Fecal Butyrate Concentrations Research Articles

Surgery for Crohn’s Disease Is Associated with a Dysbiotic Microbiome and Metabolome: Results from Two Prospective Cohorts

Background and AimsCrohn’s disease is associated with alterations in the gut microbiome and metabolome described as dysbiosis. We characterized the microbial and metabolic consequences of ileal resection, the most common Crohn’s disease surgery. MethodsPatients with and without intestinal resection were identified from the Diet to Induce Remission in Crohn’s Disease and Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease studies. Stool samples were analyzed with shotgun metagenomics sequencing. Fecal butyrate was measured with 1H nuclear magnetic resonance spectroscopy. Fecal bile acids and plasma 7α-hydroxy-4-cholesten-3-one (C4) was measured with mass spectrometry. ResultsIntestinal resection was associated with reduced alpha diversity and altered beta diversity with increased Proteobacteria and reduced Bacteroidetes and Firmicutes. Surgery was associated with higher representation of genes in the KEGG pathway for ABC transporters and reduction in genes related to bacterial metabolism. Surgery was associated with reduced concentration of the But gene but this did not translate to reduced fecal butyrate concentration. Surgery was associated with decreased abundance of bai operon genes, with increased plasma C4 concentration, increased primary bile acids and reduced secondary bile acids, including isoLCA. Additionally, E lenta, A equalofaciens and G pamelaeae were lower in abundance among patients with prior surgery in both cohorts. ConclusionsIn two different populations, prior surgery in Crohn’s disease is associated with altered fecal microbiome. Patients who had undergone ileal resection had reduction in the potentially beneficial bacteria E lenta and related actinobacteria as well as secondary bile acids, including isoLCA, suggesting that these could be biomarkers of patients at higher risk for disease progression.

Beneficial Effects of Dietary Fiber in Young Barley Leaf on Gut Microbiota and Immunity in Mice.

The health benefits of young barley leaves, rich in dietary fiber, have been studied for several decades; however, their beneficial effects on the intestinal microenvironment remain to be elucidated. To investigate the effects of young barley leaf-derived dietary fiber (YB) on the gut microbiota and immunity, mice were fed an AIN-93G diet containing cellulose or YB and subjected to subsequent analysis. The population of MHC-II-positive conventional dendritic cells (cDCs) and CD86 expression in the cDCs of Peyer's patches were elevated in the YB-fed mice. MHC-II and CD86 expression was also elevated in the bone marrow-derived DCs treated with YB. 16S-based metagenomic analysis revealed that the gut microbiota composition was markedly altered by YB feeding. Among the gut microbiota, Lachnospiraceae, mainly comprising butyrate-producing NK4A136 spp., were overrepresented in the YB-fed mice. In fact, fecal butyrate concentration was also augmented in the YB-fed mice, which coincided with increased retinaldehyde dehydrogenase (RALDH) activity in the CD103+ cDCs of the mesenteric lymph nodes. Consistent with elevated RALDH activity, the population of colonic IgA+ plasma cells was higher in the YB-fed mice than in the parental control mice. In conclusion, YB has beneficial effects on the gut microbiota and intestinal immune system.

Chronotropic and vasoactive properties of the gut bacterial short chain fatty acids in larval zebrafish.

Short-chain fatty acids (SCFAs) by the gut bacteria have been associated with cardiovascular dysfunction in humans and rodents. However, studies exploring effects of SCFAs on cardiovascular parameters in the zebrafish, an increasingly popular model in cardiovascular research, remain limited. Here, we performed fecal bacterial 16S sequencing and gas chromatography/mass spectrometry (GC-MS) to determine the composition and abundances of gut microbiota and SCFAs in adult zebrafish. Following this, the acute effects of major SCFAs on heart rate and vascular tone were measured in anaesthetized zebrafish larvae using fecal concentrations of butyrate, acetate, and propionate. Lastly, we investigated if co-incubation with butyrate may lessen the effects of angiotensin II (Ang II) and phenylephrine (PE) on vascular tone in anaesthetized zebrafish larvae. We found that the abundance in Proteobacteria, Firmicutes, and Fusobacteria phyla in the adult zebrafish resembled those reported in rodents and humans. SCFA levels with highest concentration of acetate (27.43µM), followed by butyrate (2.19µM) and propionate (1.65µM) were observed in the fecal samples of adult zebrafish. Immersion in butyrate and acetate produced a ~20% decrease in heart rate (HR), respectively, with no observed effects of propionate. Butyrate alone also produced a ~25% decrease in the cross-sectional width of the dorsal aorta (DA) at 60 min (*P<0.05), suggesting compensatory vasoconstriction, with no effects of either acetate or propionate. In addition, butyrate significantly alleviated the decrease in DA cross-sectional width produced by both Ang II and PE. We demonstrate the potential for zebrafish in investigation of host-microbiota interactions in cardiovascular health.

