Modulation Of Gut Microbiome Research Articles

You are what you vape: Implications of THC chronic self-administration in changes in the gut microbiome of rats.

Abstract Vaping of cannabis and its constituents, such as Δ9-tetrahydrocanabinol (THC), has been promoted as a safer alternative to smoked cannabis. Nevertheless, chronic effect of THC vaping in gut microbiome modulation and its effect of health and or disease is still largely unknown. Hence, this project intends to study the effect of chronic THC vapor self-administration on changes in the gut microbiome of Sprague-Dawley rats. Animals were randomly assigned to either vehicle vapor (100% propylene glycol [PG]) or THC vapor groups and were allowed to self-administer PG or THC vapor puffs in operant chambers for one hour on intermittent days for a total of nine months. At the end of this period, a subset of rats was tested for anxiety-like behavior using the open field test. Afterwards, rats were euthanized with isoflurane overdose and rapid decapitation. Feces, metabolic and immune organs, and serum were collected at the time of necropsy. Fecal DNA was extracted, and relative bacterial gut abundance was determined sequencing 16S hypervariable region V4. Rats exposed to THC vape show anxiety-like behavior in the open field test, when compared with the PG exposed group. This change in behavior is also accompanied by an imbalance in their Firmicutes/Bacteroides ratio, having less Firmicutes and more Bacteroides, specifically members of the Muribaculaceae family. Currently, the effect of this dysbiosis on immune markers expression, such as: CCL2, IL-6, TNF-a, IFNa, IFNb, MX1 and TRAIL, are being studied to determine if there is any disruption on immune homeostasis caused by altered microbiome abundance. R01DA052859-03S1

The IBD-candidate gene, PTPN2, is a Key Regulator of Ileal Paneth Cell Function in Mice

Loss-of-function variants in the Protein Tyrosine Phosphatase non-receptor Type 2 ( PTPN2) gene are associated with increased risk of Inflammatory Bowel Disease (IBD). PTPN2 encodes T Cell Protein Tyrosine Phosphatase (TCPTP), a negative regulator of intracellular signaling pathways including JAK-STAT. PTPN2 is critical for intestinal epithelial cell (IEC) barrier maintenance, IEC-macrophage crosstalk, and modulating the gut microbiome in mice, although the mechanism in which PTPN2 loss affects gut microbiome is unknown. IBD patient biopsies and studies in transgenic mice show that IBD-associated genes can modify IEC subtypes and their functional roles in intestinal homeostasis. Hypothesis: PTPN2 loss compromises modulation of gut microbiome by impairing number and function of IEC subtypes. Methods: To identify how loss of PTPN2 activity in vivo affects ileal IEC subtypes and their function, RNA and protein were isolated from ileal IECs of whole-body Ptpn2-wild-type (WT), heterozygous (Het) and KO mice. RNA was assayed by two separate Nanostring ® panels: PanCancer and AutoImmune totaling >1500 targets. Dysregulated targets associated with IEC function were validated by Western blot, immunostaining, and transmission electron microscopy (TEM). Altered genes were then investigated in tamoxifen-inducible intestinal epithelial-specific Ptpn2 knockout mice ( Ptpn2 Δ IEC ) and Ptpn2 fl/fl controls. Results: 1398 targets had detectable expression. Notably, Paneth cell (PC)-associated genes Lyz1, Defa6, Pla2g2a, and Fgfr3 were markedly downregulated (p<0.05 and FDR<0.1; n=4). Reduced PC numbers in whole-body Ptpn2-KO mice were confirmed by decreased Lysozyme and Cryptdin-1 staining (p<0.001; n=5), reduced Lysozyme protein levels by western blotting (p=0.004; n=5), and loss of PC phenotype by TEM (n=3). Ki-67 staining revealed elevated ileal crypt cell proliferation (p=0.02; n=3) and longer villi (p=0.03; n=9) in Ptpn2-KO mice vs. WT. However, unchanged cleaved caspase 3 and TUNEL staining indicated no increase in IEC apoptosis. Further, TEM analysis showed disrupted endoplasmic reticulum (ER) architecture in PCs of Ptpn2-KO mice (n=3) accompanied by higher protein levels of the ER stress marker CHOP (p=0.01; n=8). Conversely, Ptpn2 Δ IEC mice showed no change in ileal villus length (n=6), number of PCs (n=7), and TEM showed abundant cytosolic granules compared to Ptpn2 fl/fl (n=4). However, immunostaining (n=6) and Western blotting (p<0.05; n=6) showed reduced Lysozyme protein accompanied by elevated levels of unfolded protein response Xbp-1s in Ptpn2 Δ IEC mice (p<0.05; n=6). Conclusion: Ptpn2-deficiency affects Paneth cell viability by decreasing cell number, promoting ER stress, and impairing production of PC-associated antimicrobial peptides. This likely contributes to the increased susceptibility to infection and the dysbiotic microbiota in Ptpn2-deficient mice and may explain the association of PTPN2 variants with dysbiosis in clinical IBD. Supported by NIH 2R01DK091281, 1R01AI153314-01, R21AI152017 and R01AI165490 (DFM) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Evidence of the Dysbiotic Effect of Psychotropics on Gut Microbiota and Capacity of Probiotics to Alleviate Related Dysbiosis in a Model of the Human Colon.

