Novel Insights Into the Interactions Between the Gut Microbiome, Inflammasomes, and Gasdermins During Colorectal Cancer

Colorectal cancer (CRC) is one of the most prevalent and deadly forms of cancer in Western countries. Inflammation is a well-known driver of colonic carcinogenesis; however, its role in CRC extends beyond colitis-associated cancer. Over the last decades, numerous associations between intestinal dysbiosis and CRC have been identified, with more recent studies providing mechanistic evidence of a causative relationship. Nonetheless, much remains to be discovered regarding the precise implications of microbiome alterations in the pathogenesis of CRC. Research confirms the importance of a bidirectional crosstalk between the gut microbiome and the mucosal immune system in which inflammasomes, multiprotein complexes that can sense “danger signals,” serve as conduits by detecting microbial signals and activating innate immune responses, including the induction of microbicidal activities that can alter microbiome composition. Current evidence strongly supports an active role for this “inflammasome–microbiome axis” in the initiation and development of CRC. Furthermore, the gasdermin (GSDM) family of proteins, which are downstream effectors of the inflammasome that are primarily known for their role in pyroptosis, have been recently linked to CRC pathogenesis. These findings, however, do not come without controversy, as pyroptosis is reported to exert both anti- and protumorigenic functions. Furthermore, the multi-faceted interactions between GSDMs and the gut microbiome, as well as their importance in CRC, have only been superficially investigated. In this review, we summarize the existing literature supporting the importance of the inflammasome–microbiota axis, as well as the activation and function of GSDMs, to gain a better mechanistic understanding of CRC pathogenesis.

Intestinal Taxa Abundance and Diversity in Inflammatory Bowel Disease Patients: An Analysis including Covariates and Confounders

Intestinal dysbiosis has been widely documented in inflammatory bowel diseases (IBDs) and is thought to influence the onset and perpetuation of gut inflammation. However, it remains unclear whether such bacterial changes rely in part on the modification of an IBD-associated lifestyle (e.g., smoking and physical activity) and diet (e.g., rich in dairy products, cereals, meat and vegetables). In this study, we investigated the impact of these habits, which we defined as confounders and covariates, on the modulation of intestinal taxa abundance and diversity in IBD patients. 16S rRNA gene sequence analysis was performed using genomic DNA extracted from the faecal samples of 52 patients with Crohn’s disease (CD) and 58 with ulcerative colitis (UC), which are the two main types of IBD, as well as 42 healthy controls (HC). A reduced microbial diversity was documented in the IBD patients compared with the HC. Moreover, we identified specific confounders and covariates that influenced the association between some bacterial taxa and disease extent (in UC patients) or behaviour (in CD patients) compared with the HC. In particular, a PERMANOVA stepwise regression identified the variables “age”, “eat yogurt at least four days per week” and “eat dairy products at least 4 days per week” as covariates when comparing the HC and patients affected by ulcerative proctitis (E1), left-sided UC (distal UC) (E2) and extensive UC (pancolitis) (E3). Instead, the variables “age”, “gender”, “eat meat at least four days per week” and “eat bread at least 4 days per week” were considered as covariates when comparing the HC with the CD patients affected by non-stricturing, non-penetrating (B1), stricturing (B2) and penetrating (B3) diseases. Considering such variables, our analysis indicated that the UC extent differentially modulated the abundance of the Bifidobacteriaceae, Rikenellaceae, Christensenellaceae, Marinifilaceae, Desulfovibrionaceae, Lactobacillaceae, Streptococcaceae and Peptostreptococcaceae families, while the CD behaviour influenced the abundance of Christensenellaceae, Marinifilaceae, Rikenellaceae, Ruminococcaceae, Barnesiellaceae and Coriobacteriaceae families. In conclusion, our study indicated that some covariates and confounders related to an IBD-associated lifestyle and dietary habits influenced the intestinal taxa diversity and relative abundance in the CD and UC patients compared with the HC. Indeed, such variables should be identified and excluded from the analysis to characterize the bacterial families whose abundance is directly modulated by IBD status, as well as disease extent or behaviour.

Antimicrobial Stewardship Program: Reducing Antibiotic’s Spectrum of Activity Is not the Solution to Limit the Emergence of Multidrug-Resistant Bacteria

Overconsumption of antibiotics in hospitals has led to policy implementation, including the control of antibiotic prescriptions. The impact of these policies on the evolution of antimicrobial resistance remains uncertain. In this work, we review the possible limits of such policies and focus on the need for a more efficient approach. Establishing a causal relationship between the introduction of new antibiotics and the emergence of new resistance mechanisms is difficult. Several studies have demonstrated that many resistance mechanisms existed before the discovery of antibiotics. Overconsumption of antibiotics has worsened the phenomenon of resistance. Antibiotics are responsible for intestinal dysbiosis, which is suspected of being the source of bacterial resistance. The complexity of the intestinal microbiota composition, the impact of the pharmacokinetic properties of antibiotics, and the multiplicity of other factors involved in the acquisition and emergence of multidrug-resistant organisms, lead us to think that de-escalation, in the absence of studies proving its effectiveness, is not the solution to limiting the spread of multidrug-resistant organisms. More studies are needed to clarify the ecological risk caused by different antibiotic classes. In the meantime, we need to concentrate our efforts on limiting antibiotic prescriptions to patients who really need it, and work on reducing the duration of these treatments.

