Dietary fibre reverses adverse post-stroke outcomes in mice via short-chain fatty acids and its sensing receptors GPR41, GPR43 and GPR109A

Over 12 million people suffer from a stroke each year and 50% of them may not survive. Stroke is often associated with intestinal dysmotility, microbiota dysbiosis, and disruption of the intestinal epithelial barrier. Experimental and clinical trial data have shown that the microbiota-gut-brain axis significantly impacts stroke outcomes. Dietary fiber has also been associated with fewer ischaemic stroke cases, likely due to its role in balancing gut microbial dysbiosis and supporting a healthy intestinal epithelial barrier. This study investigated the importance of fermentable dietary fiber in stroke prevention, recovery, and post-stroke outcomes, as well as post-stroke recovery dependence on short-chain fatty acid (SCFA) receptors GPR41, GPR43, and GPR109A and associated mechanisms. C57BL/J male mice were fed either the control or nutrient-matched diets with low- or high-fiber content for 28 days before photothrombotic (PT) stroke surgery and seven days after the surgery. The study demonstrated that a low-fiber diet in mice exacerbated post-stroke outcomes and was reversed by a high-fiber diet or direct supplementation with SCFAs immediately after the stroke. The effect was a modulation of the gut microbiome and improved gut epithelial barrier integrity, associated with fewer activated neutrophils and more neuroblast cells in the brain. The study also used a triple knockout mouse model to investigate the SCFA-receptors GPR41/43/109A, which exhibited poorer stroke outcomes and recovery. These results support dietary fiber use and SCFA supplementation as new therapeutic strategies for stroke-induced brain injury. 

Key takeaways:

• Dietary fiber consumption has been associated with fewer ischaemic stroke cases.
• Low-fiber intake leads to worse stroke outcomes, which can be reversed by high-fiber or SCFA supplementation.
• Dietary fiber and SCFA supplementation act in post-stroke recovery via signaling of SCFA receptors GPR41, GPR43, and GPR109A. 
• Future studies that focus on downstream signaling pathways after SCFA receptor activation in the post-stroke brain could be beneficial for the development of novel stroke therapies. 

Access to the study: https://www.biorxiv.org/content/10.1101/2023.05.15.540735v1

Reference: Peh, A., Dinakis, E., Jama, H., Anderson, D., Creek, D. J., Zheng, G., de Veer, M., Mackay, C. R., Zheng, T., Kemp-Harper, B. K., Broughton, B. R. S., & Marques, F. Z. (2023). Dietary Fibre Reverses Adverse Post-Stroke Outcomes in Mice via Short-Chain Fatty Acids and Its Sensing Receptors GPR41, GPR43 and GPR109A. https://doi.org/10.1101/2023.05.15.540735

The Effect of Inulin-Type Fructans on Plasma Trimethylamine N-Oxide Levels in Peritoneal Dialysis Patients: A Randomized Crossover Trial

Chronic kidney disease (CKD) is a serious condition that affects millions of people worldwide and is characterized by a progressive decline in renal function. Trimethylamine n-oxide (TMAO) is a proatherogenic uremic toxin derived from trimethylamine (TMA), a product of the gut microbiota’s metabolism of choline, carnitine, and betaine, and oxidized to TMAO in the liver. In CKD patients, reduced renal function leads to decreased TMAO excretion and TMAO accumulation. Additionally, the combination of impaired renal function and gut dysbiosis may contribute to increased TMAO. Since kidney function is not modifiable, manipulating the gut microbiota may be a promising strategy for reducing TMAO retention. This randomized, double-blind, placebo-controlled, crossover trial explored the effects of inulin-type fructans (ITFs) on circulating TMAO and TMA-producing gut microbiota gene clusters in peritoneal dialysis patients. Twenty-two participants undergoing continuous ambulatory peritoneal dialysis were randomized to 10 g/day ITF oral intervention (50/50 mixture of long-chain inulin and oligofructose) and placebo (maltodextrin). The study duration was nine months, with three months of ITFs, three months of washout, and three months of placebo. TMA-producing gene clusters were annotated using shotgun metagenomic sequencing. Gut microbiome, fecal and plasma TMA, plasma TMAO, and daily urine excretion and dialysis removal of TMAO were measured. The ITF intervention increased the Firmicutes/Bacteroidetes (F/B) ratio in the gut microbiome (p=0.049), but showed no significant influence on the fecal TMA content, circulating TMAO levels, or TMA-producing gene clusters. A plausible cause for the lack of significance in the study was speculated to be the insufficient dosage and small sample size. Although this study showed that 10 g/day of ITFs for three months may not reduce plasma TMAO levels in peritoneal dialysis patients, it does, however, improve the gut microbiome composition.  

Key takeaways:

• Dialysis patients may report higher TMAO, a proatherogenic uremic toxin produced in the liver.
• The gut microbiota is involved in TMAO production via metabolizing its precursor, TMA.
• ITFs may positively manipulate the gut microbiota, increasing the Firmicutes/Bacteroidetes (F/B) ratio.

