Alterations In Gut Microbiome Research Articles

The microbiome: a link between obesity and breast cancer risk

Globally, breast cancer is the leading cause of cancer incidence and mortality among all female cancers. Hereditary factors only account for 5-10% of breast cancers, highlighting the importance of non-hereditary factors, such as obesity. The increasing prevalence of obesity underscores the need to understand its contribution to breast cancer risk. Multiple mechanisms may mediate pro-carcinogenic effects of obesity, including altered adipokine levels, local and systemic inflammation, disruption of insulin and insulin-like growth factor signaling, increased estrogen levels, and alterations of the microbiome. In this review, we focus on the link between gut microbiome alterations and breast cancer risk in the context of obesity. First, we discuss how obesity influences the gut microbiome. Next, we describe the effect of such microbiome alterations on breast carcinogenesis, highlighting underlying molecular mechanisms. Finally, we review preclinical data on the interactions between host and bacteria, current challenges to study the obesity-microbiome connection, and future perspectives in this field.

Implications of intestinal microecology and immune function alterations for immunotherapy outcomes in advanced unresectable lung adenocarcinoma.

This investigation aims to explore alterations in intestinal microecology and immune function among patients with advanced, unresectable lung adenocarcinoma undergoing different outcomes from immunotherapy. A cohort of 30 patients diagnosed with advanced unresectable lung adenocarcinoma received sintilimab immunotherapy as a monotherapy. Post four treatment cycles, efficacy was assessed, leading to the segregation of patients into two distinct cohorts: those responsive to treatment and those nonresponsive. Analysis involved observing variations in the abundance, distribution, and composition of fecal intestinal microorganisms pretreatment and posttreatment via 16S rRNA gene sequencing. In this study involving 30 advanced lung adenocarcinoma patients, significant observations were made regarding the impact of immunotherapy on immune function and the gut microbiome composition. Patients were divided into treatment and control groups, revealing that immunotherapy led to a significant increase in CD4+ T cells and a decrease in CD8+ T cells among the treatment-responsive individuals, indicating an enhanced immune response. Furthermore, an in-depth analysis of the gut microbiome showed an increase in diversity and abundance of beneficial bacteria such as Faecalibacterium and Subdoligranulum in the treatment group. These findings highlight the dual effect of immunotherapy on modulating immune function and altering gut microbiome diversity, suggesting its potential therapeutic benefits in improving the health status of patients with advanced lung adenocarcinoma. The structuring of gut flora plays a pivotal role in augmenting the efficacy of anti-tumor immunotherapy, underscoring the interplay between intestinal microecology and immune response in cancer treatment outcomes.

Genetic and microbial determinants of azoxymethane-induced colorectal tumor susceptibility in Collaborative Cross mice and their implication in human cancer

ABSTRACT The insights into interactions between host genetics and gut microbiome (GM) in colorectal tumor susceptibility (CTS) remains lacking. We used Collaborative Cross mouse population model to identify genetic and microbial determinants of Azoxymethane-induced CTS. We identified 4417 CTS-associated single nucleotide polymorphisms (SNPs) containing 334 genes that were transcriptionally altered in human colorectal cancers (CRCs) and consistently clustered independent human CRC cohorts into two subgroups with different prognosis. We discovered a set of genera in early-life associated with CTS and defined a 16-genus signature that accurately predicted CTS, the majority of which were correlated with human CRCs. We identified 547 SNPs associated with abundances of these genera. Mediation analysis revealed GM as mediators partially exerting the effect of SNP UNC3869242 within Duox2 on CTS. Intestine cell-specific depletion of Duox2 altered GM composition and contribution of Duox2 depletion to CTS was significantly influenced by GM. Our findings provide potential novel targets for personalized CRC prevention and treatment.

