in the caecum to 80 +/- 11 in the descending colon. The presence of branched chain fatty acids was also noted. A significant trend from high to low concentrations was found on passing distally from caecum to descending colon. pH also changed with region from 5.6 +/- 0.2 in the caecum to 6.6 +/- 0.1 in the descending colon. pH and SCFA concentrations were inversely related. Total SCFA (mumol/l) in blood was, portal 375 +/- 70, hepatic 148 +/- 42 and peripheral 79 +/- 22. In all samples acetate was the principal anion but molar ratios of the three principal SCFA changed on going from colonic contents to portal blood to hepatic vein indicating greater uptake of butyrate by the colonic epithelium and propionate by the liver. These data indicate that substantial carbohydrate, and possibly protein, fermentation is occurring in the human large intestine, principally in the caecum and ascending colon and that the large bowel may have a greater role to play in digestion than has previously been ascribed to it.
Article
Resistant starch decreases the concentration of secondary bile acids in the feces and the proliferation rate of colonic mucosal cells in healthy volunteers. This may reduce the risk of colon cancer. We investigated 23 patients with recently removed colonic adenoma(s) in a controlled parallel trial. They consumed 45 g of maltodextrin per day as placebo for four weeks and were randomly assigned to either 45 g of native amylomaize starch, containing 28 g of resistant starch type II or 45 g of maltodextrin for another four weeks. No effect on colorectal cell proliferation, fecal wet and dry weights, pH, and short-chain fatty acid excretion was seen. The bile acid concentration in fecal water decreased by 15% (P = 0.048) and the percentage secondary bile acids decreased by 14% (P = 0.002) on resistant starch relative to placebo. Whether this has a substantial role in colon cancer prevention in these patients remains to be established.
Article
Sixty-four crossbred pigs averaging 24 kg liveweight were used to study the effects of dietary propionic acid (PA) on plasma and tissue cholesterol concentrations of pigs fed hypercholesterolemic diets for 10 wk. Four diets, based on barley, wheat and soybean meal, consisting of a control diet and a diet containing 10% tallow, both fed with and without the addition of 5% PA were used in this study. Addition of PA to the control diet decreased feed intake (ADF) by 16%, decreased average daily gain (ADG) by 8% and improved feed conversion efficiency (FCE) by 8%. Addition of tallow to the control diet resulted in a 15% reduction in ADF, a 3% improvement in ADG and an 18% improvement in FCE. When both tallow and PA were present, ADF was depressed 26%, ADG decreased 5% and FCE improved 23%. The addition of tallow significantly increased the levels of total plasma cholesterol while the addition of PA significantly decreased the plasma cholesterol levels in comparison with the control diet and prevented the increase noted in the tallow group. Addition of PA to the control diet significantly increased the cholesterol content of backfat and significantly reduced the cholesterol content of the kidneys. Addition of PA to the tallow diet significantly reduced the cholesterol content of kidneys, but did not significantly affect the cholesterol content of backfat. It is suggested that the increased cholesterol content of backfat in pigs fed diets containing PA reflects a reduced transport of cholesterol from peripheral tissues to the liver for excretion in the bile.
Article
Propionate caused an inhibition of ketogenesis from butyrate by bovine liver slices. When succinate, fumarate and aspartate were included in the incubation mixtures as sources of oxaloacetate, they were not as inhibitory as propionate. The possibility of competition between propionate and butyrate for cofactors required for activation was discounted when neither ATP (17 mM), nor carnitine (3.5 mM), added to expand the coenzyme A (CoA) pool, relieved the antiketogenic effect of propionate. The 3-hydroxy-3-methylglutaryl-CoA pathway appeared to be the major route for formation of acetoacetate from acetoacetyl-CoA in liver extracts, on the basis of enzyme assays. At a concentration of 0.5 mM, propionyl-CoA caused an apparent decrease of 3-hydroxy-3-methylglutaryl-CoA synthase activity of 46%, whereas propionate and methylmalonyl-CoA were not effective. At a concentration of 15 mM, propionate resulted in 30% inhibition of synthase activity. Propionyl-CoA did not affect the activity of 3-hydroxy-3-methylglutaryl-CoA lyase. It was suggested that in bovine liver the antiketogenic effect of propionate is achieved, at least in part, through inhibition of formation of acetoacetate from acetoacetyl-CoA.