Growing evidence indicates that non-antibiotic therapeutics significantly impact human health by modulating gut microbiome composition and metabolism. In this study, we investigated the impact of two psychotropic drugs, aripiprazole and (S)-citalopram, on gut microbiome composition and its metabolic activity, as well as the potential of probiotics to attenuate related dysbiosis using an ex vivo model of the human colon. After 48 h of fermentation, the two psychotropics demonstrated distinct modulatory effects on the gut microbiome. Aripiprazole, at the phylum level, significantly decreased the relative abundances of Firmicutes and Actinobacteria, while increasing the proportion of Proteobacteria. Moreover, the families Lachnospiraceae, Lactobacillaceae, and Erysipelotrichaceae were also reduced by aripiprazole treatment compared to the control group. In addition, aripiprazole lowered the levels of butyrate, propionate, and acetate, as measured by gas chromatography (GC). On the other hand, (S)-citalopram increased the alpha diversity of microbial taxa, with no differences observed between groups at the family and genus level. Furthermore, a probiotic combination of Lacticaseibacillus rhamnosus HA-114 and Bifidobacterium longum R0175 alleviated gut microbiome alterations and increased the production of short-chain fatty acids to a similar level as the control. These findings provide compelling evidence that psychotropics modulate the composition and function of the gut microbiome, while the probiotic can mitigate related dysbiosis.

Anti-Inflammatory, Barrier Maintenance, and Gut Microbiome Modulation Effects of Saccharomyces cerevisiae QHNLD8L1 on DSS-Induced Ulcerative Colitis in Mice.

The use of probiotics has been considered as a new therapy option for ulcerative colitis (UC), and yeast has recently received widespread recommendation for human health. In this study, the probiotic characteristics of four yeast strains, Saccharomyces boulardii CNCMI-745, Kluyveromyces marxianus QHBYC4L2, Saccharomyces cerevisiae QHNLD8L1, and Debaryomyces hansenii QSCLS6L3, were evaluated in vitro; their ability to ameliorate dextran sulfate sodium (DSS)-induced colitis was investigated. Among these, S. cerevisiae QHNLD8L1 protected against colitis, which was reflected by increased body weight, colon length, histological injury relief, decreased gut inflammation markers, and intestinal barrier restoration. The abundance of the pathogenic bacteria Escherichia-Shigella and Enterococcaceae in mice with colitis decreased after S. cerevisiae QHNLD8L1 treatment. Moreover, S. cerevisiae QHNLD8L1 enriched beneficial bacteria Lactobacillus, Faecalibaculum, and Butyricimonas, enhanced carbon metabolism and fatty acid biosynthesis function, and increased short chain fatty acid (SCFAs) production. Taken together, our results indicate the great potential of S. cerevisiae QHNLD8L1 supplementation for the prevention and alleviation of UC.

Abstract 2883: Gut microbiome dysbiosis promotes immune suppression and lung cancer development

