Mapping gut feelings and immune control.

A chemogenetic screen reveals links between nociceptors and gut immune function.

More on the interplay between gut microbiota, autophagy, and inflammatory bowel disease is needed.

The concept of inflammatory bowel disease (IBD), which encompasses Crohn's disease and ulcerative colitis, represents a complex and growing global health concern resulting from a multifactorial etiology. Both dysfunctional autophagy and dysbiosis contribute to IBD, with their combined effects exacerbating the related inflammatory condition. As a result, the existing interconnection between gut microbiota, autophagy, and the host's immune system is a decisive factor in the occurrence of IBD. The factors that influence the gut microbiota and their impact are another important point in this regard. Based on this initial perspective, this manuscript briefly highlighted the intricate interplay between the gut microbiota, autophagy, and IBD pathogenesis. In addition, it also addressed the potential targeting of the microbiota and modulating autophagic pathways for IBD therapy and proposed suggestions for future research within a more specific and expanded context. Further studies are warranted to explore restoring microbial balance and regulating autophagy mechanisms, which may offer new therapeutic avenues for IBD management and to delve into personalized treatment to alleviate the related burden.

Pro and anti-inflammatory diets as strong epigenetic factors in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is the consequence of a complex interplay between environmental factors, like dietary habits, that alter intestinal microbiota in response to luminal antigens in genetically susceptible individuals. Epigenetics represents an auspicious area for the discovery of how environmental factors influence the pathogenesis of inflammation, prognosis, and response to therapy. Consequently, it relates to gene expression control in response to environmental influences. The increasing number of patients with IBD globally is indicative of the negative effects of a food supply rich in trans and saturated fats, refined sugars, starches and additives, as well as other environmental factors like sedentarism and excess bodyweight, influencing the promotion of gene expression and increasing DNA hypomethylation in IBD. As many genetic variants are now associated with Crohn's disease (CD), new therapeutic strategies targeting modifiable environmental triggers, such as the implementation of an anti-inflammatory diet that involves the removal of potential food antigens, are of growing interest in the current literature. Diet, as a strong epigenetic factor in the pathogenesis of inflammatory disorders like IBD, provides novel insights into the pathophysiology of intestinal and extraintestinal inflammatory disorders.

Immunological aspects of necrotizing enterocolitis models: a review.

Necrotizing enterocolitis (NEC) is one of the most devasting diseases affecting preterm neonates. However, despite a lot of research, NEC's pathogenesis remains unclear. It is known that the pathogenesis is a multifactorial process, including (1) a pathological microbiome with abnormal bacterial colonization, (2) an immature immune system, (3) enteral feeding, (3) an impairment of microcirculation, and (4) possibly ischemia-reperfusion damage to the intestine. Overall, the immaturity of the mucosal barrier and the increased expression of Toll-like receptor 4 (TLR4) within the intestinal epithelium result in an intestinal hyperinflammation reaction. Concurrently, a deficiency in counter-regulatory mediators can be seen. The sum of these processes can ultimately result in intestinal necrosis leading to very high mortality rates of the affected neonates. In the last decade no substantial advances in the treatment of NEC have been made. Thus, NEC animal models as well as in vitro models have been employed to better understand NEC's pathogenesis on a cellular and molecular level. This review will highlight the different models currently in use to study immunological aspects of NEC.

Multi-omics analysis reveals a feedback loop amplifying immune responses in acute graft-versus-host disease due to imbalanced gut microbiota and bile acid metabolism.

Acute graft-versus-host disease (aGVHD) is primarily driven by allogeneic donor T cells associated with an altered composition of the host gut microbiome and its metabolites. The severity of aGVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not solely determined by the host and donor characteristics; however, the underlying mechanisms remain unclear. Using single-cell RNA sequencing, we decoded the immune cell atlas of 12 patients who underwent allo-HSCT: six with aGVHD and six with non-aGVHD. We performed a fecal microbiota (16SrRNA sequencing) analysis to investigate the fecal bacterial composition of 82 patients: 30 with aGVHD and 52 with non-aGVHD. Fecal samples from these patients were analyzed for bile acid metabolism. Through multi-omic analysis, we identified a feedback loop involving "immune cell-gut microbes-bile acid metabolites" contributing to heightened immune responses in patients with aGVHD. The dysbiosis of the gut microbiota and disruption of bile acid metabolism contributed to an exaggerated interleukin-1 mediated immune response. Our findings suggest that resistin and defensins are crucial in mitigating against aGVHD. Therefore, a comprehensive multi-omic atlas incorporating immune cells, gut microbes, and bile acid metabolites was developed in this study and used to propose novel, non-immunosuppressive approaches to prevent aGVHD.