P876 Efficacy and safety of microencapsulated butyrate add-on therapy in induction of remission in patients with mild-to-moderate Ulcerative Colitis - results from multi-center, double-blind, randomized, placebo-controlled clinical study

Abstract Background Butyrate is the most beneficial among short-chain fatty acids (SCFA’s) that plays a key role in intestinal homeostasis by modifying: gut microbiome, gut barrier integrity, and reducing inflammation. There are some evidence of its usefulness in the treatment of Ulcerative Colitis (UC), however the data are not clear. The aim of our study was to assess the efficacy and safety of oral microencapsulated sodium butyrate (MSB) as add-on treatment in induction of remission in active UC. Methods 100 patients with mild to moderate UC were enrolled in the study and randomized to MSB group treated with 2x300 mg/d of butyrate or placebo group (C); 96 of those patients completed all study protocol. Total Mayo Score (TMS), endoscopic images and fecal calprotectin were investigated to estimate the effect of MSB administration in induction remission, as well as relation between fecal butyrate concentrations (C4) and effectiveness of treatment. Results Clinical and endoscopic improvement (p &amp;lt; 0.001 and p = 0.042) and clinical remission (p &amp;lt; 0.001) was observed in MSB group. Accordingly, an improvement in the endoscopic image(defined as Mayo Score (MS) difference ≥ 1) at 8 weeks of follow up was achieved in 26patients (55.3%) in the study group and 16 (32.7%) in placebo group (p=0.042). Clinical improvement (defined as TMS difference ≥ 3) was observed in 39 (83%) study group patients and 15 (30.6%) in placebo group (p &amp;lt; 0.001). Clinical remission (TMS at visit 2 ≤ 2) was obtained in 30 (63.84%) MSB group patients and 11 (22.4%) in control group (p &amp;lt; 0.001). Significant improvement was also expressed as reduction of calprotectin level. In MSB group significant increase of C4 was observed in the group with clinical improvement, clinical remission and endoscopic improvement, and it was significantly higher than among non-responders. (MD =1.35 CI 95 [0.51;3.56], p &amp;lt; 0.001), clinical remission (MD = 1.69 CI 95 [0.44;3.45], p = 0.001) and endoscopic improvement (MD = 1.99 CI 95 [0.84;2.82], (p &amp;lt; 0.001)). In C group the level of C4 was significantly lower, regardless of clinical response. No side effects was observed during treatment. Conclusion MSB supplementation increases the fecal butyrate concentration and results in clinical remission and endoscopic improvement in mild to moderate UC. Our study clearly showed that MSB appears to be a beneficial and safe add-on treatment of those patients.

Alteration in the gut microbiome is associated with changes in bone metabolism after laparoscopic sleeve gastrectomy.

Laparoscopic sleeve gastrectomy (LSG), the most common bariatric surgical procedure, leads to durable weight loss and improves obesity-related comorbidities. However, it induces abnormalities in bone metabolism. One unexplored potential contributor is the gut microbiome, which influences bone metabolism and is altered after surgery. We characterized the relationship between the gut microbiome and skeletal health in severe obesity and after LSG. In a prospective cohort study, 23 adults with severe obesity underwent skeletal health assessment and stool collection preoperatively and 6mo after LSG. Gut microbial diversity and composition were characterized using 16S rRNA gene sequencing, and fecal concentrations of short-chain fatty acids (SCFA) were measured with LC-MS/MS. Spearman's correlations and PERMANOVA analyses were applied to assess relationships between the gut microbiome and bone health measures including serum bone turnover markers (C-terminal telopeptide of type 1 collagen [CTx] and procollagen type 1N-terminal propeptide [P1NP]), areal BMD, intestinal calcium absorption, and calciotropic hormones. Six months after LSG, CTx and P1NP increased (by median 188% and 61%, P< .01) and femoral neck BMD decreased (mean -3.3%, P< .01). Concurrently, there was a decrease in relative abundance of the phylum Firmicutes. Although there were no change in overall microbial diversity or fecal SCFA concentrations after LSG, those with greater within-subject change in gut community microbial composition (β-diversity) postoperatively had greater increases in P1NP level (ρ= 0.48, P= .02) and greater bone loss at the femoral neck (ρ= -0.43, P= .04). In addition, within-participant shifts in microbial richness/evenness (α-diversity) were associated with changes in IGF-1 levels (ρ= 0.56, P< .01). The lower the postoperative fecal butyrate concentration, the lower the IGF-1 level (ρ= 0.43, P= .04). Meanwhile, the larger the decrease in butyrate concentration, the higher the postoperative CTx (ρ= -0.43, P= .04). These findings suggest that LSG-induced gut microbiome alteration may influence skeletal outcomes postoperatively, and microbial influences on butyrate formation and IGF-1 are possible mechanisms.

The effects of hydrolyzed protein on macronutrient digestibility, fecal metabolites and microbiota, oxidative stress and inflammatory biomarkers, and skin and coat quality in adult dogs.