Article
Partially hydrolyzed guar gum (PHGG, average M. W. 20,000) digested by ß-D-mannanase was given as a beverage after every meal (36 g/3 times/day) to eight healthy men for 4 weeks. Diet with PHGG increased fecal weight and output frequency while lowering the pH of feces without an influence on fat, protein or mineral excretion. Among the fecal volatile fatty acids (VFA), only acetic acid significantly increased. Total serum cholesterol was reduced (p<0.05) by a diet with PHGG compared with the controlled diet period, while other serum lipid parameters were unaffected during the study. In conclusion, PHGG increased the bulking capacity without any influence on utilization of other nutrients.
Article
Two mechanisms have been proposed for the hypocholesterolaemic effects of dietary oat bran, i.e. acceleration of cholesterol catabolism or inhibition of cholesterol biosynthesis. The latter is proposed to occur via propionate formed through large bowel microbial fermentation of fibre. We have examined both of these mechanisms in rats fed dietary oat bran and have found that faecal bile acid and neutral sterol excretion was enhanced compared with animals fed cellulose. In contrast, concentrations of propionate in the hepatic portal vein, although raised by dietary oat bran, were less than 2% of those at which inhibition of hepatic cholesterogenesis has been observed in vitro. When hepatic cholesterol synthesis was measured with 3H2O, it was increased in oat branfed rats. Therefore, it appears most likely that the hypocholesterolaemic effects of this cereal fibre preparation can be explained by increased faecal steroid excretion and not through inhibition of cholesterogenesis by volatile fatty acids of large bowel origin.
Article
A diet high in fiber is associated with a decreased incidence and growth of colon cancers. Butyrate, a four-carbon short-chain fatty acid product of fiber fermentation within the colon, appears to mediate these salutary effects. We sought to determine the molecular mechanism by which butyrate mediates growth inhibition of colonic cancer cells and thereby to elucidate the molecular link between a high-fiber diet and the arrest of colon carcinogenesis. We show that concomitant with growth arrest, butyrate induces p21 mRNA expression in an immediate-early fashion, through transactivation of a promoter cis-element(s) located within 1.4 kb of the transcriptional start site, independent of p53 binding. Studies using the specific histone hyperacetylating agent, trichostatin A, and histone deacetylase 1 indicate that growth arrest and p21 induction occur through a mechanism involving histone hyperacetylation. We show the critical importance of p21 in butyrate-mediated growth arrest by first confirming that stable overexpression of the p21 gene is able to cause growth arrest in the human colon carcinoma cell line, HT-29. Furthermore, using p21-deleted HCT116 human colon carcinoma cells, we provide convincing evidence that p21 is required for growth arrest to occur in response to histone hyperacetylation, but not for serum starvation nor postconfluent growth. Thus, p21 appears to be a critical effector of butyrate-induced growth arrest in colonic cancer cells, and may be an important molecular link between a high-fiber diet and the prevention of colon carcinogenesis.
Article
The short chain fatty acids acetate, propionate and butyrate are produced when dietary fibre is fermented by the colonic bacteria. We have previously shown that sodium butyrate induces apoptosis in 3 colorectal tumour cell lines. We have extended our study to 3 adenoma and 4 carcinoma cell lines and investigated whether propionate and acetate also induce apoptosis. All 3 short chain fatty acids induced apoptosis at physiological concentrations, but of the 3, butyrate was the most effective. Since these fatty acids are produced as a result of bacterial fermentation of dietary fibre, this may in part explain the correlation between a high-fibre diet and low colorectal cancer incidence. Sodium butyrate induced apoptosis in all 7 of the cell lines studied; however, 2 of the 4 carcinoma cell lines (PC/JW/F1 and S/KS/F1) were more resistant to butyrate-induced apoptosis than the 3 adenoma cell lines, suggesting that at least some carcinomas may evolve mechanisms to protect the cells from the induction of apoptosis. The bile acid deoxycholic acid has previously been reported as a possible tumour promoter in the large intestine and its levels are reduced by dietary fibre. Concentrations of between 10 nM and 0.1 mM had no effect on either the proliferation or apoptosis of colonic tumour cells in vitro. However, a significant induction of apoptosis was obtained at a concentration of 0.5 mM. These results may have significance for the aetiology of colorectal cancer. © 1995 Wiley-Liss, Inc.