Ambient long-term exposure to organophosphorus pesticides and the human gut microbiome: an observational study

BackgroundOrganophosphorus pesticides (OP) have been associated with various human health conditions. Animal experiments and in-vitro models suggested that OP may also affect the gut microbiota. We examined associations between ambient chronic exposure to OP and gut microbial changes in humans.MethodsWe recruited 190 participants from a community-based epidemiologic study of Parkinson’s disease living in a region known for heavy agricultural pesticide use in California. Of these, 61% of participants had Parkinson’s disease and their mean age was 72 years. Microbiome and predicted metagenome data were generated by 16S rRNA gene sequencing of fecal samples. Ambient long-term OP exposures were assessed using pesticide application records combined with residential addresses in a geographic information system. We examined gut microbiome differences due to OP exposures, specifically differences in microbial diversity based on the Shannon index and Bray–Curtis dissimilarities, and differential taxa abundance and predicted Metacyc pathway expression relying on regression models and adjusting for potential confounders.ResultsOP exposure was not associated with alpha or beta diversity of the gut microbiome. However, the predicted metagenome was sparser and less evenly expressed among those highly exposed to OP (p = 0.04). Additionally, we found that the abundance of two bacterial families, 22 genera, and the predicted expression of 34 Metacyc pathways were associated with long-term OP exposure. These pathways included perturbed processes related to cellular respiration, increased biosynthesis and degradation of compounds related to bacterial wall structure, increased biosynthesis of RNA/DNA precursors, and decreased synthesis of Vitamin B1 and B6.ConclusionIn support of previous animal studies and in-vitro findings, our results suggest that ambient chronic OP pesticide exposure alters gut microbiome composition and its predicted metabolism in humans.

Gut Microbial Dysbiosis Differs in Two Distinct Cachectic Tumor-Bearing Models Consuming the Same Diet.

The impact of cancer cachexia on the colonic microbiota is poorly characterized. This study assessed the effect of two cachectic-producing tumor types on the gut microbiota to determine if a similar dysbiosis could be found. In addition, it was determined if a diet containing an immunonutrient-rich food (walnuts) known to promote the growth of probiotic bacteria in the colon could alter the dysbiosis and slow cachexia. Male Fisher 344 rats were randomly assigned to a semi-purified diet with or without walnuts. Then, within each diet group, rats were further assigned randomly to a treatment group: tumor-bearing ad libitum fed (TB), non-tumor-bearing ad libitum fed (NTB-AL), and non-tumor-bearing group pair-fed to the TB (NTB-PF). The TB group was implanted either with the Ward colon carcinoma or MCA-induced sarcoma, both transplantable tumor lines. Fecal samples were collected after the development of cachexia, and bacteria species were identified using 16S rRNA gene analysis. Both TB groups developed cachexia but had a differently altered gut microbiome. Beta diversity was unaffected by treatment (NTB-AL, TB, and NTB-PF) regardless of tumor type but was affected by diet. Also, diet consistently changed the relative abundance of several bacteria taxa, while treatment and tumor type did not. The control diet increased the abundance of A. Anaeroplasma, while the walnut diet increased the genus Ruminococcus. There were no common fecal bacterial changes characteristic of cachexia found. Diet consistently changed the gut microbiota, but these changes were insufficient to slow the progression of cachexia, suggesting cancer cachexia is more complex than a few gut microbiota shifts.

Gut microbiome and metabolome profiling in Framingham heart study reveals cholesterol-metabolizing bacteria

Accumulating evidence suggests that cardiovascular disease (CVD) is associated with an altered gut microbiome. Our understanding of the underlying mechanisms has been hindered by lack of matched multi-omic data with diagnostic biomarkers. To comprehensively profile gut microbiome contributions to CVD, we generated stool metagenomics and metabolomics from 1,429 Framingham Heart Study participants. We identified blood lipids and cardiovascular health measurements associated with microbiome and metabolome composition. Integrated analysis revealed microbial pathways implicated in CVD, including flavonoid, γ-butyrobetaine, and cholesterol metabolism. Species from the Oscillibacter genus were associated with decreased fecal and plasma cholesterol levels. Using functional prediction and invitro characterization of multiple representative human gut Oscillibacter isolates, we uncovered conserved cholesterol-metabolizing capabilities, including glycosylation and dehydrogenation. These findings suggest that cholesterol metabolism is a broad property of phylogenetically diverse Oscillibacter spp., with potential benefits for lipid homeostasis and cardiovascular health.

