Contribution Of Gut Microbiota Research Articles

Gut microbiota, cognitive frailty and dementia in older individuals: a systematic review.

Cognitive frailty, defined as the coexistence of mild cognitive impairment symptoms and physical frailty phenotype in older persons, is increasingly considered the main geriatric condition predisposing to dementia. Recent studies have demonstrated that gut microbiota may be involved in frailty physiopathology by promoting chronic inflammation and anabolic resistance. The contribution of gut microbiota to the development of cognitive impairment and dementia is less defined, even though the concept of “gut–brain axis” has been well demonstrated for other neuropsychiatric disorders. The aim of this systematic review was to summarize the current state-of-the-art literature on the gut microbiota alterations associated with cognitive frailty, mild cognitive impairment and dementia and elucidate the effects of pre- or probiotic administration on cognitive symptom modulation in animal models of aging and human beings. We identified 47 papers with original data (31 from animal studies and 16 from human studies) suitable for inclusion according to our aims. We concluded that several observational and intervention studies performed in animal models of dementia (mainly Alzheimer’s disease) support the concept of a gut–brain regulation of cognitive symptoms. Modulation of vagal activity and bacterial synthesis of substances active on host neural metabolism, inflammation and amyloid deposition are the main mechanisms involved in this physiopathologic link. Conversely, there is a substantial lack of human data, both from observational and intervention studies, preventing to formulate any clinical recommendation on this topic. Gut microbiota modulation of cognitive function represents, however, a promising area of research for identifying novel preventive and treatment strategies against dementia.

Diverse Profiles of Toll-Like Receptors 2, 4, 7, and 9 mRNA in Peripheral Blood and Biopsy Specimens of Patients with Celiac Disease.

Background and Aims Both adaptive and innate immunity are involved in the development of celiac disease (CD). Altered Toll-like receptors (TLR) expression and activation may be partially responsible for the inflammation and subsequently crypt hyperplasia, but the main driver for inflammation is gliadin-reactive T-cells. Therefore, the aim of this study was to investigate the TLRs 2, 4, 7, and 9 gene expressions in both peripheral blood and intestinal mucosa of patients with celiac disease compared to healthy control (HC). Material and Methods Blood samples from 120 confirmed active CD patients and 120 age- and sex-matched healthy volunteers served as control group were collected during 2015-2016. Also, 20 biopsy specimens from the study group were randomly collected. Total RNA was isolated using a standard commercial kit. The mRNA expression of TLRs was quantified by relative qPCR with β2 microglobulin (β2m) as a reference gene. Results TLR4 (P = 0.01) and TLR9 (P = 0.02) mRNA were significantly elevated in blood samples from CD patients compared to the healthy controls. Moreover, TLR2 (P = 0.03) and TLR4 (P = 0.0003) expression level was increased in CD biopsy specimens compared to controls, whereas expression of TLR9 mRNA was significantly decreased in CD patients. There was no significant difference in the expression of TLR7 in biopsy and blood specimens. Conclusions The alteration of TLR4 and TLR9 expression in the blood and biopsy samples of patients with CD supports the critical role of the innate immune system in the pathogenesis of this disease. Upregulation of TLR4 and TLR9 suggests the contribution of gut microbiota or dysregulation of the immune response to commensal flora in small bowel mucosa in celiac patients.

Impact of HIV and Type 2 diabetes on Gut Microbiota Diversity, Tryptophan Catabolism and Endothelial Dysfunction