Abstract Mounting evidence supports synergistic roles for the gut microbiome in cancer progression. Yet, the interplay between the gut microbiome and immune responses in cancer is still poorly understood. We recently showed that gut microbiome changes are closely associated with development of Kras-mutant lung adenocarcinoma (KM-LUAD) in a human-relevant, tobacco-associated mouse model (Gprc5a-/-; G). Knockout of the antimicrobial protein Lcn2 in these mice (Gprc5a-/-/Lcn2-/-; GL) further reduced microbial diversity while enhancing inflammation and tumor development. We thus hypothesized that microbial dysbiosis in the gut, such as that incurred by loss of Lcn2, may exacerbate LUAD development. Here, we investigated the effects of gut microbiome modulation on LUAD pathogenesis using fecal microbiota transfer (FMT) in both syngeneic and tobacco carcinogenesis models. Syngeneic G mice (transplant of G LUAD cells) that received FMT from GL donors (G < GL) exhibited significantly increased tumor growth relative to littermates with FMT from G mice (G < G). These effects were recapitulated in an independent syngeneic model (KrasG12D LKR13 cells in wild type mice). Tobacco carcinogen-exposed G < GL mice also exhibited increased lung tumor development compared with similarly exposed G < G littermates. 16S rDNA-Seq analysis of fecal pellets revealed significant differences in gut beta diversity between syngeneic G < G and G < GL mice. G < GL mice additionally displayed elevated relative abundance of tumor-promoting Alistipes, while Ruminoccocus and Akkermansia, taxa associated with favorable response to immunotherapy, were reduced. We next performed single-cell RNA-sequencing to comprehensively probe the tumor immune microenvironment (TIME) and the immune milieu near the gut of tumors and mesenteric lymph nodes (MLNs), respectively. The TIME in G < GL mice displayed an overall enhanced immunosuppressive phenotype evidenced by prominently increased fractions of T regulatory and Cd4+ Izumo1r+ exhausted T cells and, conversely, reduced levels of activated Isg15+ Cd8a+ T cells. MLNs from G < GL mice showed markedly increased fractions of memory B cells expressing the immunosuppressor Bank1 and reduced levels of follicular B cells and Cd8a+ Clec9a+ class 1 dendritic cells (cDC1). Flow cytometry further showed enhanced immunosuppression in G < GL relative to G < G mice, including increased fractions of myeloid-derived suppressor cells in the TIME of the former group. Our findings show that gut microbiome dysbiosis fosters lung cancer development by promoting immunosuppression, perhaps via a local and systemic gut microbiota-immune system crosstalk. Modulating the gut microbiome may be a promising strategy for interception or early treatment of lung cancer. Citation Format: Zahraa Rahal, Fuduan Peng, Yuejiang Liu, Matthew C. Ross, Ansam Sinjab, Ke Liang, Jiping Feng, Chidera O. Chukwuocha, Manvi Sharma, Elizabeth Tang, Camille Abaya, Joseph Petrosino, Junya Fujimoto, Seyed Javad Moghaddam, Linghua Wang, Kristi L. Hoffman, Humam Kadara. Gut microbiome dysbiosis promotes immune suppression and lung cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2883.

Abstract 4228: Replacing red and processed meat with legumes modulates gut microbiome and microbiota-related metabolites linked to gut health and cancer prevention in healthy working-aged men

Abstract Background and Aim: Changing dietary habits have great potential for colorectal cancer (CRC) prevention. Regardless of the accumulated evidence on the relationship between dietary protein sources and CRC, the explaining mechanisms remain not well established. Diet-delivered microbial metabolites such as secondary bile acids (BA), N-nitroso compounds (NOC), trimethylamine N-oxide (TMAO), short-chain fatty acid (SCFA), and branched-chain fatty acids (BCFA) have been suggested to mediate the relationship. The aim of this study was to examine the effects of partial replacement of red and processed meat (RPM), associated with higher CRC risk, with legumes on the fecal microbiota composition and metabolite profiles in healthy men. Methods: The study was a partly controlled 6-wk parallel design randomized clinical trial (n=102, age 37 y (range 21 - 61 y), BMI 25.5 ± 3.3 kg/m2) with two groups following either a diet supplemented with RPM (meat group) or a diet supplemented with legumes and RPM (legume group). The amount of RPM (200 g/wk) in the legume group was based on the maximum amount recommended by the EAT-Lancet Commission whereas the amount in the meat group (760 g/wk) corresponded the average intake of Finnish men. Fecal SCFAs (µg/ml) and BCFAs (µg/ml) were analyzed with GS-MS, BAs (arbitrary, analyte/standard ratios) with UHPLC-MS/MS, and NOCs (pmol/mg) with selective de-nitrosation and chemiluminescence-based detection. Urine TMAO was quantified by NMR and fecal microbiota composition was analyzed using 16S rRNA amplicon sequencing techniques. Dietary intakes were analyzed with 4-day food records. Results: At the baseline, no significant differences (p > 0.05) were reported in age, BMI, dietary intake of total fiber (g/d), protein (E%), fat (E%), or in the fecal metabolites. The legume group had more pronounced effects on the gut microbiota community level, indicating ecosystem level differences. Total NOCs (p < 0.0001) and heme-originated NOCs (FeNO; p < 0.0001) were smaller in the legume group than in the meat group. Significant differences between the groups were observed in intake of total fiber (p < 0.001), cholesterol (mg/d, p < 0.001), saturated (p < 0.005), and polyunsaturated fat (p < 0.001). Although not significant (p > 0.05), total, secondary and unconjugated BAs, and total BCFA were higher in the meat group, whereas primary and conjugated BAs and total SCFAs were higher in the legume group. The concentration of total SCFA and individual SCFA decreased in both groups during the intervention period. Overall, a large sample-to-sample variation was observed. Conclusions: The results indicate that partial replacement of RPM with legume products can potentially change microbiota activity and gut metabolites, suggesting a protective gut metabolic profile against colorectal cancer. Citation Format: Tuulia Pietilä, Isabell Schreck, Tiina Pellinen, Johanna Vauhkonen, Essi Päivärinta, Mikko Neuvonen, Mikko Niemi, Anne Salonen, Anne-Maria Pajari. Replacing red and processed meat with legumes modulates gut microbiome and microbiota-related metabolites linked to gut health and cancer prevention in healthy working-aged men. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4228.