Multi-Omics Analysis of the Gut-Liver Axis Reveals the Mechanism of Liver Injury in Colitis Mice

Liver injury is a common complication of inflammatory bowel disease (IBD). However, the mechanisms of liver injury development are not clear in IBD patients. Gut microbiota is thought to be engaged in IBD pathogenesis. Here, by an integrated analysis of host transcriptome and colonic microbiome, we have attempted to reveal the mechanism of liver injury in colitis mice. In this study, dextran sulfate sodium (DSS) -induced mice colitis model was constructed. Liver transcriptome showed significant up- and down-regulation of pathways linked to immune response and lipid metabolism, respectively. Whilst the colon transcriptome exhibited dramatic alterations in immune response and pathways associated with cell growth and death. The microbiota of DSS-treated mice underwent strong transitions. Correlation analyses identified genes associated with liver and colon injury, whose expression was associated with the abundance of liver and gut health-related bacteria. Collectively, the results indicate that the liver injury in colitis mice may be related to the intestinal dysbiosis and host-microbiota interactions. These findings may provide new insights for identifying potential targets for the treatment of IBD and its induced liver injury.

Intestinal dysbiosis featuring abundance of Streptococcus associates with Henoch-Schönlein purpura nephritis (IgA vasculitis with nephritis) in adult

Background The pathogenesis of Henoch-Schönlein purpura nephritis (HSPN) is closely associated with mucosal infection. But whether intestinal microbiota dysbiosis plays a role in it is not clear. Methods A total of 52 participants including 26 HSPN patients and 26 healthy controls were included. By using 16S ribosomal RNA gene sequencing, the intestinal microbiota composition between HSPN and healthy controls was compared. The diagnostic potency was evaluated by Receiver operating characteristic (ROC) with area under curves (AUC). Meanwhile, correlation analysis was also performed. Results The lower community richness and diversity of fecal microbiota was displayed in HSPN patients and the structure of gut microbiota was remarkedly different. A genus-level comparison indicated a significant increase in the proportions of g-Bacteroides, g-Escherichia–Shigella and g-Streptococcus, and a marked reduction of g-Prevotella_9 in HSPN patients, suggesting that the overrepresentation of potential pathogens and reduction of profitable strains were the main feature of the dysbiosis. The differential taxonomic abundance might make sense for distinguishing HSPN from healthy controls, with AUC of 0.86. The relative abundance of the differential bacteria was also concerned with clinical indices. Among them, Streptococcus spp. was positively associated with the severity of HSPN (P < 0.050). It was found that HSPN patients with higher level of Streptococcus spp. were more likely to suffering from hematuria and hypoalbuminemia (P < 0.050). Conclusions The dysbiosis of gut microbiota was obvious in HSPN patients, and the intestinal mucosal streptococcal infection was distinctive, which was closely related to its severity.

Regulation of the intestinal dysbiosis of high – fat diet obese mice via gut microbia–TLR2 / 4 pathway by electroacupuncture

Objective: We design experimental study to explore the impacts of electroacupuncture (EA) treatment on the interaction between TLR2 / 4 pathway and gut flora in high – fat diet obese mice. Methods: Reverse transcriptase polymerase chain reaction, western blotting and 16S rRNA pyrosequencing were to study the association among groups (normal (N), model (M), electroacupuncture for 7 d (A7), 14 d (A14), 21 d (A21) and 28 d (A28) group). Results: EA reduced the relative expression of TLR2 / 4 gene and protein, and regulated the significant difference species flora in different levels, such as Firmicutes and Actinobacteria in Phylum, Coriobacteriia in Class, Coriobacteriales in Order, Atopobiaceae in Family, and Oscillibacter, Intestinimonas, Lachniclostridium and Acetatifactor in Genus. In all acupuncture groups, the analytical data of A21 group was similar to normal mice. Conclusion: These findings suggested the interaction between TLR2/ 4 pathway and gut flora could be a novel target of EA treatment against obesity.