Article
Colonic contents were obtained from two human sudden-death victims within 3 h of death. One of the subjects (1) was methanogenic, the other (2) was a non-CH, producer. Measurements of bacterial fermentation products showed that in both individuals short-chain fatty acids, lactate and ethanol concentrations were highest in the caecum and ascending colon. In contrast, products of protein fermentation, such as ammonia, branched chain fatty acids and phenolic compounds, progressively increased from the right to the left colon, as did the pH of gut contents. In Subject 1, cell population densities of methanogenic bacteria (MB) increased distally through the gut and methanogenic activity was lower in the right (0.78–1–18 μmol CH4 produced/h/g dry wt contents) than in the left colon (1.34 μmol CH4 produced/h/g dry wt contents). Methane production rates did not correlate with MB numbers.Sulphate-reducing bacteria (SRB) were not found and dissimilatory sulphate reduction was not detected in any region of the colon. Methanogenic bacteria did not occur in subject 2, but high numbers of SRB were present throughout the gut (ca 109/g dry wt contents). Sulphate reduction rates were maximal in the ascending and transverse colons (0.24 and 0.22 μmol 35SO2–4 reduced/h/g dry wt contents, respectively). Short-chain fatty acid production by caecal contents was up to eight-fold higher than contents from the sigmoid/rectum. These findings demonstrate significant differences in fermentation reactions in different regions of the large gut.
Article
In the human large intestine bifidobacteria are a numerically important group of micro-organisms which are considered to exert a range of biological activities related to host health. One aspect is the inhibitory effect of these bacteria on other species, possibly excluding long term colonization by invasive pathogens. It has been suggested that the mechanism of inhibition carried out by bifidobacteria is related to the fermentative production of acids such as acetate and lactate. Experiments reported in this paper attemptedto address this theory. Co-culture experiments whereby Bifidobacterium infantis was incubated with Escherichia coli and Clostridium perfringens, in a varietyof fermentation systems, indicated that the bifidobacterium was able to exert an inhibitory effect not necessarily related to acid production. Further studies showed that eight species of bifidobacteria could variously excrete an anti-microbial substance with a broadspectrum of activity. Species belonging to the genera Salmonella, Listeria, Campylobacter and Shigella, as well as Vibrio cholerae, were all affected. These results show that bifidobacteria are able to exert more than one mechanism of inhibition, which may be of some importance with regard to protection against gastroenteritis.
Article
Colon cells from patients with ulcerative colitis utilize short-chain fatty acids inefficiently and may be exposed to decreased concentrations of these compounds. To test whether irrigation of the inflamed mucosa with short-chain fatty acids is useful, we conducted a six-week preliminary trial in 12 patients with distal colitis. Each patient used twice daily rectal irrigations with 100 ml of a solution containing acetate (80 mM), propionate (30 mM), and butyrate (40 mM). Two patients stopped at three weeks, one because of no improvement and the other because of complete resolution of symptoms. Of the 10 who completed the trial, nine were judged to be at least much improved and showed a change in a mean disease activity index score from 7.90.3 (se) to 1.80.6 (se) (P0.002) and in a mucosal histology score from 7.70.7 (se) to 2.60.7 (se) (P0.002). Thus, ulcerative colitis patients appear to benefit from increased contact with or higher than usual levels of these critical energy substrates.
Article
Resistant starch is by definition that part of starch that escapes digestion in the small bowel. Cecal fermentation of resistant starch into short-chain fatty acids will result subsequently in a decrease in pH. Thus, resistant starch may have the same effect on colonic luminal contents and mucosa as some fiber components. We studied the effects of adding 45 g native amylomaize (Hylon-VII) to a standardized diet in 14 healthy volunteers on fermentation and colonic mucosal proliferation. Hylon-VII is a high amylose maize starch, containing 62% resistant starch. During amylomaize consumption, breath hydrogen excretion rose 85% and fecal short chain fatty acid output increased 35% (PP=0.002). Subsequently, cytotoxicity of the aqueous phase of feces—as measured on a colon cancer cell line—decreased (P=0.007). Colonic mucosal proliferation in rectal biopsies (proliferating cell nuclear antigen immunostaining) decreased from 6.7 to 5.4% (P=0.05). We speculate that resistant starch consumption decreases colonic mucosal proliferation as a result of the decreased formation of cytotoxic secondary bile acids, which is possibly mediated through acidification of the large bowel by production of short-chain fatty acids.