Antibiotics within first year are linked to infant gut microbiome disruption and elevated atopic dermatitis risk

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in both pediatric and adult populations. The development of AD has been linked to antibiotic usage, which causes perturbation of the microbiome and has been associated with abnormal immune system function. However, imbalances in the gut microbiome itself associated with antibiotic usage have been inconsistently linked to AD. This study aimed to elucidate the timing and specific factors mediating the relationship between systemic (oral or intravenous) antibiotic usage and AD. We used statistical modelling and differential analysis to link CHILD participants' history of antibiotic usage and early-life gut microbiome alterations to atopic dermatitis. Here we report that systemic antibiotics during the first year of life, as compared to later, are associated with AD risk (adjusted odds ratio (aOR) = 1.81 [95% CI = 1.28 - 2.57], p < 0.001), with an increased number of antibiotic courses corresponding to a dose-response-like increased risk of AD risk (1 course: aOR = 1.67 [95% CI = 1.17 - 2.38]; 2 or more courses: aOR = 2.16 [95% CI = 1.30 - 3.59]). Further, we demonstrate that microbiome alterations associated with both AD and systemic antibiotic usage fully mediate the effect of antibiotic usage on the development of AD (βindirect = 0.072, p < 0.001). Alterations in the 1-year infant gut microbiome of participants who would later develop AD included increased Tyzzerella nexilis, increased monosaccharide utilization, and parallel decreased Bifidobacterium, Eubacterium spp., and fermentative pathways. Our findings indicate that early-life antibiotic usage, especially in the first year of life, modulates key gut microbiome components that may be used as markers to predict and possibly prevent the development of AD.

“Trust Your Gut”: Promising Precision Approaches in Childhood Neuropsychiatric Disorders

The gut-brain axis has been increasingly linked to pediatric neurodevelopmental and neuropsychiatric disorders. Accumulating evidence indicates that there are microbial fingerprints in these conditions, which may lead to personalized therapies. However, few review articles have provided a comprehensive synthesis to guide clinical translation. We aim to summarize current evidence of gut microbiome alterations in these childhood disorders, and opportunities for precision management approaches. There are numerous promising early-life interventions including probiotics and fecal microbial transplants. These treatment modalities may become targeted strategies to reduce both the risk of developing these disorders and their concurrent comorbidity. [ Psychiatr Ann. 2024;54(4):e103–e107.]

Gut microbiome alterations at acute myeloid leukemia diagnosis are associated with muscle weakness and anorexia.

The gut microbiota makes critical contributions to host homeostasis, and its role in the treatment of acute myeloid leukaemia (AML) has attracted attention. We investigated whether the gut microbiome is affected by AML, and whether such changes are associated with cachectic hallmarks. Biological samples and clinical data were collected from 30 antibiotic-free AML patients at diagnosis and matched volunteers (1:1) in a multicenter cross-sectional prospective study. The composition and functional potential of the faecal microbiota were analyzed using shotgun metagenomics. Faecal, blood, and urine metabolomics analyses were performed. AML patients displayed muscle weakness, anorexia, signs of altered gut function, and glycaemic disorders. The composition of the faecal microbiota differed between patients with AML and control subjects, with an increase in oral bacteria. Alterations in bacterial functions and faecal metabolome support an altered redox status in the gut microbiota, which may contribute to the altered redox status observed in patients with AML. Eubacterium eligens, reduced 3-fold in AML patients, was strongly correlated with muscle strength and citrulline, a marker of enterocyte mass and function. Blautia and Parabacteroides, increased in patients with AML, were correlated with anorexia. Several bacterial taxa and metabolites (e.g. Blautia, Prevotella, phenylacetate, and hippurate) previously associated with glycaemic disorders were altered. Our work revealed important perturbations in the gut microbiome of AML patients at diagnosis, which are associated with muscle strength, altered redox status, and anorexia. These findings pave the way for future mechanistic work to explore the function and therapeutic potential of the bacteria identified in this study.

Abstract 753: CEACAM1 induces microbiome and metabolite driven diversion of TGF-β signaling to promote colon cancer