Research on protein hydrolysates has observed various properties and functionalities on ingredients depending on the type of hydrolysate. The objective of this study was to evaluate the effects of hydrolyzed chicken protein that was incorporated into diets on digestibility, gut health, skin and coat health, oxidative stress, and intestinal inflammation markers in healthy adult dogs. Five complete and balanced diets were manufactured: (1) CONd: 25% chicken meal diet; (2) 5% CLHd: 5% chicken liver and heart hydrolysate plus 20% chicken meal diet; (3) CLHd: 25% chicken liver and heart hydrolysate diet; (4) 5% CHd: 5% chicken hydrolysate plus 20% chicken meal diet; (5) CHd: 25% chicken hydrolysate diet. A replicated 5 × 5 Latin square design was used which included 10 neutered adult Beagles. Each of the 5 periods consisted of a 7-d washout time and a 28-d treatment period. All diets were well accepted by the dogs. Fecal butyrate concentration was higher while fecal isovalerate and total phenol/indole were lower in dogs fed CLHd than CONd (P < 0.05). Dogs fed CHd had higher fecal immunoglobulin A concentration when compared with CLHd (P < 0.05); however, both groups were comparable to the CONd. There was no difference among groups in serum cytokine concentrations, serum oxidative stress biomarkers, or skin and coat health analyses (P > 0.05). Fecal microbiota was shifted by CLHd with higher abundance in Ruminococcus gauvreauii group as well as lower Clostridium sensu stricto 1, Sutterella, Fusobacterium, and Bacteroides when compared with CONd (P < 0.05). There was also a difference in beta diversity of fecal microbiota between CLHd and CHd (P < 0.05). In conclusion, chicken protein hydrolysate could be incorporated into canine extruded diets as a comparable source of protein to traditional chicken meal. The test chicken protein hydrolysates showed the potential to support gut health by modulating immune response and microbiota; however, functional properties of protein hydrolysates are dependent on inclusion level and source.

Dietary crude protein time-dependently modulates the bacterial community and metabolites and changes dietary nutrient efficiency in growing pigs

The reduced nutrient digestibility of low-protein (LP) diets has been shown to be caused by the weakened fermentative capacity of the post-gut flora. The dynamic regulation of dietary protein contents on post-gut microbial population and fermentative metabolism is unclear. Twelve growing barrows (19.9 ± 0.8 kg) fitted with a T-cannula at the blind end of the cecum were randomly administered a high-protein (HP, 21.5% crude protein [CP]) diet or an LP (15.5% CP) diet for 28 d. The cecal content and feces were collected at d 1, 14, and 28 of the experiment for microflora structures and metabolite concentrations analysis. The nutrient digestibility coefficient and plasma biochemical parameters were also determined. Compared with the HP treatment, the LP treatment showed decreased plasma urea nitrogen concentration and apparent total tract digestibility of dry matter, gross energy, and CP (P < 0.01). In addition, urinary nitrogen losses, total nitrogen losses, and daily nitrogen retention in the LP treatment were lower than those in the HP treatment (P < 0.01), and the nitrogen retention-to-nitrogen intake ratio in the LP treatment was increased (P < 0.01). The HP group showed increased cecal total short-chain fatty acids (SCFA) concentration and fecal propionate, butyrate, and total SCFA concentrations (P < 0.05) on d 14 and 28, which may be mainly related to the elevated abundance of SCFA-producing bacteria, such as Ruminococcus, Lactobacillus, and Prevotella (P < 0.05). Probiotics, such as Bifidobacterium, Bacteroidales S24-7, and Rikenella, enriched in the LP treatment possibly contributed to reduced plasma endotoxin content. The differences in the abundances of almost all the above-mentioned flora appeared on d 28 but not d 14. Likewise, differences in the Simpson and Shannon indices and clustering patterns of the microbiota between treatments were also only observed on d 28. To sum up, in a time-dependent manner, the LP diet increased probiotics with gut-improving functions and decreased SCFA-producing bacteria, which may cause enhanced intestine health and reduced nutrient digestibility.