Gut microbiome-modulated dietary strategies in EAE and multiple sclerosis.

Over the last few decades, the incidence of multiple sclerosis has increased as society's dietary habits have switched from a whole foods approach to a high fat, high salt, low dietary fiber, and processed food diet, termed the "Western diet." Environmental factors, such as diet, could play a role in the pathogenesis of multiple sclerosis due to gut microbiota alterations, gut barrier leakage, and subsequent intestinal inflammation that could lead to exacerbated neuroinflammation. This mini-review explores the gut microbiome alterations of various dietary strategies that improve upon the "Western diet" as promising alternatives and targets to current multiple sclerosis treatments. We also provide evidence that gut microbiome modulation through diet can improve or exacerbate clinical symptoms of multiple sclerosis, highlighting the importance of including gut microbiome analyses in future studies of diet and disease.

Digestion profile, antioxidant, and antidiabetic capacity of Morchella esculenta exopolysaccharide: in vitro, in vivo and microbiota analysis.

Novel functional polysaccharides from fungi are important nutraceuticals. An exopolysaccharide, Morchella esculenta exopolysaccharide (MEP 2), was extracted and purified from the fermentation liquor of M. esculenta. The aim of this study was to investigate its digestion profile, antioxidant capacity, and effect on the microbiota composition in diabetic mice. The study found that MEP 2 was stable during in vitro saliva digestion but was partially degraded during gastric digestion. The digest enzymes exerted a negligible effect on the chemical structure of MEP 2. Molecular weight and atomic force microscope (AFM) images suggest that both smaller chains and larger aggregations were produced. Scanning electron microscope (SEM) images reveal that the surface morphology was much altered after intestinal digestion. After digestion, the antioxidant ability increased as revealed by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays. Both MEP 2 and its digested components showed strong α-amylase and moderate α-glucosidase inhibition activity, leading us to further investigate its ability to modulate the diabetic symptoms. The MEP 2 treatment ameliorated the inflammatory cell infiltration and increased the size of pancreas inlets. Serum concentration of HbA1c was significantly reduced. Blood glucose level during the oral glucose tolerance test (OGTT) was also slightly lower. The MEP 2 increased the diversity of the gut microbiota and modulated the abundance of several important bacteria including Alcaligenaceae, Caulobacteraceae, Prevotella, Brevundimonas, Demequina, and several Lachnospiraceae species. It was found that MEP 2 was partially degraded during in vitro digestion. Its potential antidiabetic bioactivity may be associated with its α-amylase inhibition and gut microbiome modulation ability. © 2023 Society of Chemical Industry.

ROLE OF INULIN IN NONALCOHOLIC FATTY LIVER DISEASE TREATMENT AND CHANGES OFTHE GUT MICROBIOME

Bacterial translocation and endotoxemia due to dysbiosis and increased intestinalpermeability have been proposed as the possible mechanism that provokes developmentand progression of nonalcoholic fatty liver disease (NAFLD). Microbiome variationscould lead to positive and negative effect due to the impact on different links of theNAFLD pathogenesis – from biochemical markers to the fat accumulation in the liver.Therefore, looking for thetherapy that could effectively influence on the liver steatosisprevention has become a topic research during recent years.Objective – to study the gut microbiome composition and biochemical markers in patientswith nonalcoholic fatty liver disease before and after inulin treatment.Materials and methods. The study design included 93 patients with NAFLD who weregiven 5 g of Inulin- Neo (Sunchoke extract) twice daily. NAFLD diagnosis was basedon the ultrasound and liver elastography examination. The gut microbiome beforeand after treatment was determined by the real-time PCR methodology and includedthe Bacteroidetes, Firmicutes, Actinobacteria measurement, as well as the qualitativedetermination of Candida albicans, Candida glabrata and Candida krusei. The durationof treatment was 20 days. Results. There were Actinobacteria and Firmicutes growth in gut microbiome,improvement of biochemical indicators (gamma glutamyltransferase (GGT), triglycerides(TG), high density lipoproteins (HDL), high-sensitive CRP (hs- CRP)) after the Inulintreatment. Also, a negative correlational relationship was marked between the level ofActinobacteria and intestinal Candidosis after the Inulin therapy.Conclusions. Inulin can be a part of therapy in patients with NAFLD due to its positiveeffect on the biochemical indicators of steatosis and by gut microbiome modulation,which affects the reduction of pro-inflammatory markers and the endotoxemia level.