Gut microbiota and pancreatic cancer risk, and the mediating role of immune cells and inflammatory cytokines: a Mendelian randomization study.

Introduction: Gut microbiota (GM) influences the occurrence and development of pancreatic cancer (PC), potentially through the involvement of inflammatory cytokines (IC) and immune cells (IM). We aimed to investigate the causal impact of the gut microbiota (GM) on pancreatic cancer (PC) and identify potential IC and IM mediators. Methods: The summary statistics data from whole-genome association studies of gut microbiota, immune cells, inflammatory cytokines, and four types of pancreatic tumors (MNP: Malignant neoplasm of pancreas; BNP: Benign neoplasm of pancreas; ADCP: Adenocarcinoma and ductal carcinoma of pancreas; NTCP: Neuroendocrine tumor and carcinoma of pancreas). Two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and mediation analysis were employed to assess the causal relationship between gut microbiota (GM) and pancreatic cancer (PC), as well as potential IC and IM mediators. Results: The two-sample UVMR analysis showed causal relationships between 20 gut microbiota species and pancreatic cancer, with pancreatic cancer affecting the abundance of 37 gut microbiota species. Mediation analysis revealed that Interleukin-6 (IL-6), "CD4 on naive CD4+ T cell" and "SSC-A on HLA DR+ Natural Killer" mediated the causal effects of gut microbiota on pancreatic cancer. Conclusion: This Mendelian randomization study demonstrates causal relationships between several specific gut microbiota and pancreatic cancer, as well as potential mediators (IC, IM).

Humoral immune responses primed by the alteration of gut microbiota were associated with galactose-deficient IgA1 production in IgA nephropathy.

Introduction: Galactose-deficient IgA1 (GdIgA1) is critical in the formation of immunodeposits in IgA nephropathy (IgAN), whereas the origin of GdIgA1 is unknown. We focused on the immune response to fecal microbiota in patients with IgAN. Methods: By running 16S ribosomal RNA gene sequencing, we compared IgAN samples to the control samples from household-matched or non-related individuals. Levels of plasma GdIgA1 and poly-IgA complexes were measured, and candidate microbes that can either incite IgA-directed antibody response or degrade IgA through specific IgA protease activities were identified. Results: The IgAN group showed a distinct composition of fecal microbiota as compared to healthy controls. Particularly, high abundance of Escherichia-Shigella was associated with the disease group based on analyses using receiver operating characteristic (area under curve, 0.837; 95% CI, 0.738-0.914), principle coordinates, and the linear discriminant analysis effect size algorithm (linear discriminant analysis score, 4.56; p < 0.001). Accordingly, the bacterial levels directly correlated with high titers of plasma GdIgA1(r = 0.36, p < 0.001), and patients had higher IgA1 against stx2(2.88 ± 0.46 IU/mL vs. 1.34 ± 0.35 IU/mL, p = 0.03), the main antigen of Escherichia-Shigella. Conversely, the healthy controls showed relatively higher abundance of the commensal bacteria that produce IgA-degrading proteases. Particularly, the abundance of some intestinal bacteria expressing IgA proteases showed an inverse correlation with the levels of plasma GdIgA1 in IgAN. Conclusion: Our data suggest that mucosal IgA production, including those of GdIgA1, is potentially linked to the humoral response to gut Escherichia-Shigella as one of the sources of plasma GdIgA1. Conversely, the IgA protease-producing microbiota in the gut are suppressed in patients with IgAN.

Skin exposure to soil microbiota elicits changes in cell-mediated immunity to pneumococcal vaccine.

A resilient immune system is characterized by its capacity to respond appropriately to challenges, such as infections, and it is crucial in vaccine response. Here we report a paired randomized intervention-control trial in which we evaluated the effect of microbially rich soil on immune resilience and pneumococcal vaccine response. Twenty-five age and sex matched pairs of volunteers were randomized to intervention and control groups. The intervention group rubbed hands three times a day in microbially rich soil until participants received a pneumococcal vaccine on day 14. Vaccine response, skin and gut bacteriome and blood cytokine levels were analyzed on days 0, 14 and 35. Peripheral blood mononuclear cells (PBMCs) were stimulated with vaccine components and autoclaved soil for cytokine production. Commensal bacterial community shifted only in the intervention group during the 14-day intervention period. When PBMCs collected on day 14 before the vaccination were stimulated with the vaccine components, IFN-y production increased in the intervention but not in the control group. On day 35, vaccination induced a robust antibody response in both groups. In parallel, gut bacterial community was associated with TGF-ß plasma levels and TGF-ß decrease in plasma was lower in the intervention group. The results indicate that exposure to microbially rich soil can modulate the cell-mediated immunity to components in pneumococcal vaccine.