HIV infection and type 2 diabetes are associated with altered gut microbiota, chronic inflammation, and increased cardiovascular risk. We aimed to investigate the combined effect of these diseases on gut microbiota composition and related metabolites, and a potential relation to endothelial dysfunction in individuals with HIV-infection only (n = 23), diabetes only (n = 16) or both conditions (n = 21), as well as controls (n = 24). Fecal microbiota was analyzed by Illumina sequencing of the 16 S rRNA gene. Markers of endothelial dysfunction (asymmetric dimethylarginine [ADMA]), tryptophan catabolism (kynurenine/tryptophan [KT]-ratio), and inflammation (neopterin) were measured by liquid chromatography-tandem mass spectrometry. The combination of HIV and type 2 diabetes was associated with reduced gut microbiota diversity, increased plasma KT-ratio and neopterin. Microbial genes related to tryptophan metabolism correlated with KT-ratio and low alpha diversity, in particular in HIV-infected with T2D. In multivariate analyses, KT-ratio associated with ADMA (β = 4.58 [95% CI 2.53–6.63], p < 0.001), whereas microbiota composition per se was not associated with endothelial dysfunction. Our results indicate that tryptophan catabolism may be related to endothelial dysfunction, with a potentially detrimental interaction between HIV and diabetes. The potential contribution of gut microbiota and the impact for cardiovascular risk should be further explored in prospective studies powered for clinical end points.

42.2 INFLAMMATION AND GUT MICROBIOME IN FIRST-EPISODE PSYCHOSIS

BackgroundPatients with first-onset psychosis have evidence of impaired glucose tolerance, but otherwise are metabolically healthy when traditional cardiovascular risk markers are used. After antipsychotic treatment is started, there is rapid weight gain and emergence of dyslipidemias. Weight gain and development of abdominal obesity is accompanied by worsening chronic low-grade inflammation. Activation of innate immunity is often present at the onset of disease. One unexplored mechanism possibly contributing to these problems is altered gut microbiota.MethodsThe Helsinki Early Psychosis Study recruited 97 patients with first-episode psychosis and 62 controls into a longitudinal study. Here, data on longitudinal changes in inflammation, weight gain and abdominal obesity during the first year of treatment in patients with first-episode psychosis is presented and compared with matched healthy controls. Three time points (baseline, 2 months, 12 months) are available for patients and two (baseline, 12 month) for controls. The possible contribution of different antipsychotics will be explored, and whether patients who were no longer using antipsychotics at the one-year follow-up have less problems in these measures. First results regarding the gut microbiome will be presented (Schwarz et al. 2017), and the possible contribution of gut microbiota to inflammation and weight gain in first-episode psychosis explored.ResultsOur previous findings from a subset of the study sample found most marked changes in innate immunity chemokines (Mäntylä et al. 2015), whereas full longitudinal data on 38 cyto- and chemokines will be available at the SIRS congress. As a preliminary result on the longitudinal course of inflammation, high-sensitivity C-reactive protein showed a significant increase during the first year of treatment in patients (median baseline 0.65 mg/l, 2 months 0.79 mg/l and 12 months 1.68 mg/l). Data on PBMC gene expression will also be presented, revealing notable differences related to different antipsychotic use.DiscussionThe findings will be discussed in the context of to what extent they may reflect underlying disease mechanisms and environmental contributions, including gut microbiota alterations, and to what extent inflammation is a secondary phenomenon related to antipsychotic use and weight gain.References1) Mäntylä T, Mantere O, Raij TT, Kieseppä T, Laitinen H, Leiviskä J, Torniainen M, Tuominen L, Vaarala O, Suvisaari J. Altered activation of innate immunity associates with white matter volume and diffusion in first-episode psychosis. PLoS One. 2015 May 13;10(5):e0125112.2)Schwarz E, Maukonen J, Hyytiäinen T, Kieseppä T, Orešič M, Sabunciyan S, Mantere O, Saarela M, Yolken R, Suvisaari J. Analysis of microbiota in first episode psychosis identifies preliminary associations with symptom severity and treatment response. Schizophr Res. 2017 [Epub ahead of print]

Short‐term captopril treatment causes persistently decreased blood pressure associated with long‐lasting shifts in gut microbiota and improvement in gut pathology