Abstract Background: Colon cancer is rising in younger individuals in the United States. Potential causal factors are altered diets and gut microbiomes. Yet key signaling pathways, host-microbe interactions, and metabolites such as ammonia in cancer remain unclear. CEACAM1 responds to pathogenic microbes, interacts with the TGF-β/SPTBN1 and levels are raised in invasive colon cancer. Alterations in the TGF-β pathway occur ~40% of human GI cancers, and mouse models with disrupted TGF-β signaling (Tgfbr2−/−, Smad4+/−Sptbn1+/−, and Tgfb1−/−) develop colorectal cancer (CRC) that is dependent upon an altered gut microbiome. Our previous studies indicate the lipid metabolites (reactive aldehydes) form toxic adducts with cleaved SPTBN1 and divert TGF-β signaling to pro-oncogenic process. Poor prognosis CRC is associated with raised levels of microbial metabolites, such as ammonia. Thus, we hypothesized that “the intricate relationships among pathogen-binding CEACAM1, the gut microbiome, metabolites such as ammonia, and βII-Spectrin drive colon cancer development”. Methods: We examined gut microbiota composition, immune cell population, inflammation, and cancers in Smad4+/−Sptbn1+/− and Sptbn1LSKO mice fed a normal chow diet or a high-fat diet (HFD). We evaluated CEACAM1 and TGF-β member alterations in in CRCs using TCGA datasets. Alphafold-based molecular modeling predicted interaction sites between βII-Spectrin and CEACAM1 was followed by functional studies. Results: Increased CEACAM1 levels with alterations in TGF-β members were associated with lower survival (TCGA). Mice with disrupted TGF-β signaling (Smad4+/−Sptbn1+/−) develop CRC, have high CEACAM1 levels, and an altered gut microbiome signature. CEACAM1 interacts with βII-Spectrin, and levels are restored to normal in βII-Spectrin LSKO which restores the gut microbiome and blocks inflammation and cancer. Ammonia induces CASPASE-3 mediated cleavage of βII-Spectrin, forms toxic adducts and divert TGF-β signaling to pathological pro-oncogenic signaling, triggering CRC. Conclusion: We have found a critical role for CEACAMs in CRC cancer development, through diverting the TGF-β signaling pathway to a pro-oncogenic phenotype. CEACAM1 and βII-Spectrin are attractive therapeutic targets for CRC. Citation Format: Krishanu Bhowmick, Kazufumi Ohshiro, Xiyan Xiang, Sahara John, Xiaochun Yang, Kevin Idicula, Nicole Beauchemin, Raja Mazumder, Keith A. Crandall, Mohammad I. Hassan, Taj Mohammad, Lopa Mishra. CEACAM1 induces microbiome and metabolite driven diversion of TGF-β signaling to promote colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 753.

Abstract 460: Fecal microRNA and microbiome profiles in colorectal cancer patients: Are they predictor of survival and how do behave in longitudinal samples

Abstract Background: Colorectal cancer (CRC) is characterized by a high complexity that significantly influences treatment response and survival. There is still a lack of prognostic factors after surgery that could help predict postoperative survival. Currently, lymph node metastases are the single most important prognostic factor but it gives no clue on tumor aggressiveness and recurrence. Our group recently contributed to the identification of a fecal microRNA (miRNA) signature that accurately discriminates sporadic CRC and aimed at improving non-invasive diagnosis (Pardini et al, Gastroenterology 2023) as well as altered gut microbiome species associated with CRC (Thomas et al, Nat. Medicine 2019), but there are scanty evidence on the potentiality of such markers for prognosis. Aims: In the same cohort, we investigated if the fecal miRNome and gut microbiome at diagnosis are associated with CRC patients’ prognosis. Moreover, we assessed fecal miRNA in a new set of CRC patients collected longitudinally before and after the surgery to investigate whether such associations reflect miRNA profiles over time. Methods. We performed small RNA and shotgun metagenomic sequencing in stool samples in 3 cohorts from: Italy (IT, 128 CRC), Czech Republic (CZ, 69 CRC), and Turkey (TU, 34 CRC, 40 controls). Stool samples from TU CRC subjects were collected before surgery and after 6 months. Preliminary Results: In the IT and CZ cohorts, an average of 479 fecal miRNAs were detected with 209 differentially expressed (DE) miRNAs significantly associated with survival, including miR-1246 which was present in the CRC-associated signature identified by us. Two miRNAs (miR-197-5p and miR-6081-5p) were significantly down-regulated in patients with the worst prognosis (adj.p&amp;lt;0.01, HR&amp;lt;0.50) in both cohorts. In TU cohort, 494 miRNAs were DE in CRC (pre-surgery) vs controls. Among them, the 25 DE miRNAs detected in our previous work were also significantly altered, including the 5-miRNA CRC signature (miR-149-3p, miR-607-5p, miR-1246, miR-4488, and miR-6777-5p) identified by machine learning. Notably, after 6 months from surgery, levels of such miRNAs reverted to those measured in controls (for miR-1246 p&amp;lt;0.001 in both controls vs pre- and vs post-surgery comparisons). More analyses on the longitudinal fecal miRNA data are ongoing as well as for the metagenome data assessing the abundancies of CRC-associated microbial species before and after tumor resection and their possible association with survival. Conclusions: Fecal miRNAs may serve as biomarkers for CRC prognosis. Following tumor resection, CRC levels of altered miRNAs return in a range comparable with those of healthy controls in a time-dependent manner. These data further support the use of fecal miRNAs as accurate diagnostic CRC biomarkers and provide preliminary information on their possible translation as a prognostic tool. Citation Format: Barbara Pardini, Nazim Arda Keles, Giulio Ferrero, Sonia Tarallo, Giulia Francescato, Amedeo Gagliardi, Virginia Alberini, Carla Di Battista, Veronika Vymetalkova, Fatma Turkoglu, Ozgul Duzgun, Omer Faruk Ozkan, Bilge Guvenc Tuna, Pavel Vodicka, Soner Dogan, Alessio Naccarati. Fecal microRNA and microbiome profiles in colorectal cancer patients: Are they predictor of survival and how do behave in longitudinal samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 460.