Article
Diminished production of short-chain fatty acids (SCFA) by altered flora has been suggested in the pathogenesis of diversion colitis (DC). We evaluated prospectively the effectiveness of SCFA irrigation in 13 patients with excluded colon (eight males, five females; mean age, 48 years). The causes of diversion were inflammatory bowel disease (n=4), colonic cancer (n=2), sigmoid diverticulitis with perforation (n=3), ischiorectal abscess (n=2), and miscellaneous (n=2). Patients were given, twice a day for 14 days in a double-blind manner, a 60-ml enema containing either SCFA (acetate: 60 mmol/liter; proprionate: 30 mmol/liter; and N-butyrate: 40 mmol/ liter) (Group 1; n=7) or isotonic NaCl (Group 2; n=6). Endoscopy with biopsies was performed before starting the trial (D1) and 14 days later (D14). On D1 all patients had endoscopic and histologic findings suggestive of DC. No endoscopic or histologic changes were observed on D14 in either group. We conclude that endoscopic and histologic lesions of DC were not improved by SCFA irrigation during the 14 days.
Article
Inulin, a carbohydrate derived from plant sources, can be classified as a soluble fiber. Since inulin has a bland flavor and a fat-like texture, it can be incorporated into various food preparations to replace sugar and fat. Soluble fibers have been shown to modulate serum lipids, therefore, the present study examined the effect of consuming three servings per day of inulin-containing foods, compared to similar foods without inulin, on serum lipid profiles among hypercholesterolemic men and women. In addition, the practicality of including 18 g/day of inulin in a low-fat diet was investigated. The study was a randomized, double-blind, crossover trial with two six-week treatment periods, separated by a six-week washout. Twenty-one men and women with baseline low density lipoprotein cholesterol (LDL-C) 3.36–5.17 mmol/L completed the trial. Within each treatment sequence, total and LDL-C increased significantly (7.4% and 12.3%, respectively) during the control phase. There were small, non-significant declines in total- (1.3%) and LDL-C (2.1%) during the inulin phase. Thus, differences in response between periods (inulin minus control) were statistically significant (P < 0.05) for LDL-C (−14.4%) and total cholesterol (−8.7%), respectively. Mild gastrointestinal discomfort was more common during the inulin than control food phase, however, the gastrointestinal side effect profile of inulin was similar to that of other soluble fibers. Although it is not possible to draw firm conclusions from these data, inulin may have blunted the hypercholesterolemic effects observed during consumption of control foods. Additional research will be required to confirm the possible lipid-modulating properties of dietary inulin in humans.
Article
Short-chain fatty acids (SCFA) are derived from endogenous (metabolism of fat, carbohydrate, and amino acids) and exogenous (colonic fermentation) sources. To see how time of day and glucose tolerance status influenced serum SCFA concentrations, we determined serum SCFA throughout the day in 22 subjects with impaired glucose tolerance (IGT) and 10 young and eight middle-aged normal controls. On 1 day, insulin sensitivity was assessed as the steady-state plasma glucose (SSPG) level achieved during intravenous infusion of glucose insulin, and somatostatin. On another day, plasma glucose and insulin and serum SCFA levels were measured 12 times over 12 hours subjects eating a standard diet. SSPG in young onctrols (5.5 ± 1.1 mmol/L) was less than in middle-aged controls (9.3 ± 1.6 mmol/L), which in turn was less than in IGT subjects (13.7 ± 0.6 mmol/L; P < .01). Mean plasma glucose in IGT subjects was greater than in normal controls, and mean plasma insulin in IGT subjects was higher than in young controls but similar to the levels in middle-aged controls. Mean 12-hour serum acetate in young controls (143 ± 13 μmol/L) was greater than in middle-aged controls (104 ± 11 μmol/L) and IGT subjects (113 ± 5 μmol/L; P < .05). Mean 12-hour serum propionate in young controls (3.8 ± 0.5 μmol/L) was less than in IGT subjects (5.4 ± 0.3 μmol/L; P < .01), with middle-aged controls being intermediate (4.6 ± 0.3 μmol/L). Both young (1.6 ± 0.3 μmol/L) and middle-aged (1.0 ± 0.2) controls had lower mean butyrate than IGT subjects (3.1 ± 0.4 μmol/L; P < .05). Levels of all three SCFA varied significantly during the day, tending to decrease after breakfast and increase transiently after lunch and dinner. It is concluded that both time of day and glucose tolerance status affect serum SCFA levels in nondiabetic humans. The results suggest that serum acetate is derived primarily from colonic fermentation, serum butyrate primarily from endogenous fatty acid metabolism, and serum propionate from both exogenous and endogenous sources.