IntroductionAngiotensin‐converting enzyme inhibitors such as captopril (CAP), are widely used and preferred treatment option for high blood pressure (BP) control. It has been shown that only ~30% of orally administrated CAP is absorbed by the rat intestine. Increasing importance of gut microbiota in drug metabolism coupled with dysbiosis linked to high BP has raised interesting questions regarding the role of gut microbial community in drug‐resistant hypertension. In addition, previous studies found sustained effects of CAP on BP after withdrawal of CAP in spontaneously hypertensive rats (SHR). Thus, our objective was to test the effects of CAP on gut microbiota and whether any alteration in gut microbiota and pathology is preserved after withdrawal of CAP, which may be involved in the maintenance of lowered BP.MethodsMale normotensive Wistar Kyoto (WKY) and SHR were kept either with or without CAP (250mg/day/kg) in the drinking water for 4 weeks, and then all rats were placed on regular water until week 16. BP was measured by tail cuff on week 3 (CAP ON) and week 6 (CAP OFF). Fecal microbiota collected on week 4 (CAP ON) and week 8 (CAP OFF) was analyzed. Intestinal morphology was evaluated at week 16.ResultsCAP treatment for 4 weeks altered gut microbial composition in WKY and SHR, and the altered gut microbiota was preserved 4 weeks after CAP withdrawal, characterized by aggregated clusters of CAP ON and CAP OFF groups for both WKY and SHR in principal coordinate analysis. Microbial richness was significantly increased in SHR in the presence of CAP for 4 weeks (control: 6386±514.6 vs CAP ON: 8637±271.8, P=0.0014), and maintained a trend to be increased at 8 weeks (control: 6386±514.6 vs CAP OFF: 7601±355.5, P=0.0688). Intestine H&amp;E staining demonstrated significant and sustained improvement in the fibrotic area (control: 12.98±0.81% vs CAP OFF: 10.23±0.69%, P=0.036), goblet cell number (control: 39±3.57 cells/villi vs CAP OFF: 65±5.29 cells/villi, P=0.0006) and villi length (control: 271.4±9.85 μm vs CAP OFF: 388.8±12.29 μm, P&lt;0.0001) in the SHR 12 weeks post‐withdrawal of CAP. In line with microbial and intestinal changes, a significant decrease in systolic BP was observed in the CAP‐treated SHR (control: 166.8±7.1 mmHg vs CAP ON: 107.0±5.4 mmHg, P&lt;0.0001). After withdrawal of CAP, the reduction in systolic BP in CAP‐treated SHR (control: 208.8±3.5 mmHg vs CAP OFF: 182.2±9.5 mmHg, P=0.03) was sustained.ConclusionOral administration of CAP significantly improved gut microbiota and pathology in SHR. Persistent reduction in BP during and post‐withdrawal of CAP was associated with sustained gut microbial alterations and pathological improvement, indicating potential contribution of gut microbiota in the CAP‐mediated reduction in BP.Support or Funding InformationU.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) ‐ 5R01HL033610‐32 [Raizada]U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) ‐ 5R01HL132448‐02 [Raizada]This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Gut microbiota mediates diurnal variation of acetaminophen induced acute liver injury in mice

Acetaminophen (APAP) induced hepatotoxicity is a leading cause of acute liver failure worldwide. It is well established that the liver damage induced by acetaminophen exhibits diurnal variation. However, the detailed mechanism for the hepatotoxic variation is not clear. Herein, we aimed to determine the relative contributions of gut microbiota in modulating the diurnal variation of hepatotoxicity induced by APAP. Male Balb/C mice were treated with or without antibiotics and a single dose of orally administered APAP (300 mg/kg) at ZT0 (when the light is on-start of resting period) and ZT12 (when the light is off-start of active period). In agreement with previous findings, hepatic injury was markedly enhanced at ZT12 compared with ZT0. Interestingly, upon antibiotic treatment, ZT12 displayed a protective effect against APAP hepatotoxicity similar to ZT0. Moreover, mice that received the cecal content from ZT12 showed more severe liver damage than mice that received the cecal content from ZT0. 16S sequencing data revealed significant differences in the cecal content between ZT0 and ZT12 in the compositional level. Furthermore, metabolomic analysis showed that the gut microbial metabolites were also different between ZT0 and ZT12. Specifically, the level of 1-phenyl-1,2-propanedione (PPD) was significantly higher at ZT12 than ZT0. Treatment with PPD alone did not cause obvious liver damage. However, PPD synergistically enhanced APAP-induced hepatic injury in vivo and in vitro. Finally, we found Saccharomyces cerevisiae, which could reduce intestinal PPD levels, was able to markedly alleviate APAP-induced liver damage at ZT12. The gut microbial metabolite PPD was responsible, at least in part, for the diurnal variation of hepatotoxicity induced by APAP by decreasing glutathione levels. Acetaminophen (APAP) induced acute liver failure because of over dose is a leading public health problem. APAP-induced liver injury exhibits diurnal variation, specifically APAP causes more severe liver damage when taken at night compared with in the morning. Herein, we showed that gut microbial metabolite, 1-phenyl-1,2-propanedione is involved in the rhythmic hepatotoxicity induced by APAP, by depleting hepatic glutathione (an important antioxidant) levels. Our data suggest gut microbiota may be a potential target for reducing APAP-induced acute liver injury.