Chronic variable stress leads to sex specific gut microbiome alterations in mice

Stress has been implicated in the incidence and severity of psychiatric and gastrointestinal disorders. The immune system is capable of modulating the activity and composition of the gut following stress and vice versa. In this study we sought to examine the sequential relationship between immune signaling and microbiome composition occurring in male and female mice over time using a variable stress paradigm. Tissue was collected prior to, during, and after the stress paradigm from the same mice. Cytokines from plasma and brain were quantified using a multiplexed cytokine assay. Fecal samples were collected at the same timepoints and 16S rRNA amplicon sequencing was performed to determine the relative abundance of microbiota residing in the guts of stressed and control mice. We found sex differences in the response of the gut microbiota to stress following 28 days of chronic variable stress but not 6 days of sub-chronic variable stress. Immune activation was quantified in the nucleus accumbens immediately following Sub-chronic variable when alterations of gut composition had not yet occurred. In both sexes, 28 days of stress induced significant changes in the proportion of Erysipelotrichaceae and Lactobacillaceae, but in opposite directions for male and female mice. Alterations to the gut microbiome in both sexes were associated with changes in cytokines related to eosinophilic immune activity. Our use of an animal stress model reveals the immune mechanisms that may underly changes in gut microbiome composition during and after stress. This study reveals potential drug targets and microbiota of interest for the intervention of stress related conditions.

Microbiota analysis in individuals with type two diabetes mellitus and end‑stage renal disease: A pilot study.

Chronic kidney disease (CKD) is a widespread health concern, which affects ~9.1% of the global population and 12-15% of individuals in upper-middle income countries. Notably, ~2% of patients with CKD progress to end-stage renal disease (ESRD), which leads to a substantial decline in the quality of life, an increased risk of mortality and significant financial burden. Patients with ESRD often still suffer from uremia and uremic syndromes, due to the accumulation of toxins between dialysis sessions and the inadequate removal of protein-bound toxins during dialysis. A number of these toxins are produced by the gut microbiota through the fermentation of dietary proteins or cholines. Furthermore, the gut microbial community serves a key role in maintaining metabolic and immune equilibrium in individuals. The present study aimed to investigate the gut microbiota patterns in individuals with type 2 diabetes mellitus (T2DM) and ESRD via quantitative PCR analysis of the 16S and 18S ribosomal RNA of selected members of the gut microbiota. Individuals affected by both T2DM and ESRD displayed distinctive features within their intestinal microbiota. Specifically, there were increased levels of Gammaproteobacteria observed in these patients, and all subjects exhibited a notably increased presence of Enterobacteriaceae compared with healthy individuals. This particular microbial community has established connections with the presence of inflammatory processes in the colon. Moreover, the elevated levels of Enterobacteriaceae may serve as an indicator of an imbalance in the intestinal microbiota, a condition known as dysbiosis. In addition, the Betaproteobacteria phylum was significantly more prevalent in the stool samples of patients with both T2DM and ESRD when compared with the control group. In conclusion, the present pilot study focused on gut microbiome alterations in T2DM and ESRD. Understanding the relationship between dysbiosis and CKD may identify new areas of research and therapeutic interventions aimed at modulating the gut microbiota to improve the health and outcomes of individuals with CKD and ESRD.