196 The Effect of Hydrolyzed Protein on Fecal Microbiota in Adult Dogs

Abstract Research on protein hydrolysates has observed various properties and functionalities of these ingredients depending on the type of hydrolysate. The objective of this study was to evaluate the effect of hydrolyzed chicken protein that was incorporated into diets on gut health in healthy adult dogs. Five complete and balanced treatment diets were manufactured: 1) CONd: chicken meal diet; 2) 5% CLHd: 5% substitution of chicken liver hydrolysate of chicken meal diet; 3) CLHd: chicken liver hydrolysate diet; 4) 5% CHd: 5% substitution of chicken hydrolysate of chicken meal diet; and 5) CHd: chicken hydrolysate diet. A 5×5 Latin square design was used which included 10 neutered adult beagles. Each of the 5 periods consisted of a 7-d washout time and a 28-d treatment period. All diets were well accepted by the dogs. For fecal metabolites, there was greater fecal butyrate concentration as well as reduced isovalerate, 4-ethylphenol, and indole in dogs fed CLHd than CONd (P &amp;lt; 0.05). Regarding the overall microbiota composition, Firmicutes, Bacteriodota, Fusobacteriota, Actinobacteriota, and Proteobacteria were the top 5 most abundant phyla. At the class level, samples from CHd group had greater relative abundances of Bacteriodia and Fusobacteriia as well as less Bacilli. On the other hand, CLHd group had greater abundances of Bacilli and Actinobacteria with less Fusobacteriia. At the level of order, CHd group had greater Bacteriodales and Fusobacteriales while CLHd group had greater Bifidobacteriales. At the family level, CHd group showed a greater abundance of Muribaculaceae and a decreased abundance of Bifidobacteriaceae when compared with the other groups. Alternatively, CLHd group demonstrated a greater abundance of Bifidobacteriaceae together with reduced abundance of Fusobacteriaceae, Muribaculaceae, Sutterrellaceae, and Ruminococcaceae. Fecal microbiota was shifted by CLHd with greater differential abundance in Ruminococcus gauvreauii group as well as reduced Clostridium sensu stricto 1, Sutterella, Fusobacterium, and Bacteroides compared with CONd (P &amp;lt; 0.05). There was also a difference in beta diversity of fecal microbiota between CLHd and CHd (P &amp;lt; 0.05). However, no difference was observed in alpha diversity among treatment groups (P &amp;lt; 0.05). Fecal butyrate concentration was negatively correlated with the genera Blautia, Phascolarctobacterium, Sutterella, Faecalibacterium, and Bacteriodes. Conversely, Allobaculum and Bifidobacterium were positively correlated with butyrate concentration. In conclusion, the test chicken protein hydrolysates may have potential to support gut health by modulating microbiota.

PSVIII-13 Evaluating the Effects of a Dried brewer’s Yeast Product on the Fecal Characteristics, Metabolites, and Microbiota Populations of Adult Dogs

Abstract Inclusion of brewer’s yeast in pet foods has become popular because of the potential health benefits it provides. However, more research is needed to evaluate the effects of different brewer’s yeast products on canine gut health outcomes. This study aimed to investigate the effects of a brewer’s yeast product on the fecal characteristics, metabolites, and microbiota populations of adult dogs. Sixteen healthy adult dogs (BW: 9.0 ± 1.7 kg) were acclimated for 7 days and then randomly assigned to a control diet containing no yeast or a brewer’s yeast-containing diet (n = 8/group) for a 21-day period. Fresh fecal samples were collected before and after treatment for measurement of fecal scores, pH, dry matter content, metabolite concentrations [short-chain fatty acids (SCFA), branched-chain fatty acids (BCFA), ammonia, phenols, indoles], and microbiota populations. All data were analyzed as a percent change from baseline using the PROC MIXED procedure of SAS, with treatment as the main effect and dog as a random effect. Significance was declared at P ≤ 0.05, and trends reported if 0.05 &amp;lt; P ≤ 0.10. The brewer’s yeast treatment tended to increase (P = 0.10) fecal butyrate concentrations more than that of controls, but fecal characteristics (pH; dry matter; fecal scores) and other metabolite concentrations were not affected by treatment. Fecal bacterial alpha diversity metrics were not affected by treatment, but beta diversity analysis (unweighted UniFrac distances) tended (P = 0.09) to show a shift between treatments. Change in relative abundance of fecal Blautia was less (P = 0.05) in dogs fed brewer’s yeast than controls, but other bacterial genera were unaffected by diet. In conclusion, this study suggests that the dried brewer's yeast products tested had little impact on fecal characteristics, metabolites, or microbiota populations of adult dogs. The tendency of greater fecal butyrate concentrations in dogs fed brewer’s yeast is encouraging, but further research is needed to identify the potential health benefits of these products in canine diets.

PSIX-6 The Effects of Hydrolyzed Protein on Macronutrient Digestibility, Fecal Metabolites, Oxidative Stress and Inflammatory Biomarkers, and Skin and Coat Quality in Adult Dogs