Optimization of fecal sample processing for microbiome study - The journey from bathroom to bench.

Although great interest has been displayed by researchers in the contribution of gut microbiota to human health, there is still no standard protocol with consensus to guarantee the sample quality of metagenomic analysis. Here we reviewed existing methodology studies and present suggestions for optimizing research pipeline from fecal sample collection to DNA extraction. First, we discuss strategies of clinical metadata collection as common confounders for microbiome research. Second, we propose general principles for freshly collected fecal sample and its storage and share a DIY stool collection kit protocol based on the manual procedure of Human Microbiome Project (HMP). Third, we provide a useful information of collection kit with DNA stabilization buffers and compare their pros and cons for multi-omic study. Fourth, we offer technical strategies as well as information of novel tools for sample aliquoting before long-term storage. Fifth, we discuss the substantial impact of different DNA extraction protocols on technical variations of metagenomic analysis. And lastly, we point out the limitation of current methods and the unmet needs for better quality control of metagenomic analysis. We hope the information provided here will help investigators in this exciting field to advance their studies while avoiding experimental artifacts.

Gut Microbiota Dysbiosis in Cafeteria Diet Fed Sprague Dawley Rats

Diet plays a major role in the body physiology and metabolism. The quantity, nature and stability of the macronutrients present in the diet have a major impact on the composition of gut microbiota. Gut microbiota plays a major role in the body metabolism and leads to obese or lean phenotype. Bacteriodetes, Firmicutes, Proteobacteria and Actinobacteria are the major microbes that inhabit in the region of the gut. We made an attempt to study the effects of Cafeteria (CAF) diets and normal chow diets on diet consumption, weight gain, metabolism and composition of gut microbiota in fecal and cecum samples from three weeks old Sprague Dawley (SD) rats (n = 18/group) using 16S rDNA high throughput sequencing. Results revealed that distinctive diet based phenotypical changes were observed in some of the Cafeteria diet fed rats. Interestingly, some weight gain resistant (WGR) animals in Cafeteria diet fed groups show similar trend like that of control normal chow fed rats. Fecal microbiome analysis indicates that the ratio of Bacteriodetes is higher than the Firmicutes in cecum samples of Cafeteria diet fed rats whereas no significant difference is found in fecal samples of Cafeteria diet fed rats and as well as in control rats. Further analysis of other taxa at the level of family and genus of microbial abundance are also discussed. Our study suggests that contribution of gut microbiota towards obesity is not at the phylum level, and microbiome composition even at the level of species or strain may exert impact on the metabolism of the Cafeteria diet.

Gut microbiota in 2017: Contribution of gut microbiota-host cooperation to drug efficacy.

2017 has witnessed key advances in knowledge about the metabolic capacities of the gut microbiota, enabling the progression of our understanding of the principles driving xenobiotic–bacteria–host interplay. This research paves the way for the long road towards personalized medicine and nutrition, which could be based on gut microbial metabolism.

Impact of gut microbiota on drug metabolism: an update for safe and effective use of drugs.