Influence of intestinal microbiota on the immunopathogenesis of atopic dermatitis in children

Particular attention is paid to atopic dermatitis (AD) as one of the earliest and most frequent clinical manifestations of allergy in children. AD is a multifactorial disease, the development of which is closely related to genetic defects in the immune response and adverse environmental influences. It was found that the action of these factors determines the rate of development of AD, especially in young children. One of these factors is a violation of the intestinal microbiota, which plays an essential role in the development of the child's immune system and has a protective effect in the formation of atopy. It has been shown that 80-95% of patients with AD have intestinal dysbiosis, while, along with a deficiency of lactobacilli and bifidobacteria, there is an excessive growth of Staphilococcus. The use of modern molecular genetics technologies made it possible to obtain a fairly complete understanding of the number, genetic heterogeneity and complexity of the bacterial components of the intestinal microbiota, while clinical studies have shown the importance of its interactions with the host organism in the formation of various forms of pathology. It has been established that the human intestinal microbiota is an evolutionary set of microorganisms that exists as a balanced microecological system in which the symbiotic microflora is in dynamic equilibrium, forms microbial associations that occupy a certain ecological niche in it, and is one of the most important factors affecting human health. The gut microbiota plays an important role in the pathogenesis of atopic dermatitis, which causes immunosuppression, but the exact mechanism of its action is still unclear. It is widely known that probiotics act on the immune system. These are living microorganisms with immunomodulatory effects that stimulate Th1 cytokines and suppress Th2 responses, which are being investigated for the treatment of several diseases. The most commonly used probiotics are part of the intestinal microflora such as lactobacilli, bifidobacteria and enterococci. The purpose of this article: to systematize the information available today on the influence of the composition of the intestinal microflora on the immunopathogenesis of atopic dermatitis.

Oral-Gut-Brain Axis in Experimental Models of Periodontitis: Associating Gut Dysbiosis With Neurodegenerative Diseases

Periodontitis is considered a non-communicable chronic disease caused by a dysbiotic microbiota, which generates a low-grade systemic inflammation that chronically damages the organism. Several studies have associated periodontitis with other chronic non-communicable diseases, such as cardiovascular or neurodegenerative diseases. Besides, the oral bacteria considered a keystone pathogen, Porphyromonas gingivalis, has been detected in the hippocampus and brain cortex. Likewise, gut microbiota dysbiosis triggers a low-grade systemic inflammation, which also favors the risk for both cardiovascular and neurodegenerative diseases. Recently, the existence of an axis of Oral-Gut communication has been proposed, whose possible involvement in the development of neurodegenerative diseases has not been uncovered yet. The present review aims to compile evidence that the dysbiosis of the oral microbiota triggers changes in the gut microbiota, which creates a higher predisposition for the development of neuroinflammatory or neurodegenerative diseases.The Oral-Gut-Brain axis could be defined based on anatomical communications, where the mouth and the intestine are in constant communication. The oral-brain axis is mainly established from the trigeminal nerve and the gut-brain axis from the vagus nerve. The oral-gut communication is defined from an anatomical relation and the constant swallowing of oral bacteria. The gut-brain communication is more complex and due to bacteria-cells, immune and nervous system interactions. Thus, the gut-brain and oral-brain axis are in a bi-directional relationship. Through the qualitative analysis of the selected papers, we conclude that experimental periodontitis could produce both neurodegenerative pathologies and intestinal dysbiosis, and that periodontitis is likely to induce both conditions simultaneously. The severity of the neurodegenerative disease could depend, at least in part, on the effects of periodontitis in the gut microbiota, which could strengthen the immune response and create an injurious inflammatory and dysbiotic cycle. Thus, dementias would have their onset in dysbiotic phenomena that affect the oral cavity or the intestine. The selected studies allow us to speculate that oral-gut-brain communication exists, and bacteria probably get to the brain via trigeminal and vagus nerves.

A specific structure and high richness characterize intestinal microbiota of HIV-exposed seronegative individuals

Intestinal microbiota facilitates food breakdown for energy metabolism and influences the immune response, maintaining mucosal homeostasis. Overall, HIV infection is associated with intestinal dysbiosis and immune activation, which has been related to seroconversion in HIV-exposed individuals. However, it is unclear whether microbiota dysbiosis is the cause or the effect of immune alterations and disease progression or if it could modulate the risk of acquiring the HIV infection. We characterize the intestinal microbiota and determine its association with immune regulation in HIV-exposed seronegative individuals (HESN), HIV-infected progressors (HIV+), and healthy control (HC) subjects. For this, feces and blood were collected. The microbiota composition of HESN showed a significantly higher alpha (p = 0.040) and beta diversity (p = 0.006) compared to HC, but no differences were found compared to HIV+. A lower Treg percentage was observed in HESN (1.77%) than HC (2.98%) and HIV+ (4.02%), with enrichment of the genus Butyrivibrio (p = 0.029) being characteristic of this profile. Moreover, we found that Megasphaera (p = 0.017) and Victivallis (p = 0.0029) also are enriched in the microbiota composition in HESN compared to HC and HIV+ subjects. Interestingly, an increase in Succinivibrio and Prevotella, and a reduction in Bacteroides genus, which is typical of HIV-infected individuals, were observed in both HESN and HIV+, compared to HC. Thus, HESNs have a microbiota profile, similar to that observed in HIV+, most likely because HESN are cohabiting with their HIV+ partners.