Abstract Research on protein hydrolysates has observed various properties and functionalities of these ingredients depending on the type of hydrolysate. The objective of this study was to evaluate the effects of hydrolyzed chicken protein that was incorporated into diets on digestibility, gut health, skin and coat health, oxidative stress, and inflammation in healthy adult dogs. Five complete and balanced treatment diets were manufactured: 1) CONd: chicken meal diet; 2) 5% CLHd: 5% substitution of chicken liver hydrolysate of chicken meal diet; 3) CLHd: chicken liver hydrolysate diet; 4) 5% CHd: 5% substitution of chicken hydrolysate of chicken meal diet; and 5) CHd: chicken hydrolysate diet. A 5×5 Latin square design was used which included 10 neutered adult beagles. Each of the 5 periods consisted of a 7-d washout time and a 28-d treatment period. All diets were well accepted by the dogs. There was greater (P &amp;lt; 0.05) fecal butyrate (226.8 μmol/g DMB) concentration as well as decreasedr isovalerate (6.8 μmol/g DMB), 4-ethylphenol (1.4 μmol/g DMB), and indole (0.7 μmol/g DMB) in dogs fed CLHd than CONd (149.3, 10.8, 2.5, and 1.5 μmol/g DMB, respectively). Doges fed CHd had greater (P &amp;lt; 0.05) fecal immunoglobulin A concentration (2.86 mg/g) when compared with CLHd (0.91 mg/g); however, both groups were comparable to the control. There was no difference among groups in serum cytokine concentrations, serum oxidative stress biomarkers, or skin and coat health analyses (P &amp;gt; 0.05). In conclusion, chicken protein hydrolysate could be incorporated into canine extruded diets as a comparable source of protein to traditional chicken meal. The test chicken protein hydrolysates may have potential to support gut health by modulating immune response and fermentative activity; however, more research is needed to confirm the effect.

JK5G postbiotics attenuate immune-related adverse events in NSCLC patients by regulating gut microbiota: a randomized controlled trial in China.

This study aimed to evaluate the effects of JK5G postbiotics to regulate imbalanced gut microbiota and its impacts on the efficacy and incidence rate of immune-related adverse events (irAEs) in non-small-cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). This randomized, double-blind, placebo-controlled trial was conducted in China and included non-squamous or squamous NSCLC patients without EGFR, ROS1, and ALK alteration, treatment-naive, and stage IIIb-IV. Patients were randomly (1:1) divided into two groups to receive four cycles (three weeks for each cycle) of programmed cell death-1 (PD-1) plus chemotherapy plus placebo (control group, n = 30) or to receive PD-1 plus chemotherapy plus JK5G postbiotics (JK5G group, n = 30). The primary endpoint was objective response rate. The secondary endpoints were quality of life (QoL), adverse effects, and the 16S DNA sequencing of gut microbiota, blood inflammatory cytokines, and lymphocyte subsets. This study was registered at www.chictr.org.cn (ChiCTR2200064690). Sixty patients were enrolled. The objective response rate was 36.67% (11/30) in the control group and 50.00% (15/30) in the JK5G group (p = 0.297). The JK5G group had better QoL and nutritional levels, as well as lower depression symptoms than the control group (all p < 0.05). Moreover, the JK5G group had a lower incidence of anemia (63.33% vs. 13.33%, p < 0.001), decreased lymphocyte count (20.00% vs. 0%, p = 0.010), decreased appetite (53.33% vs. 16.67%, p = 0.003), nausea (33.33% vs. 6.67%, p = 0.010), and asthenia (30.00% vs. 6.67%, p = 0.017) than the control group. Moreover, JK5G attenuated gut microbiota imbalance, accompanied by increased Faecalibacterium, Ruminococcaceae, and fecal butyrate concentration, and diminished Escherichia-Shigella. Furthermore, JK5G administration significantly decreased the levels of pro-inflammatory markers, including TNF-α, IL-2, and C-reactive protein (CRP) (all p < 0.05). Significant increases in CD3+CD4+ T cells and CD4/CD8 ratio were observed in the peripheral blood of JK5G group patients (all p < 0.05). The enterotype data showed that patients were clustered into Blautia (E1) and Escherichia-Shigella (E2) enterotypes, and JK5G postbiotics intervention might be related to enterotype modulations. Our current findings indicated that JK5G postbiotics might attenuate irAEs, and enhance the QoL and nutrition levels of advanced NSCLC patients who received ICIs. JK5G postbiotics could also improve the gut microbiota structures and ameliorate the tumor microenvironment andinflammation. www.chictr.org.cn, identifier ChiCTR2200064690.

Effects of a wholegrain-rich diet on markers of colonic fermentation and bowel function and their associations with the gut microbiome: a randomised controlled cross-over trial.