Article
Measurements of polysaccharide-degrading activity in different fractions of human faeces showed that bacterial polysaccharidases and glycosidases were primarily associated with the washed bacterial fractions. Amylase, pectinase and xylanase were the major polysaccharide-hydrolysing enzymes detected, whilst α-L-arabinofuranosidase, β-D-xylosidase, β-D-galactosidase and β-D-glucosidase were the most active glycosidases. Starch and 3 non-starch polysaccharides (NSP; pectin, xylan and arabinogalactan) were fermented by mixed populations of human faecal bacteria in batch culture. Detailed carbohydrate analysis demonstrated that starch and pectin were the most rapidly degraded substrates and that arabinogalactan and the relatively insoluble polysaccharide xylan were broken down more slowly. Free sugars and oligosaccharides did not accumulate in culture media with any polysaccharide tested. Time-course measurements of polysaccharide remaining in the batch culture fermentations showed that the arabinose side chains of pectin, xylan and arabinogalactan were co-utilised with the backbone sugars. In these cultures, polysaccharide-degrading activity was mainly cell-associated, but extracellular polysaccharidase activity increased as the fermentations progressed. Molar ratios of acetate, propionate and butyrate produced in these experiments were dependent upon the polysaccharide substrate tested. Molar ratios of acetate, propionate and butyrate in the starch, arabinogalactan, xylan and pectin fermentations were 50:22:29, 50:42:8, 82:15:3, and 84:14:2, respectively. The presence of starch did not inhibit the breakdown of arabinogalactan, xylan or pectin by faecal bacterial, providing evidence that multicomponent substrate utilisation occurs when complex populations of faecal bacteria are provided with mixed polysaccharide substrates.
Article
Increased interest in the metabolism and therapeutic potential of short-chain fatty acids (SCFA) prompted this study of the absorption rates of acetate, propionate, and butyrate in the human rectosigmoid, and in the human stomach. In human rectosigmoid, all SCFA were absorbed from neutral infusates, but propionate and butyrate absorption exceeded that of acetate. In human stomach, acetate was absorbed in the protonated form only, and butyrate was absorbed at a faster rate than acetate. These observations are compatible with both popular models of SCFA absorption: non-ionic diffusion, and carrier-mediated anionic exchange.
Article
Daily intake of 8.0 g per day of fructo-oligosaccharides for fourteen days significantly reduced mean fasting blood glucose levels by 15 mg/dl, mean serum total cholesterol levels by 19 mg/dl and LDL-cholesterol levels by 17 mg/dl in diabetic subjects (n=18), while the control diabetic subjects (n=10) who were given 5.0 g per day of sucrose showed no significant changes. The levels of serum HDL-cholesterol, triglycerides or free fatty acids were not significantly affected either by fructo-oligosaccharides or sucrose. These results indicate that the daily intake of fructo-oligosaccharides ameliorates the derangements of carbohydrate and lipid metabolism in diabetic subjects.
Article
An in vitro fecal incubation system was used to demonstrate how lactulose influences ammonia metabolism in the colon. Lactulose and other fermentable substrates (glucose, mannitol, and sorbitol), pH and organic acid were varied independently so that their different effects could be determined. Fermentable substrate caused a fall in ammonia concentration during the period of fermentation. Acidification to pH 5.0 or less, with hydrochloric acid or a lactic-acetic acid mixture, significantly reduced ammonia generation, but unlike fermentable substrates, did not lower the existing ammonia concentration. The lactic-acetic acid mixture did not reduce ammonia generation significantly below that found with acidification by hydrochloric acid. The effect of lactulose in reducing ammonia concentration is attributed to its role as a bacterial substrate in either increasing bacterial assimilation of ammonia or reducing deamination of nitrogenous compounds. The effect of low pH in reducing generation of ammonia appears to be part of a general reduction in bacterial metabolism.