The intestinal mucosa and liver have long been considered as the main sites of drug metabolism, and the contribution of gut microbiota to drug metabolism has been under-estimated. However, it is now generally accepted that the gut microbiota plays an important role in drug metabolism prior to drug absorption or during enterohepatic circulation via various microbial enzymatic reactions in the intestine. Moreover, some drugs are metabolized by gut microbiota to specific metabolite(s) that cannot be formed in the liver. More importantly, the metabolism of drugs by gut microbiota prior to absorption can alter the systemic bioavailability of certain drugs. Therefore, understanding drug metabolism by gut microbiota is critical for explaining changes in the pharmacokinetics of drugs, which may cause significant alterations in drug-induced pharmacodynamics and toxicities. In this review, we describe recent progress with regard to the role of metabolism by gut microbiota in some drug-induced alterations of either pharmacological or toxicological effects to emphasize the clinical importance of gut microbiota for safe and effective use of drugs.

Gut Microbial Dysbiosis Is Associated with Altered Hepatic Functions and Serum Metabolites in Chronic Hepatitis B Patients.

Chronic hepatitis B (CHB) is a global epidemic disease that results from hepatitis B virus (HBV) infection and may progress to severe liver failure, including liver fibrosis, cirrhosis and hepatocellular carcinoma. Previous evidence has indicated that the dysbiosis of gut microbiota occurs after liver virus infection and is associated with severe liver disease. The aim of this study is to elucidate the compositional and functional characteristics of the gut microbiota in early-stage CHB and to understand their influence on disease progression. We investigated the gut microbial composition of stool samples from 85 CHB patients with low Child-Pugh scores and 22 healthy controls using the Illumina MiSeq sequencing platform. Furthermore, the serum metabolome of 40 subjects was measured by gas chromatography mass spectrometry. Compared with the controls, significant alteration in the gut microbiota was observed in the CHB patients; 5 operational taxonomic units (OTUs) belonging to Actinomyces, Clostridium sensu stricto, unclassified Lachnospiraceae and Megamonas were increased, and 27 belonging to Alistipes, Asaccharobacter, Bacteroides, Butyricimonas, Clostridium IV, Escherichia/Shigella, Parabacteroides, Ruminococcus, unclassified Bacteria, unclassified Clostridiales, Unclassified Coriobacteriaceae, unclassified Enterobacteriaceae, unclassified Lachnospiraceae and unclassified Ruminococcaceae were decreased. The inferred metagenomic information of gut microbiota in CHB showed 21 enriched and 17 depleted KEGG level-2 pathways. Four OTUs, OTU38 (Streptococcus), OTU124 (Veillonella), OTU224 (Streptococcus), and OTU55 (Haemophilus), had high correlations with hosts' hepatic function indices and 10 serum metabolites, including phenylalanine and tyrosine, which are aromatic amino acids that play pathogenic roles in liver disease. In particular, these 4 OTUs were significantly higher in patients with higher Child-Pugh scores, who also showed diminished phenylalanine and tryptophan metabolisms in the inferred gut metagenomic functions. These compositional and functional changes in the gut microbiota in early-stage CHB patients suggest the potential contributions of gut microbiota to the progression of CHB, and thus provide new insight into gut microbiota-targeted interventions to improve the prognosis of this disease.

Strain-level Determination of the Contribution of Gut Microbiota to the Development of Bacteremia in Patients Undergoing Stem Cell Transplantation

BackgroundInfection is a major preventable cause of transplant-related morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HCT). Bacteremia is the most common infectious complication in HCT, often occurring during periods of mucositis when the risk for microbial translocation from the intestine is increased. Prior research in HCT patients using 16S rRNA sequencing demonstrated that gut microbiota dominance by either Enterococcus spp. or Proteobacteria was associated with the development of bacteremia with Enterococcus spp. and Gram-negative organisms, respectively. No studies to date, however, have compared bacteremia isolates and gut microbiota samples at a strain-specific level using next-generation shotgun metagenomic sequencing (NGS).MethodsIn order to assess the degree of genetic similarity between bacteremia isolates and the gut microbiota, we identified patients who had undergone HCT at Stanford and developed a bacteremia between October 2015 and September 2016 for whom we had both saved blood culture isolates and stool samples within 30 days preceding bacteremia. We identified 15 patients from whom we had 17 bacteremia isolates, and performed NGS (Illumina HiSeq 4000) on stool and isolate DNA. We generated draft assemblies of isolate genomes using the SPAdes assembler, and aligned stool metagenomic reads to the draft isolate genomes using Bowtie2, filtering reads for perfect end-to-end alignment.ResultsEnteric gram-negative bacteremia isolates were identical to those in the gut microbiota, as has been demonstrated in prior studies using older strain-typing Methods. Surprisingly, we also identified gram-positive organisms that were identical in both the blood and stool prior to bacteremia, which challenges existing dogma regarding sources of gram-positive bacteremia-causing organisms.ConclusionUsing a highly sensitive and accurate NGS-based strain typing method, we provide evidence of translocation of organisms from the gut microbiota and subsequent bacteremia. The gut was confirmed as a source for both classic enteric gram-negative and classically non-enteric Gram-positive bacteremia in HCT patients. These findings may have implications for the origins of bacteremia in HCT patients previously classified as CLABSIs.Disclosures A. Bhatt, Janssen Human Microbiome Institute / Johnson and Johnson: Consultant, Consulting fee