Diets rich in whole grains are associated with health benefits. Yet, it remains unclear whether the benefits are mediated by changes in gut function and fermentation. We explored the effects of whole-grain vs. refined-grain diets on markers of colonic fermentation and bowel function, as well as their associations with the gut microbiome. Fifty overweight individuals with increased metabolic risk and a high habitual intake of whole grains (~69 g/day) completed a randomised cross-over trial with two 8-week dietary intervention periods comprising a whole-grain diet (≥75 g/day) and a refined-grain diet (<10 g/day), separated by a washout period of ≥6 weeks. A range of markers of colonic fermentation and bowel function were assessed before and after each intervention. The whole-grain diet increased the levels of faecal butyrate (p = 0.015) and caproate (p = 0.013) compared to the refined-grain diet. No changes in other faecal SCFA, BCFA or urinary levels of microbial-derived proteolytic markers between the two interventions were observed. Similarly, faecal pH remained unchanged. Faecal pH did however increase (p = 0.030) after the refined-grain diet compared to the baseline. Stool frequency was lower at the end of the refined-grain period compared to the end of the whole-grain diet (p = 0.001). No difference in faecal water content was observed between the intervention periods, however, faecal water content increased following the whole-grain period compared to the baseline (p = 0.007). Dry stool energy density was unaffected by the dietary interventions. Nevertheless, it explained 4.7% of the gut microbiome variation at the end of the refined-grain diet, while faecal pH and colonic transit time explained 4.3 and 5%, respectively. Several butyrate-producers (e.g., Faecalibacterium, Roseburia, Butyriciococcus) were inversely associated with colonic transit time and/or faecal pH, while the mucin-degraders Akkermansia and Ruminococcaceae showed the opposite association. Compared with the refined-grain diet, the whole-grain diet increased faecal butyrate and caproate concentrations as well as stool frequency, emphasising that differences between whole and refined grains affect both colonic fermentation and bowel habits.

Gut Microbial Metabolite Butyrate and Its Therapeutic Role in Inflammatory Bowel Disease: A Literature Review.

Background and objective: Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder characterized by aberrant immune responses and compromised barrier function in the gastrointestinal tract. IBD is associated with altered gut microbiota and their metabolites in the colon. Butyrate, a gut microbial metabolite, plays a crucial role in regulating immune function, epithelial barrier function, and intestinal homeostasis. In this review, we aim to present an overview of butyrate synthesis and metabolism and the mechanism of action of butyrate in maintaining intestinal homeostasis and to discuss the therapeutic implications of butyrate in IBD. Methods: We searched the literature up to March 2023 through PubMed, Web of Science, and other sources using search terms such as butyrate, inflammation, IBD, Crohn's disease, and ulcerative colitis. Clinical studies in patients and preclinical studies in rodent models of IBD were included in the summary of the therapeutic implications of butyrate. Results: Research in the last two decades has shown the beneficial effects of butyrate on gut immune function and epithelial barrier function. Most of the preclinical and clinical studies have shown the positive effect of butyrate oral supplements in reducing inflammation and maintaining remission in colitis animal models and IBD patients. However, butyrate enema showed mixed effects. Butyrogenic diets, including germinated barley foodstuff and oat bran, are found to increase fecal butyrate concentrations and reduce the disease activity index in both animal models and IBD patients. Conclusions: The current literature suggests that butyrate is a potential add-on therapy to reduce inflammation and maintain IBD remission. Further clinical studies are needed to determine if butyrate administration alone is an effective therapeutic treatment for IBD.

Short-chain fatty acids are associated with adiposity, energy and glucose homeostasis among different metabolic phenotypes in the Nutritionists' Health Study.

The gut microbiome is associated with obesity, mainly mediated by bacteria-produced short-chain fatty acids (SCFAs). It is unknown how SCFA concentrations are associated with the phenotypes metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy obese/overweight (MHO), and metabolically unhealthy obese/overweight (MUO). We compared plasma and fecal SCFA concentrations among adult women categorized according to the metabolic phenotypes mentioned above and examined associations between SCFA and adiposity and components of energy and glucose homeostasis. This was a cross-sectional study involving 111 participants. Body composition was assessed by DEXA. Energy and glycemic homeostasis were assessed by the standard mixed-meal tolerance test coupled with indirect calorimetry. SCFAs were quantified by gas chromatography and mass spectrometry. Only plasma propionate was increased in the MHNW phenotype compared to the MHO and MUO phenotypes [p < 0.05]. Fecal propionate and butyrate concentrations and plasma propionate concentrations were inversely associated with total and visceral adiposity [p < 0.05]. Fecal and plasma SCFA concentrations were associated with reduced glucose, insulin and HbA1c levels, increased fasting and postprandial GLP-1 levels; and more preserved beta-cell function [p < 0.05]. Fecal and plasma SCFA concentrations were positively correlated with resting energy expenditure and lipid oxidation rate and inversely correlated with the oxidation rate of carbohydrates [p < 0.05]. These findings reinforce the concept that fecal and plasma SCFA concentrations are linked to specific components of energy and glucose homeostasis; and body adiposity. However, it was not possible to discriminate the different metabolic phenotypes of adiposity based on the determination of fecal SCFA concentrations.