Abstract P425: Diets Enriched in Stearate, Palmitate, and Oleate Differentially Modulate Gut Microbiome Composition in Post-Menopausal Women

Objective: Dietary stearic acid (18:0), a major saturated fatty acid (SFA) in Western diets, does not raise plasma LDL-C concentrations relative to other shorter chain SFAs (palmitic [16:0], myristic [14:0] and lauric [12:0]), and is associated with lower CVD risk. We investigated whether the cardioprotective effects of 18:0 and its metabolic product oleic acid (18:1, a monounsaturated fatty acid) relative to 16:0 is mediated via alterations in the gut microbiome. Methods: Twenty mildly hypercholesterolemic (LDL-C>100mg/dL) post-menopausal women (50-85 years; BMI 25-35kg/m 2 ) consumed each of 3 isocaloric diets for 5 weeks according to a randomized controlled cross-over design. Diets provided 55%E carbohydrate, 15%E protein and 30%E fat with half of the fat provided by 16:0, 18:0 or 18:1, respectively. Fecal samples were collected at the end of each diet phase and shotgun metagenomic sequencing was performed. Alpha diversity (Shannon index, Simpson index and observed counts) was compared between diet groups using two-sample non-parametric tests. Beta-diversity was assessed using Bray-Curtis dissimilarity with PERMANOVA test. Differences in metagenomic features by diet group were evaluated using Partial Least Squares-Discriminant Analysis (PLS-DA) models of pairwise diet differences developed using the R package ‘mixOmics’. Results: No significant differences were observed in alpha and beta diversity between diet groups. However, the variability in microbial relative abundance was greater after participants consumed the 18:0 and 18:1 diets compared to the 16:0 diet. Specifically, mean relative abundance of Bacterioides dorei , Bacteroides vulgatus , and Ruminococcus were highest after participants consumed the 18:0 relative to the 16:0 diet and intermediate after the 18:1 diet. The relative abundance of Coprococcus , Parabacteroides distasonis , Coprobacillus and Blautia were higher after participants consumed the 18:1 relative to the 16:0 diet. These microbial species have been associated with several anti-inflammatory pathways and decreased bacterial lipopolysaccharide production. Conclusion: These data document modest but distinctive effects of dietary SFAs on gut microbiome composition and functionality, suggesting that the favorable effects of 18:0 and 18:1 relative to 16:0 on CVD risk factors could be mediated, in part, by the gut microbiome.

Mimicking seasonal changes in light-dark cycle and ambient temperature modulates gut microbiome in mice under the same dietary regimen.

To better adapt to seasonal environmental changes, physiological processes and behaviors are regulated seasonally. The gut microbiome interacts with the physiology, behavior, and even the diseases of host animals, including humans and livestock. Seasonal changes in gut microbiome composition have been reported in several species under natural environments. Dietary content significantly affects the composition of the microbiome, and, in the natural environment, the diet varies between different seasons. Therefore, understanding the seasonal regulatory mechanisms of the gut microbiome is important for understanding the seasonal adaptation strategies of animals. Herein, we examined the effects of changing day length and temperature, which mimic summer and winter conditions, on the gut microbiome of laboratory mice. Principal coordinate analysis and analysis of the composition of microbiomes of 16S rRNA sequencing data demonstrated that the microbiomes of the cecum and large intestine showed significant differences between summer and winter mimicking conditions. Similar to previous studies, a daily rhythm was observed in the composition of the microbiome. Furthermore, the phylogenetic investigation of communities by reconstruction of unobserved states predicted seasonal changes in several metabolic pathways. Changing day length and temperature can affect the composition of the gut microbiome without changing dietary contents.

Probiotic potential of β‑galactosidase‑producing lactic acid bacteria from fermented milk and their molecular characterization.