HUMAN GUT MICROBIOTA AND ITS EFFECTS ON HUMAN HEALTH IN NORMAL AND PATHOLOGICAL CONDITIONS

The medical research of the last 1-2 decades allows us to look at the human gut microbiota and microbiome as to a structure that can promote health and sometimes initiate disease. It works like an endocrine organ: releasing specific metabolites, using environmental inputs, e.g. diet, or acting through its structural compounds, that signal human host receptors, to finally contributing to the pathogenesis of several gastrointestinal and non-gastrointestinal diseases. The same commensal microbes were found as shapers of the human host response to drugs (cardiovascular, oncology etc.). New technologies played an important role in these achievements, facilitating analysis of the genetic and metabolic profile of this microbial community. Once the inputs, the pathways and a lot of human host receptors were highlighted, the scientists were encouraged to go further into research, in order to develop new pathogenic therapies, targeting the human gut flora. Dual therapies, evolving these “friend microbes”, are another actual research subjects. This review gives an update on the current knowledge in the area of microbiota disbalances under environmental factors, the contribution of gut microbiota and microbiome to the pathogenesis of obesity, obesity associated metabolic disorders and cardiovascular disease, as well as new perspectives in preventing and treating these diseases, with high prevalence in contemporary, economically developed societies. It brings the latest and most relevant evidences relating to: probiotics, prebiotics, polyphenols and fecal microbiota transplantation, dietary nutrient manipulation, microbial as well as human host enzyme manipulation, shaping human responses to currently used drugs, manipulating the gut microbiome by horizontal gene transfer.

Microbiota in digestive cancers: our new partner?

Evolution led to an essential symbiotic relationship between the host and commensal microbiota, regulating physiological functions including inflammation and immunity. This equilibrium can be disturbed by environmental factors such as lifestyle, diet or antibiotic pressure, contributing to create a dysbiosis. There is much evidence about the gut microbiota's contribution to carcinogenesis, involving pro-inflammatory and immunosuppressive signals. At the same time, it seems to be increasingly clear that commensal microbes can modulate cancer therapy efficacy and safety, in particular, innovating treatments as immune checkpoint inhibitors. In this review, we discuss how the microbiota can promote digestive tract carcinogenesis, responsiveness to cancer therapeutics and cancer-associated complications.