Maternal obesity increases the risk of hepatocellular carcinoma through the transmission of an altered gut microbiome

Maternal obesity increases the risk of hepatocellular carcinoma through the transmission of an altered gut microbiome

Alterations in gut microbiome associated with severity of atopic dermatitis in infants.

Atopic dermatitis (AD) often arises in infancy, and gut microbial dysbiosis is associated with the development of AD. However, less is known about specific changes in early-life gut microbiome associated with AD and AD severity. This study aims to reveal the gut microbial composition and function profiles associated with the severity of AD in infants. Sixty-two infants (mean [SD] age, 4.7[1.9] months) with different severities of AD were enrolled and divided into three groups (mild, moderate and severe) according to the Scoring Atopic Dermatitis (SCORAD) index. The profiles of gut microbial composition and function were analysed by sequencing 16S ribosomal RNA amplicons. Quality of life on children and the family was evaluated using published questionnaires. Decreased levels of Clostridium sensu stricto, Collinsella and increased level of Parabacteroides presented in the severe AD group compared with the mild AD group after adjusting potential confounders (p < 0.05). There were strong positive correlations between the Scoring Atopic Dermatitis (SCORAD) index and the relative abundance (RA) of Bacteroides and functional pathways for metabolism of sphingolipids and glycosphingolipids (p < 0.05). The SCORAD index was negatively correlated with the RA of Clostridium sensu stricto (p < 0.05), and was also positively correlated with the index of quality of life on children and the family (p < 0.05). Discrepancies in gut microbial composition and functional pathways were observed in infants with mild-to-severe AD. Alterations in butyrate-producing bacteria (Clostridium sensu stricto), sphingolipid-producing bacteria (Parabacteroides, Bacteroides), and related functional pathways were associated with the severity of AD infants.

Solid organ transplantation and gut microbiota: a review of the potential immunomodulatory properties of short-chain fatty acids in graft maintenance.

Transplantation is the treatment of choice for several end-stage organ defects: it considerably improves patient survival and quality of life. However, post-transplant recipients may experience episodes of rejection that can favor or ultimately lead to graft loss. Graft maintenance requires a complex and life-long immunosuppressive treatment. Different immunosuppressive drugs (i.e., calcineurin inhibitors, glucocorticoids, biological immunosuppressive agents, mammalian target of rapamycin inhibitors, and antiproliferative or antimetabolic agents) are used in combination to mitigate the immune response against the allograft. Unfortunately, the use of these antirejection agents may lead to opportunistic infections, metabolic (e.g., post-transplant diabetes mellitus) or cardiovascular (e.g., arterial hypertension) disorders, cancer (e.g., non-Hodgkin lymphoma) and other adverse effects. Lately, immunosuppressive drugs have also been associated with gut microbiome alterations, known as dysbiosis, and were shown to affect gut microbiota-derived short-chain fatty acids (SCFA) production. SCFA play a key immunomodulatory role in physiological conditions, and their impairment in transplant patients could partly counterbalance the effect of immunosuppressive drugs leading to the activation of deleterious pathways and graft rejection. In this review, we will first present an overview of the mechanisms of graft rejection that are prevented by the immunosuppressive protocol. Next, we will explain the dynamic changes of the gut microbiota during transplantation, focusing on SCFA. Finally, we will describe the known functions of SCFA in regulating immune-inflammatory reactions and discuss the impact of SCFA impairment in immunosuppressive drug treated patients.

Faecal hsa-miR-7704 inhibits the growth and adhesion of Bifidobacterium longum by suppressing ProB and aggravates hepatic encephalopathy

Both gut microbiome and microRNAs (miRNAs) play a role in the development of hepatic encephalopathy (HE). However, the functional link between the microbiome and host-derived miRNAs in faeces remains poorly understood. In the present study, patients with HE had an altered gut microbiome and faecal miRNAs compared with patients with chronic hepatitis B. Transferring faeces and faecal miRNAs from patients with HE to the recipient mice aggravated thioacetamide-induced HE. Oral gavage of hsa-miR-7704, a host-derived miRNA highly enriched in faeces from patients with HE, aggravated HE in mice in a microbiome-dependent manner. Mechanistically, hsa-miR-7704 inhibited the growth and adhesion of Bifidobacterium longum by suppressing proB. B. longum and its metabolite acetate alleviated HE by inhibiting microglial activation and ammonia production. Our findings reveal the role of miRNA–microbiome axis in HE and suggest that faecal hsa-miR-7704 are potential regulators of HE progression.