Probiotics have attained significant interest in recent years as a result of their gut microbiome modulation and gastrointestinal health benefits. Numerous fermented foods contain lactic acid bacteria (LAB) which are considered as GRAS and probiotic bacteria. The present study aimed to investigate indigenous LAB from homemade fermented milk samples collected in remote areas of Karnataka (India), in order to isolate the most potent and well-adapted to local environmental conditions bacteria, which were then evaluated using a step-by-step approach focused on the evaluation of probiotic traits and β-galactosidase-producing ability. LAB were screened using 5-bromo-4-chloro-3-indole-D-galactopyranoside (X-Gal) and O-nitrophenyl-β-D-galactopyranoside (ONPG) as substrate, and exhibited β-galactosidase activity ranging from 728.25 to 1,203.32 Miller units. The most promising isolates were selected for 16S rRNA gene sequence analysis and identified as Lactiplantibacillus plantarum, Limosilactobacillus fermentum, Lactiplantibacillus pentosus and Lactiplantibacillus sp. Furthermore, these isolates were evaluated by in vitro, viz., survival in gastrointestinal tract, antibiotic susceptibility, antimicrobial activity, cell surface characteristics, and haemolytic activity. All eight isolates demonstrated strong adherence and prevented pathogen penetration into HT-29 cells, indicating potential of the bacteria to scale up industrial level production of milk products for lactose intolerants.

Fecal microbiome transplantation and tributyrin improves early cardiac dysfunction and modifies the BCAA metabolic pathway in a diet induced pre-HFpEF mouse model.

More than 50% of patients with heart failure present with heart failure with preserved ejection fraction (HFpEF), and 80% of them are overweight or obese. In this study we developed an obesity associated pre-HFpEF mouse model and showed an improvement in both systolic and diastolic early dysfunction following fecal microbiome transplant (FMT). Our study suggests that the gut microbiome-derived short-chain fatty acid butyrate plays a significant role in this improvement. Cardiac RNAseq analysis showed butyrate to significantly upregulate ppm1k gene that encodes protein phosphatase 2Cm (PP2Cm) which dephosphorylates and activates branched-chain α-keto acid dehydrogenase (BCKDH) enzyme, and in turn increases the catabolism of branched chain amino acids (BCAAs). Following both FMT and butyrate treatment, the level of inactive p-BCKDH in the heart was reduced. These findings show that gut microbiome modulation can alleviate early cardiac mechanics dysfunction seen in the development of obesity associated HFpEF.

Prebiotic mechanisms of resistant starches from dietary beans and pulses on gut microbiome and metabolic health in a humanized murine model of aging.

Dietary pulses, being a rich source of fiber and proteins, offer an ideal and inexpensive food choice for older adults to promote gut and metabolic health. However, the prebiotic effects of dietary pulses-derived resistant starches (RS), compared to RS from cereals and tubers, remain relatively underexplored, particularly in context to their gut modulatory potential in old age. We herein investigate the prebiotic effects of pulses-derived RS on the gut microbiome and intestinal health in aged (60-week old) mice colonized with human microbiota. C57B6/J mice were fed for 20 weeks with either a western-style high-fat diet (control; CTL) or CTL diet supplemented (5% w/w) with RS from pinto beans (PTB), black-eyed-peas (BEP), lentils (LEN), chickpeas (CKP), or inulin (INU; reference control). We find that the RS supplementation modulates gut microbiome in a sex-dependent manner. For instance, CKP enriched α-diversity only in females, while β-diversity deviated for both sexes. Further, different RS groups exhibited distinct microbiome differences at bacterial phyla and genera levels. Notably, LEN fostered Firmicutes and depleted Proteobacteria abundance, whereas Bacteroidota was promoted by CKP and INU. Genus Dubosiella increased dominantly in males for all groups except PTB, whilst Faecalibaculum decreased in females by CKP and INU groups. Linear discriminant analysis effect size (LEfSe) and correlational analyzes reveal RS-mediated upregulation of key bacterial genera associated with short-chain fatty acids (butyrate) production and suppression of specific pathobionts. Subsequent machine-learning analysis validate decreased abundance of notorious genera, namely, Enterococcus, Odoribacter, Desulfovibrio, Alistipes and Erysipelatoclostridium among RS groups. CKP and LEN groups partly protected males against post-prandial glycemia. Importantly, RS ameliorated high-fat diet-induced gut hyperpermeability and enhanced expression of tight-junction proteins (claudin-1 and claudin-4), which were more pronounced for LEN. In addition, IL10 upregulation was more prominent for LEN, while TNF-α was downregulated by LEN, CKP, and INU. Together, these findings demonstrate that RS supplementation beneficially modulates the gut microbiome with a reduction in gut leakiness and inflammation, indicating their prebiotic potential for functional food and nutritional applications.