Effect of Wheat-Derived Arabinoxylan on the Gut Microbiota Composition and Colonic Regulatory T Cells

The health benefits of wheat-derived arabinoxylan, a commonly consumed dietary fiber, have been studied for decades. However, its effect on the gut microenvironment and inflammatory bowel disease remains unclear. The objective of this study was to understand the effect of wheat-derived arabinoxylan on gut microbiota, colonic regulatory T cells (Tregs), and experimental colitis. In this study, healthy and chronic colitis model mice were fed chow containing cellulose or wheat-derived arabinoxylan for 2-6 weeks and subjected to subsequent analysis. A 16S-based metagenomic analysis of the fecal DNA revealed that Lachnospiraceae, comprising butyrate-producing and Treg-inducing bacteria, were overrepresented in arabinoxylan-fed mice. In line with the changes in the gut microbiota, both the fecal butyrate concentration and the colonic Treg population were elevated in the arabinoxylan-fed mice. In a T cell transfer model of chronic colitis, wheat-derived arabinoxylan ameliorated body weight loss and colonic tissue inflammation, which may, in part, be mediated by Treg induction. Moreover, wheat-derived arabinoxylan suppressed TNFα production from type 1 helper T cells in this colitis model. In conclusion, wheat-derived arabinoxylans, by altering the gut microenvironment, may be a promising prebiotic for the prevention of colitis.

Dietary Fibers Differ in Their Effects on Large Bowel Epithelial Proliferation and Fecal Fermentation-Dependent Events in Rats

The effects of different fiber types and processing on putative protective mechanisms for colorectal cancer were evaluated. Rats were fed diets of similar nutrient balance containing either no added fiber or 10% fiber from various sources. The rate of distal colonic epithelial proliferation, measured by the metaphase arrest method, was dependent on fiber type; ranking of fibers from highest to lowest yielded the following order: methylcellulose > coarse wheat bran > fine wheat bran ≈ parboiled and extruded rice brans > no fiber (P = 0.012). Effect on stool output ranked identically. Ranking of effect on fecal pH, from most to least acidic was as follows: coarse wheat bran ≈ the rice brans > fine wheat bran > no fiber ≈ methylcellulose (P = 0.00001). Coarse wheat bran gave significantly higher fecal butyrate concentrations than did the rice brans, which in turn gave higher levels than fine wheat bran, methylcellulose and the no-fiber diet. Proximal colon epithelial proliferation was unaffected by diet although cecal short-chain fatty acid concentrations and pH were affected. Different fibers have different effects on events in the fecal environment and distal colonic epithelium. Putative protective events (increased output, low fecal pH, high butyrate, low proliferation) are not equally affected and are unlikely in themselves to allow prediction of the protective effect of a fiber.

Targeted Delivery of Butyrate Improves Glucose Homeostasis, Reduces Hepatic Lipid Accumulation and Inflammation in db/db Mice

Butyrate produced by the gut microbiota has beneficial effects on metabolism and inflammation. Butyrate-producing bacteria are supported by diets with a high fiber content, such as high-amylose maize starch (HAMS). We investigated the effects of HAMS- and butyrylated HAMS (HAMSB)-supplemented diets on glucose metabolism and inflammation in diabetic db/db mice. Mice fed HAMSB had 8-fold higher fecal butyrate concentration compared to control diet-fed mice. Weekly analysis of fasting blood glucose showed a significant reduction in HAMSB-fed mice when the area under the curve for all five weeks was analyzed. Following treatment, fasting glucose and insulin analysis showed increased homeostatic model assessment (HOMA) insulin sensitivity in the HAMSB-fed mice. Glucose-stimulated insulin release from isolated islets did not differ between the groups, while insulin content was increased by 36% in islets of the HAMSB-fed mice. Expression of insulin 2 was also significantly increased in islets of the HAMSB-fed mice, while no difference in expression of insulin 1, pancreatic and duodenal homeobox 1, MAF bZIP transcription factor A and urocortin 3 between the groups was observed. Hepatic triglycerides in the livers of the HAMSB-fed mice were significantly reduced. Finally, mRNA markers of inflammation in liver and adipose tissue were reduced in mice fed HAMSB. These findings suggest that HAMSB-supplemented diet improves glucose metabolism in the db/db mice, and reduces inflammation in insulin-sensitive tissues.

Changes in gut microbiota and short-chain fatty acids are involved in the process of canine obesity after neutering.