Article
The relationship between diet, pH, and microbial digestion of carbohydrate was examined in 24 pigs fed either a conventional or a low-protein, high-cellulose experimental diet and sacrificed 2, 4, 8, or 12 h after a meal. In animals fed the control diet contents of the cranial half of the stomach demonstrated marked, cyclic fluctuations in pH and high concentrations of organic acids. Contents of the caudal (glandular) half were lower in both pH and organic acid concentration. Despite concentrations of volatile fatty acids (VFAs) as high as 250 meq/liter in the large intestine, the pH remained relatively neutral. The VFA levels remained relatively constant throughout the length of the colon. The VFA transport across isolated gastric and large intestinal mucosa also was examined. All four types of gastric mucosa absorbed and transported VFA at substantial rates. Mucosa of pig cecum and colon transported VFA at much greater rates than gastric mucosa and greater rates than previously determined in equine large intestinal mucosa or even bovine rumen epithelium. Comparison with results of earlier studies in the pony suggested that the higher concentration of VFA in the large intestinal contents of pigs was due to the more rapid rate of digesta passage rather than to less efficient absorption of fatty acids.
Article
The association of high meat protein intakes with a high incidence oflarge bowel cancer cannot be explained on the basis of current hypotheses for the cause of this cancer. A variety of protein metabohites including the volatile phenols, tryptophan, and ammonia have been implicated in the etiology of cancer. We have, therefore, investigated by using controlled diet studies in four subjects the effect of increasing meat protein intake on bacterial metabolism in the gut as indicated by urinary volatile phenol excretion and fecal ammonia and short-chain fatty acid concentration and tryptophan excretion. The possible protective role of dietary fiber from wheat has also been assessed in relation to these products. Increasing protein intake from 62.7 to 136 g/ day increased urinary volatile phenol excretion from 74 ± 14.5 to 108 ± 14.6 mg/day and fecal ammonia concentration from 14.8 ± 1.3 to 30.4 ± 1.1 mmole/liter but did not significantly alter fecal nitrogen excretion. Adding 29.8 g dietary fiber per day to the high protein diet did not alter fecal ammonia concentration despite a large increase in stool output. Urinary total volatile phenol excretionfell(81 ± 4.8 mg/day) and fecal nitrogen excretion almost doubled. The dietary changes did not alter fecal short-chain fatty acid concentrations. Increasing meat intake, therefore, increases the concentration in the feces and excretion in the urine of certain protein metabolites some of which may be carcinogenic. The role of dietary fiber in protecting against large bowel cancer cannot be related to any one single effect on colonic metabolism and may be due to a combination of dilution of colonic contents, shortened transit time, altered bacterial metabolism, or possibly other properties such as adsorption of potentially harmful materials. Am. J. Clin. Nutr. 32: 2094-2101, 1979.
Article
The hyperacetylation of histones due to treatment of cultured cells with sodium butyrate has been studied. The hyperacetylation is due to inhibition of histone deacetylase. Other short chain fatty acids including acetic, isobutyric and propionic acid also produce increased modification. Histone H4 already deposited on the chromosome can be rapidly acetylated to the extent of about 70%. That 80% of histone H4 is acetylated after a 24 hr exposure to butyrate is due to the fact that incoming H4 histone is 100% acetylated and does not return to the parental unmodified form in the presence of butyrate.
Article
This chapter discusses the regulation of HMG-CoA reductase, which catalyzes the rate-limiting reaction of hepatic sterol synthesis. Both mitochondrial and extramitochondrial forms of acetoacetyl-CoA thiolase and the HMG-CoA synthase are present in liver tissue. The reductase activity of cultured mammalian cells or of bacteria is readily assayed in crude homogenates. The HMG-CoA reductase activity may be readily assayed in the post-mitochondrial supernatant fraction obtained by high-speed centrifugation of homogenates of tissues, including liver. The chapter also discusses familial hypercholesterolemia (FH), which is an autosomal, dominant genetic disorder estimated to affect 0.1–0.2% of the population. FH may involve defects in the regulation of both cholesterol synthesis and degradation. The data for adults heterozygous for FH indicate that the rate of cholesterol synthesis in vivo is subnormal. The basic defect in FH may be a low affinity of the cellular plasma membrane for cholesterol. This defect, observed in fibroblasts and leukocytes, leads to an impaired uptake of cholesterol from serum lipoproteins and an enhanced release of cellular cholesterol. If this defect is present in the liver, it could account for the relatively ineffective feedback suppression of cholesterol synthesis.