GUT MICROBIOME ALTERATIONS IN ALZHEIMER'S DISEASE AND THE RELATIONSHIP WITH CSF BIOMARKERS

The etiology of dementia due to Alzheimer's disease (AD) is not completely understood. Recent studies suggest that alterations in human gut microbiota contribute to neurological conditions including multiple sclerosis and Parkinson's disease, yet the contribution of the gut microbiota to the development of AD neuropathology and dementia is unknown. We investigated this by examining gut microbiota among participants in the Wisconsin Registry for Alzheimer's Prevention and Wisconsin ADRC, with and without a clinical diagnosis of mild cognitive impairment (MCI) or AD. Secondary analysis examined the extent to which cerebrospinal fluid (CSF) biomarkers of AD were associated with the composition of the gut microbiome. Bacterial 16S rRNA gene sequencing was performed on DNA extracted from fecal samples collected from AD/MCI patients (n=16), age- and sex-matched control participants (n=18), and asymptomatic middle-aged participants (n=52). Sequence processing was performed in mothur, and richness, alpha, and beta diversity metrics were calculated using normalized OTU-level data. Metastats was used to detect differential abundance between AD/MCI and controls at the family taxonomic level. Among participants who had previously undergone lumbar puncture (n=31), we tested the relationship between microbiome phylogenetic diversity and CSF levels of Aβ42 and phosphorylated tau. The microbiome of AD/MCI participants showed significantly less richness and alpha diversity (Figure 1), and a significant difference in beta diversity compared to control participants. AD/MCI participants showed elevated abundance of Lachnospiraceae, Bacteroidaceae, and Streptococcaceae, with decreased levels of Ruminococcaceae (Figure 2). Among participants with CSF data, an interaction between diagnosis and phylogenetic diversity was observed for CSF phosphorylated tau and the ratio of ptau/Aβ42 (Figure 3). Decreased richness and alpha diversity in the microbiome of AD/MCI participants parallels results observed in other conditions associated with gut dysbiosis including diabetes and obesity. Moreover, we observed that decreased microbial diversity was associated with greater AD pathology in CSF. Additional work, including animal studies and longitudinal human studies, are needed to determine the potential contribution of gut microbiota to the development of AD. Gut microbiome in AD/MCI displays decreased richness (Abundance-based coverage estimator (ACE), Chaol) and alpha diversity (Shannon Index, Faith's Phylogenetic Diversity) metrics. *p<0.05. Relative abundance differences at family taxonomic level between AD/MCI and age- and sex-matched control participants as identified by Metastats. *p<0.05 (FDR). Relationship between gut microbiome phylogenetic diversity and CSF phosphorylated tau and the ratio of tau/Aβ42.

Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy

Gut microbiota are linked to chronic inflammation and carcinogenesis. Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer patients. Here, we investigated the contribution of gut microbiota to chemoresistance in patients with colorectal cancer. We found that Fusobacterium (F.) nucleatum was abundant in colorectal cancer tissues in patients with recurrence post chemotherapy, and was associated with patient clinicopathological characterisitcs. Furthermore, our bioinformatic and functional studies demonstrated that F.nucleatum promoted colorectal cancer resistance to chemotherapy. Mechanistically, F.nucleatum targeted TLR4 and MYD88 innate immune signaling and specific microRNAs to activate the autophagy pathway and alter colorectal cancer chemotherapeutic response. Thus, F.nucleatum orchestrates a molecular network of the Toll-like receptor, microRNAs, and autophagy to clinically, biologically, and mechanistically control colorectal cancer chemoresistance. Measuring and targeting F.nucleatum and its associated pathway will yield valuable insight into clinical management and may ameliorate colorectal cancer patient outcomes.

Intestinal barrier disruption inversely regulates liver inflammation via IL-10-producing macrophages

Abstract The gut-liver axis is a clinical topic as a potential therapeutic target of liver diseases. The interaction between microbial products and immune responses in the liver is still unknown. In the current study, we have demonstrated IL-10-producing CD11b+ F4/80+ macrophages contribute to immune tolerance in the inflamed liver under diminished intestinal barrier function in murine tandem model of dextran sulfate sodium (DSS)-colitis and Concanavalin A (ConA)-hepatitis. DSS-ConA mice with increased intestinal permeability developed less liver injury compared with DW-ConA mice. Of note, the severity of colitis was inversely correlated with subsequently induced liver injury. In DSS-ConA livers, increased CD11b+ macrophages showed regulatory characteristics with IL-10 production in vitro. Pretreatment with α-IL-10 antibody partially exacerbated the suppressed liver injury by DSS-ConA in vivo. Furthermore, pretreatment with CD11b+ macrophages derived from DSS-ConA livers protected mice from the subsequent liver injury. Mechanistically, we observed the contribution of gut microbiota, as the immunological tolerance induced by DSS-ConA is partially ablated by gut sterilization. Pretreatment with the portal serum derived from DSS-ConA mice partially protected mice from the subsequent liver injury. These results suggest that altered gut microbiota and the metabolites that pass through the portal vein with disrupted intestinal barrier directly gave rise to immunological permissiveness against the excessive stimulation in the liver. This study clarified the contribution of the gut-liver axis in the maintenance of immune balance in the liver and highlighted the microbiota as a potential therapeutic target for liver diseases.