Neutering is a significant risk factor for obesity in dogs. Changes in gut microbiota and its metabolites have been identified as a key player during obesity progression. However, the mechanisms that promote neuter-associated weight gain are not well understood. Therefore, in this study, sixteen clinically healthy Beagle dogs (6 male and 10 female, mean age = 8.22 ± 0.25 mo old) were neutered. Body weight (BW) and body condition score (BCS) were recorded at 1 d before neutering, 3, 6, 10, 16, and 21 mo after neutering. Dogs were grouped based on their BCS as ideal weight group (IW, n = 4, mean BW = 13.22 ± 1.30 kg, mean BCS = 5.00 ± 0.41) and obese group (OB, n = 12, mean BW = 18.57 ± 1.08 kg, mean BCS = 7.92 ± 0.82) at 21 mo after neutering. Serum lipid profile, glucose, and hormones and fecal microbiota and short-chain fatty acids (SCFAs) were measured. Our results showed that OB dogs had greater (P < 0.0001) BW (18.57 vs. 13.22 kg), BCS (7.92 vs. 5.00), and average daily gain (12.27 vs. 5.69 g/d) than IW dogs at 21 mo after neutering, and the obesity rate was up to 60%. In addition, significant increases (P < 0.05) in serum triglyceride (TG, 1.10 vs. 0.56 mmol/L) and high-density lipoprotein cholesterol (HDL-C, 6.96 vs. 5.40 mmol/L) levels and a significant decrease (P < 0.05) in serum adiponectin (APN, 54.06 vs. 58.39 μg/L) level were observed in OB dogs; serum total cholesterol (4.83 vs. 3.75 mmol/L) (P = 0.075) and leptin (LEP, 2.82 vs. 2.53 μg/L) (P = 0.065) levels tended to be greater in OB dogs; there was a trend towards a lower (P = 0.092) APN/LEP (19.32 vs. 21.81) in OB dogs. Results of fecal microbial alpha-diversity showed that Observed_species and Chao1 indices tended to be lower (P = 0.069) in OB dogs. The STAMP and LEfSe analyses revealed that OB dogs had a greater (P < 0.05 and LDA > 2) reduction in relative abundances of Bacteroides, Prevotella_9, and Megamonas than IW dogs. In addition, OB dogs also had greater (P < 0.05) reduction in fecal acetate, propionate, and butyrate concentrations than IW dogs. Moreover, clear negative correlations (|r| > 0.5 and P < 0.05) were found between SCFAs-producing bacteria and BW, TG, and HDL-C. The functional predictions of microbial communities based on PICRUSt2 analysis revealed that lipid metabolism and endocrine system were significantly disturbed in obese dogs after neutering. Thus, intervention with SCFAs-producing bacteria might represent a new target for the prevention or treatment of canine obesity after neutering. Moreover, weight control before neutering may also contribute to the prevention of canine obesity after neutering.

Effects of the probiotic Bacillus coagulans BC69 on the metabolic and histological alterations induced by a high-sugar and high-fat diet in C57BL/6J mice.

Western-style diets are associated with metabolic syndrome, characterized by obesity and hyperglycemia, which is a major public health problem in the 21st century. Recent studies have proven that probiotics have promising effects in the management of metabolic syndrome. This study aimed to investigate the effects of Bacillus coagulans BC69 on the metabolic and histological alterations associated with metabolic syndrome in C57BL/6J mice fed with a high-sugar and high-fat (HSHF) diet. The body weight, biochemistry, histology, and gut microbiome were assessed. The results showed that administration of BC69 from the first week reduced body weight gain, liver weight, and production of pro-inflammatory cytokines (TNF-α), and restored faecal acetate and butyrate concentrations in mice. Histological sections showed that BC-69 also reduced HSHF-induced liver pathological damage in mice by improving hepatocyte disorganization and reducing inflammatory cell infiltration. In addition, 16S rRNA gene sequencing showed that BC69 improved the gut microbiome of HSHF diet-fed mice. This study revealed that BC69 has the potential to be a safe and effective tool in the treatment of metabolic syndrome.

Early life gut microbiota profiles linked to synbiotic formula effects: a randomized clinical trial in European infants

BackgroundMicrobial colonization of the gastrointestinal tract after birth is an essential event that influences infant health with life-long consequences. Therefore, it is important to investigate strategies to positively modulate colonization in early life. ObjectivesThis randomized, controlled intervention study included 540 infants to investigate the effects of a synbiotic intervention formula (IF) containing Limosilactobacillus fermentum CECT5716 and galacto-oligosaccharides on the fecal microbiome. MethodsThe fecal microbiota from infants was analyzed by 16S rRNA amplicon sequencing at 4, 12, and 24 months of age. Metabolites (e.g., short-chain fatty acids) and other milieu parameters (e.g., pH, humidity, and IgA) were also measured in stool samples. ResultsMicrobiota profiles changed with age, with major differences in diversity and composition. Significant effects of the synbiotic IF compared with control formula (CF) were visible at month 4, including higher occurrence of Bifidobacterium spp. and Lactobacillaceae and lower occurrence of Blautia spp., as well as Ruminoccocus gnavus and relatives. This was accompanied by lower fecal pH and concentrations of butyrate. After de novo clustering at 4 months of age, overall phylogenetic profiles of the infants receiving IF were closer to reference profiles of those fed with human milk than infants fed CF. The changes owing to IF were associated with fecal microbiota states characterized by lower occurrence of Bacteroides compared with higher levels of Firmicutes (valid name Bacillota), Proteobacteria (valid name Pseudomonadota), and Bifidobacterium at 4 months of age. These microbiota states were linked to higher prevalence of infants born by Cesarean section. ConclusionsThe synbiotic intervention influenced fecal microbiota and milieu parameters at an early age depending on the overall microbiota profiles of the infants, sharing a few similarities with breastfed infants.This trial was registered at clinicaltrials.gov as NCT02221687.