Effects of Paraquat, Dextran Sulfate Sodium, and Irradiation on Behavioral and Cognitive Performance and the Gut Microbiome in A53T and A53T-L444P Mice.

Heterozygous carriers of the glucocerebrosidase 1 (GBA) L444P Gaucher mutation have an increased risk of developing Parkinson's disease (PD). The GBA mutations result in elevated alpha synuclein (aSyn) levels. Heterozygous mice carrying one allele with the L444P mutation knocked-into the mouse gene show increased aSyn levels and are more sensitive to motor deficits following exposure to the neurotoxin (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) MPTP than wild-type mice. Paraquat (PQ), a herbicide, increases PD risk in most studies. Its effects on the brain involve alterations in the gut microbiome. Exposure to dextran sulfate sodium (DSS), a mouse model of colitis, can be used to determine whether gut microbiome alterations are sufficient to induce PD-relevant phenotypes. We rederived the A53T-L444P and A53T mouse lines to assess whether PQ, PQ in combination with radiation exposure (IR), and DSS have differential effects in A53T and A53T-L444P mice and whether these effects are associated with alterations in the gut microbiome. PQ and PQ + IR have differential effects in A53T and A53T-L444P mice. In contrast, effects of DSS are only seen in A53T-L444P mice. Exposure and genotype modulate the relationship between the gut microbiome and behavioral performance. The gut microbiome may be an important mediator of how environmental exposures or genetic mutations yield behavioral and cognitive impacts.

Immune checkpoint inhibitor-related colitis in patients on immunotherapy for cancer.

Immune checkpoint inhibitors, a revolutionary class of cancer immunotherapy drugs, have transformed cancer treatment by bolstering antitumor immunity for various advanced-stage solid cancers. The US Food and Drug Administration has approved 7 immune checkpoint inhibitors that target 3 major immune checkpoint proteins: cytotoxic T-lymphocyte-associated protein 4, programmed cell death 1 protein, and programmed cell death 1 ligand 1. In addition to their remarkable efficacy, however, these inhibitors have been observed causing immune-related adverse events, particularly immune checkpoint inhibitor-related colitis, which often results in severe or life-threatening clinical issues. The diagnosis of immune checkpoint inhibitor-related colitis relies on incorporation of clinical evaluation as well as endoscopic and histopathologic examination, with exclusion of other potential etiologies. The common histopathologic manifestations of immune checkpoint inhibitor-related colitis are acute active colitis, chronic active colitis, microscopic colitis (collagenous or lymphocytic), and ischemic colitis, with patterns overlapping. Notably, enterocyte apoptosis is a unique feature of immune checkpoint inhibitor toxicity. The proposed mechanisms for the pathogenesis of immune checkpoint inhibitor-related colitis are primarily associated with autoimmune-type dysregulation and gut microbiome alteration. This review summarizes the clinical and pathologic characteristics of immune checkpoint inhibitor-related colitis and elucidates its underlying pathogenic mechanisms. Future successful management of this form of colitis relies on our comprehension of the intricate interplay between tumoral and systemic immune responses to immune checkpoint inhibitors and innovative approaches to modify these responses, along with specific immune cell populations, to preclude immune-related adverse events while achieving antitumor therapeutic outcomes.

Antibacterial mouthwash alters gut microbiome, reducing nutrient absorption and fat accumulation in Western diet-fed mice

Prolonged use of antibacterial mouthwash is linked to an increased risk of systemic disease. We aimed to investigate if disturbing the oral microbiota would impact the lower gut microbiome with functional effects in diet-induced obesity. Mice were exposed to oral chlorhexidine and fed a Western diet (WD). Food intake and weight gain were monitored, and metabolic function, blood pressure, and microbiota were analyzed. Chlorhexidine reduced the number of viable bacteria in the mouth and lowered species richness in the gut but with proportional enrichment of some bacteria linked to metabolic pathways. In mice fed a Western diet, chlorhexidine reduced weight gain, body fat, steatosis, and plasma insulin without changing caloric intake, while increasing colon triglycerides and proteins, suggesting reduced absorption of these nutrients. The mechanisms behind these effects as well as the link between the oral microbiome and small intestinal function need to be pinpointed. While the short-term effects of chlorhexidine in this model appear beneficial, potential long-term disruptions in the oral and gut microbiota and possible malabsorption should be considered.