Gut-brain axis through the lens of gut microbiota and their relationships with Alzheimer's disease pathology: Review and recommendations

Alzheimer’s disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. Growing evidence suggests that the gut microbiome (GM) plays a pivotal role in the pathogenesis of AD through the microbiota-gut-brain axis (MGB). Alterations in GM composition and diversity have been observed in both animal models and in human patients with AD. GM dysbiosis has been implicated in increased intestinal permeability, blood-brain barrier (BBB) impairment, neuroinflammation and the development of hallmarks of AD. Further elucidation of the role of GM in AD could pave way for the development of holistic predictive methods for determining AD risk and progression of disease. Furthermore, accumulating evidence suggests that GM modulation could alleviate adverse symptoms of AD or serve as a preventive measure. In addition, increasing evidence shows that Type 2 Diabetes Mellitus (T2DM) is often comorbid with AD, with common GM alterations and inflammatory response, which could chart the development of GM-related treatment interventions for both diseases. We conclude by exploring the therapeutic potential of GM in alleviating symptoms of AD and in reducing risk. Furthermore, we also propose future directions in AD research, namely fecal microbiota transplantation (FMT) and precision medicine.

A pilot study of gut microbiome modulation to enable efficacy of neoadjuvant checkpoint-based immunotherapy (IO) following chemotherapy in pancreatic ductal adenocarcinoma (PDAC).

TPS759 Background: Neoadjuvant therapy is now a standard strategy for localized PDAC, and this preoperative window provides an excellent opportunity in which to test novel therapeutic approaches. Trials using IO in PDAC have largely been unsuccessful, and immune tolerance is implicated as a major mechanism of IO resistance. The gut and tumor microbiome have emerged as key modulators of response to both IO and chemotherapy. High tumor microbial diversity has been linked to longer survival in PDAC, and gut microbiota may have the ability to colonize pancreatic tumors. There is preclinical evidence that endogenous microbiota promotes the immunosuppressive tumor microenvironment characteristic of PDAC through stimulation of pro-tumor regulatory T cells and myeloid-derived suppressor cells at the expense of anti-tumor activated CD4+ and CD8+ T cells. Further, preclinical data show that ablation of the gut microbiota may induce T cell activation, improve immune surveillance, and increase sensitivity to IO. We hypothesize that ablative antibiotics (abx) will activate tumor infiltrating T cells and enhance IO activity in PDAC. Methods: This is a multi-center, single-arm, open-label pilot study of pre-operative chemotherapy followed by abx and pembrolizumab to evaluate overall immune response to abx + IO. Eligible patients will have histologically confirmed, resectable PDAC, without probiotic consumption or use of immunosuppressive agents. Patients will be enrolled at diagnosis after undergoing a baseline biopsy. They will then receive mFOLFIRINOX every 2 weeks for 5 cycles. After completion of chemotherapy, ciprofloxacin 500 mg PO BID and metronidazole 500 mg PO TID will be administered for 21 days, and pembrolizumab 200 mg IV x1 will be given 7 days after initiation of abx. Patients will then undergo surgical resection and adjuvant therapy at the investigators’ discretion. On-treatment biopsy will be obtained prior to cycle 5 of mFOLFIRINOX. Blood and stool will be collected at baseline, during mFOLFIRINOX therapy, before and after pembrolizumab administration, and postoperatively. The primary endpoint is the overall immune response, which will be measured as activation of one or more of the T cell markers HLA-DR, CD38, CD25, Ki67, and CD69, defined as an increase in expression level of at least 20% from the on-treatment specimen to the surgical specimen, before and after abx + IO. Key secondary endpoints will be the evaluation of adverse events, R0 resection rate, histologic regression score, objective response rate, and overall survival rate. Correlative studies will be carried out to evaluate immune and microbiome changes in the blood and tissue following abx and pembrolizumab. These findings will be correlated with clinical endpoints. The target study accrual is 25 patients. Clinical trial information: NCT05462496 .

Controlled manipulation of the gut microbiome improves intracortical microelectrode performance.

Intracortical microelectrode arrays (MEAs) record neuronal action potentials in the brain and can be paired with external systems to provide motor function rehabilitation to those with disabilities. Unfortunately, recording quality of MEAs consistently declines over the course of weeks to months compromising device utility. Neuroinflammation from persistent indwelling of MEAs is considered a significant contributor to the decline in recording performance. Recent evidence suggests that the gut microbiome may play a role in brain health possibly via bacteria-specific metabolites or microbiota infiltrating through the blood-brain barrier. Therefore, we hypothesize that altering the gut microbiome in mice via oral antibiotics or probiotics could change the microbiome composition in both the brain and gut, affecting neuroinflammation and MEA performance. Here, mice implanted with an MEA device for 12 weeks were treated with either antibiotics, probiotics, or normal diet to modulate gut microbiome composition. Biweekly neural recording sessions indicated temporal differences in MEA recording performance. Acutely (Weeks 1-5), antibiotic-treated mice (79% active electrode yield, AEY) and probiotic-treated mice (74% AEY) showed significantly better MEA performance than control (69% AEY). Probiotic significantly outperformed antibiotic sub-chronically (Weeks 6-11) and chronically (Weeks 12+). Differential changes to 16S RNA composition in stool and brain tissue suggested treatment-specific changes at the neural implant site. Culturing of explanted brain tissue indicated that live gut-derived bacteria were differentially found in the brain after implantation and treatment. Transcriptomic and proteomic analysis on brain tissue is underway to understand the correlation between MEA performance, microbiome composition, and neuroinflammation following MEA implantation and treatment. At minimum, our data suggest a connection between microbiome composition and recording performance. Such evidence provides a novel means for understanding and improving the lifetime of MEA devices to be used chronically in humans.