Access to the study: https://pubmed.ncbi.nlm.nih.gov/36855809/ 

Reference: Xiong, Q., Li, L., Xiao, Y., He, S., Zhao, J., Lin, X., He, Y., Wang, J., Guo, X., Liang, W., Zuo, X., & Ying, C. (2023). The Effect of Inulin-Type Fructans on Plasma Trimethylamine N-Oxide Levels in Peritoneal Dialysis Patients: A Randomized Crossover Trial. Molecular nutrition & food research, 67(9), e2200531. https://doi.org/10.1002/mnfr.202200531 

The effects of LactoCare synbiotic administration on chemotherapy-induced nausea, vomiting, diarrhea, and constipation in children with ALL: A double-blind randomized clinical trial

Chemotherapy can cause disorders of the gastrointestinal tract by changing the intestinal microbial composition and disrupting intestinal bacterial colonization, leading to the growth of pathogenic bacteria and associated side effects, including diarrhea, vomiting, and constipation. Furthermore, chemotherapy may cause adverse reactions such as chemotherapy-induced nausea and vomiting (CINV), mucositis, neutropenia, constipation, and chemotherapy-induced diarrhea (CID). This randomized, double-blind, placebo-controlled pilot study recruited 113 children aged 5-15 years with acute lymphoblastic leukemia (ALL) receiving maintenance chemotherapy. The children were randomly assigned to receive either 5 x 109 colony-forming units (CFUs) of the synbiotic LactoCare or placebo twice daily for seven days. The synbiotic contained Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus bulgaricus, Bifidobacterium breve, Bifidobacterium longum, Streptococcus thermophilus as probiotics, and fructooligosaccharide (FOS) as the prebiotic. The study reported a significant decrease in CID in the LactoCare group over the 7-day treatment period. The rate of constipation in the LactoCare group was also significantly lower than in the placebo group. With these results, this study supports the concept of synbiotic supplementation as an easy and effective way to reduce CID in ALL patients. 

Key takeaways:

• Chemotherapy may negatively impact the gastrointestinal tract, specifically the microbial communities residing in the gut.
• Chemotherapy-associated adverse effects include diarrhea, vomiting, and constipation.
• Synbiotics, via their gut-microbiota modulatory actions, may benefit ALL patients receiving chemotherapy. 
• As seen with the results of this trial, synbiotics may reduce the incidence of CID and constipation in children with ALL and receiving chemotherapy.  

Access the study: https://pubmed.ncbi.nlm.nih.gov/36975174/ 

Reference: Eghbali, A., Ghaffari, K., Khalilpour, A., Afzal, R. R., Eghbali, A., & Ghasemi, A. (2023). The effects of LactoCare synbiotic administration on chemotherapy-induced nausea, vomiting, diarrhea, and constipation in children with ALL: A double-blind randomized clinical trial. Pediatric blood & cancer, 70(6), e30328. https://doi.org/10.1002/pbc.30328 

Efficacy of 1-kestose supplementation in patients with mild to moderate ulcerative colitis: A randomised, double-blind, placebo-controlled pilot study

Ulcerative colitis (UC) is a chronic, refractory inflammatory bowel disease (IBD) characterized by bleeding diarrhoea, abdominal pain, and fever. An imbalance in the gut microbiome plays a role in the pathogenesis of UC. It has been reported that the feces of UC patients contain a lower proportion of SCFA-producing bacteria, such as Faecalibacterium, and lower concentrations of SCFAs compared with the feces of healthy individuals. 1-kestose is a FOS composed of fructose and sucrose that in nonclinical studies increased SCFAs and SCFA-producing bacteria in the gut microbiome. This single-center, randomized, double-blind, placebo-controlled, pilot study investigated the efficacy of 1-kestose against active UC. Forty patients with mild to moderately active UC randomly received either 10 g of 1-kestose powder (contains 98.1% 1-kestose, one 5 g dose twice daily) or 5 g placebo (maltose, one 2.5 g dose twice daily) taken orally for eight weeks in addition to the patient’s standard treatment. The Lichtiger clinical activity index and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) were determined and fecal samples were analyzed to evaluate the gut microbiome and metabolites. The study reported a significant decrease in the clinical activity index at week eight in the 1-kestose group compared to the placebo, as well as higher clinical remission and response rates with no reported significance. The UCEIS and the SCFA levels were not significantly different between the two groups; however, faecal sample analysis showed a significant reduction in the α-diversity in the 1-kestose group. Overall, this study showed that 1-kestose is well-tolerated at 10 g/day for eight weeks and provided clinical improvement to patients with mild to moderate UC through gut microbiome modulation. Nonetheless, additional clinical studies are needed to investigate the mechanisms by which 1-kestose confers its effect in UC.

Key takeaways:

• UC affects individuals globally, with increasing incidence and prevalence worldwide.
• Microbiome imbalance plays a role in UC pathogenesis, and prebiotics may help regulate this imbalance.  

• The 1-kestose group in this study had a significantly lower Lichtiger clinical activity index and α-diversity in the faecal samples analyzed.
• Additional studies may be warranted to investigate the mechanism of 1-kestose in UC. 

Access the study: https://pubmed.ncbi.nlm.nih.gov/36644995/ 

Reference: Ikegami, S., Nakamura, M., Honda, T., Yamamura, T., Maeda, K., Sawada, T., Ishikawa, E., Yamamoto, K., Furune, S., Ishikawa, T., Furukawa, K., Ohno, E., Ishigami, M., Kinoshita, F., Kadota, Y., Tochio, T., Shimomura, Y., Hirooka, Y., & Kawashima, H. (2023). Efficacy of 1-kestose supplementation in patients with mild to moderate ulcerative colitis: A randomised, double-blind, placebo-controlled pilot study. Alimentary pharmacology & therapeutics, 57(11), 1249–1257. https://doi.org/10.1111/apt.17387