Evaluating the Contribution of Gut Microbiota to the Variation of Porcine Fatness with the Cecum and Fecal Samples.

Microbial community in gastrointestinal tract participates in the development of the obesity as well as quite a few metabolic diseases in human. However, there are few studies about the relationship between gut microbiota and porcine fatness. Here, we used high-throughput sequencing to perform 16S rRNA gene analysis in 256 cecum luminal samples from Erhualian pigs and 244 stools from Bamaxiang pigs, and adopted a two-part model statistical method to evaluate the association of gut microbes with porcine fatness. As the results, we identified a total of 6 and 108 operational taxonomic units (OTUs), and 9 and 10 bacterial taxa which showed significant associations with fatness traits in the stool and cecum samples, respectively. Cross-validation analysis indicated that gut microbiome showed the largest effect on abdominal adipose by explaining 2.73% phenotypic variance of abdominal fat weight. Significantly more fatness-associated OTUs were identified in the cecum samples than that in the stools, suggesting that cecum luminal samples were better used for identification of fatness-associated microbes than stools. The fatness-associated OTUs were mainly annotated to Lachnospiraceae, Ruminococcaceae, Prevotella, Treponema, and Bacteroides. These microbes have been reported to produce short-chain fatty acids by fermenting dietary indigested polysaccharide and pectin. The short-chain fatty acids can regulate host body energy homeostasis, protect host from inflammation and inhibit fat mass development. Our findings suggested that the gut microbiome may be an important factor modulating fatness in pigs.

The antibiotic resistome of swine manure is significantly altered by association with the Musca domestica larvae gut microbiome.

The overuse of antibiotics as veterinary feed additives is potentially contributing to a significant reservoir of antibiotic resistance in agricultural farmlands via the application of antibiotic-contaminated manure. Vermicomposting of swine manure using housefly larvae is a promising biotechnology for waste reduction and control of antibiotic pollution. To determine how vermicomposting influences antibiotic resistance traits in swine manure, we explored the resistome and associated bacterial community dynamics during larvae gut transit over 6 days of treatment. In total, 94 out of 158 antibiotic resistance genes (ARGs) were significantly attenuated (by 85%), while 23 were significantly enriched (3.9-fold) following vermicomposting. The manure-borne bacterial community showed a decrease in the relative abundance of Bacteroidetes, and an increase in Proteobacteria, specifically Ignatzschineria, following gut transit. ARG attenuation was significantly correlated with changes in microbial community succession, especially reduction in Clostridiales and Bacteroidales. Six genomes were assembled from the manure, vermicompost (final product) and gut samples, including Pseudomonas, Providencia, Enterococcus, Bacteroides and Alcanivorax. Transposon-linked ARGs were more abundant in gut-associated bacteria compared with those from manure and vermicompost. Further, ARG-transposon gene cassettes had a high degree of synteny between metagenomic assemblies from gut and vermicompost samples, highlighting the significant contribution of gut microbiota through horizontal gene transfer to the resistome of vermicompost. In conclusion, the larvae gut microbiome significantly influences manure-borne community succession and the antibiotic resistome during animal manure processing.

Gut microbiota – a new companion on the path of cardiovascular diseases progression: surprising roles of long-time neighbors

The last decade is marked by the significant reinterpretation of the gut microbiota contribution to chronic disease progression. The researchers’ careful attention is focused on improving the understanding of the metabolic pathways of two dietary compounds – choline and L-carnitine, which stand at the origins of trimethylamine N-oxide (TMAO) formation. This small molecule of great expectations has gained an impressive appreciation due to its ability to promote atherogenesis, and thus increasing the risk of major adverse cardiovascular events and affecting patients’ prognosis. This paper aims to discuss updated concept of microbiota-dependent cardiometabolic consequences of consumption of food rich in quaternary amines as well as to touch upon the currently existing interventions in TMAO production, their limitations and future scientific directions.