Monitoring and Modulating Diet and Gut Microbes to Enhance Response and Reduce Toxicity to Cancer Treatment.

The gut microbiome comprises a diverse array of microbial species that have been shown to dynamically modulate host immunity both locally and systemically, as well as contribute to tumorigenesis. In this review, we discuss the scientific evidence on the role that gut microbes and diet play in response and toxicity to cancer treatment. We highlight studies across multiple cancer cohorts that have shown an association between particular gut microbiome signatures and an improved response to immune checkpoint blockade, chemotherapy, and adoptive cell therapies, as well as the role of particular microbes in driving treatment-related toxicity and how the microbiome can be modulated through strategies, such as fecal transplant. We also summarize the current literature that implicate high fiber and ketogenic diets in improved response rates to immunotherapy and chemotherapy, respectively. Finally, we discuss the relevance of these findings in the context of patient care, advocate for a holistic approach to cancer treatment, and comment on the next frontier of targeted gut and tumor microbiome modulation through novel therapeutics, dietary intervention, and precision-medicine approaches.

The Effect of Hydrolyzed and Fermented Arabinoxylan-Oligo Saccharides (AXOS) Intake on the Middle-Term Gut Microbiome Modulation and Its Metabolic Answer.

Although fermentation and hydrolyzation are well-known processes to improve the bioavailability of nutrients and enable the fortification with dietary fibers, the effect of such pre-treatments on the prebiotic features of arabinoxylan-oligosaccharides (AXOS) had not been explored. The middle-term in vitro simulation through the Simulator of the Human Intestinal Microbial Ecosystem (SHIME) demonstrated that the feeding with different formulations (namely oat bran, rye bran and wheat bran) containing hydrolyzed AXOS fermented by lactic acid bacteria significantly increased the synthesis of short-chain fatty acids (SCFA) by colon microbiota, with hydrolyzed and fermented rye bran displaying the highest effect. After two weeks from the interruption of intake, SCFA concentrations significantly decreased but remained still significantly higher compared to the original condition. The microbiome was also affected, with a significant abundance increase in Lactobacillaceae taxon after feeding with all fermented and hydrolyzed formulates. Hydrolyzed and fermented rye bran showed the highest changes. The fungal community, even if it had a lower variety compared to bacteria, was also modulated after feeding with AXOS formulations, with an increase in Candida relative abundance and a decrease in Issatchenkia. On the contrary, the intake of non-hydrolyzed and non-fermented wheat bran did not produce relevant changes of relative abundances. After two weeks from intake interruption (wash out period) such changes were mitigated, and the gut microbiome modulated again to a final structure that was more like the original condition. This finding suggests that hydrolyzed AXOS fermented by lactic acid bacteria could have a more powerful prebiotic effect compared to non-hydrolyzed and non-fermented wheat bran, shaping the colon microbiome and its metabolic answer. However, the intake should be continuous to assure persistent effects. Opening a window into the ecological evolutions and plausible underlying mechanisms, the findings reinforce the perspective to explore more in depth the use of hydrolyzed and fermented AXOS as additional ingredient for bread fortification.

Effects of microbial-derived biotics (meta/pharma/post-biotics) on the modulation of gut microbiome and metabolome; general aspects and emerging trends

Potential effects of metabiotics (probiotics effector molecules or signaling factors), pharmabiotics (pro-functional metabolites produced by gut microbiota (GMB)) and postbiotics (multifunctional metabolites and structural compounds of food-grade microorganisms) on GMB have been rarely reviewed. These multifunctional components have several promising capabilities for prevention, alleviation and treatment of some diseases or disorders. Correlations between these essential biotics and GMB are also very interesting and important in human health and nutrition. Furthermore, these natural bioactives are involved in modulation of the immune function, control of metabolic dysbiosis and regulation of the signaling pathways. This review discusses the potential of meta/pharma/post-biotics as new classes of pharmaceutical agents and their effective mechanisms associated with GMB-host cell to cell communications with therapeutic benefits which are important in balance and the integrity of the host microbiome. In addition, cutting-edge findings about bioinformatics /metabolomics analyses related to GMB and these essential biotics are reviewed.