The oral-gut microbiome axis in inflammatory bowel disease: from inside to insight.

Inflammatory bowel disease (IBD) is an idiopathic and persistent inflammatory illness of the bowels, leading to a substantial burden on both society and patients due to its high incidence and recurrence. The pathogenesis of IBD is multifaceted, partly attributed to the imbalance of immune responses toward the gut microbiota. There is a correlation between the severity of the disease and the imbalance in the oral microbiota, which has been discovered in recent research highlighting the role of oral microbes in the development of IBD. In addition, various oral conditions, such as angular cheilitis and periodontitis, are common extraintestinal manifestations (EIMs) of IBD and are associated with the severity of colonic inflammation. However, it is still unclear exactly how the oral microbiota contributes to the pathogenesis of IBD. This review sheds light on the probable causal involvement of oral microbiota in intestinal inflammation by providing an overview of the evidence, developments, and future directions regarding the relationship between oral microbiota and IBD. Changes in the oral microbiota can serve as markers for IBD, aiding in early diagnosis and predicting disease progression. Promising advances in probiotic-mediated oral microbiome modification and antibiotic-targeted eradication of specific oral pathogens hold potential to prevent IBD recurrence.

Immunology of bile acids regulated receptors.

Bile acids are steroids formed at the interface of host metabolism and intestinal microbiota. While primary bile acids are generated in the liver from cholesterol metabolism, secondary bile acids represent the products of microbial enzymes. Close to 100 different enzymatic modifications of bile acids structures occur in the human intestine and clinically guided metagenomic and metabolomic analyses have led to the identification of an extraordinary number of novel metabolites. These chemical mediators make an essential contribution to the composition and function of the postbiota, participating to the bidirectional communications of the intestinal microbiota with the host and contributing to the architecture of intestinal-liver and -brain and -endocrine axes. Bile acids exert their function by binding to a group of cell membrane and nuclear receptors collectively known as bile acid-regulated receptors (BARRs), expressed in monocytes, tissue-resident macrophages, CD4+ T effector cells, including Th17, T regulatory cells, dendritic cells and type 3 of intestinal lymphoid cells and NKT cells, highlighting their role in immune regulation. In this review we report on how bile acids and their metabolitesmodulate the immune system in inflammations and cancers and could be exploiting for developing novel therapeutic approaches in these disorders.

Crosstalk between gut microbiota and host immune system and its response to traumatic injury.

Millions of microorganisms make up the complex microbial ecosystem found in the human gut. The immune system's interaction with the gut microbiota is essential for preventing inflammation and maintaining intestinal homeostasis. Numerous metabolic products that can cross-talk between immune cells and the gut epithelium are metabolized by the gut microbiota. Traumatic injury elicits a great and multifaceted immune response in the minutes after the initial offense, containing simultaneous pro- and anti-inflammatory responses. The development of innovative therapies that improve patient outcomes depends on the gut microbiota and immunological responses to trauma. The altered makeup of gut microbes, or gut dysbiosis, can also dysregulate immunological responses, resulting in inflammation. Major human diseases may become more common as a result of chronic dysbiosis and the translocation of bacteria and the products of their metabolism beyond the mucosal barrier. In this review, we briefly summarize the interactions between the gut microbiota and the immune system and human disease and their therapeutic probiotic formulations. We also discuss the immune response to traumatic injury.

From poo to promise: Fecal microbiota transplants support immunotherapy re-sensitization in solid tumors.

Fecal microbiota transplants (FMTs) recently entered the cancer therapeutics field as a method to resensitize treatment-resistant melanoma patients to immune checkpoint inhibitors (ICIs). In this issue of Cell Host & Microbe, Kim and colleagues extend its utility to other solid tumors, including esophageal and hepatocellular carcinomas.1.

The intratumoral microbiota: a new horizon in cancer immunology.

Over the past decade, advancements in high-throughput sequencing technologies have led to a qualitative leap in our understanding of the role of the microbiota in human diseases, particularly in oncology. Despite the low biomass of the intratumoral microbiota, it remains a crucial component of the tumor immune microenvironment, displaying significant heterogeneity across different tumor tissues and individual patients. Although immunotherapy has emerged a major strategy for treating tumors, patient responses to these treatments vary widely. Increasing evidence suggests that interactions between the intratumoral microbiota and the immune system can modulate host tumor immune responses, thereby influencing the effectiveness of immunotherapy. Therefore, it is critical to gain a deep understanding of how the intratumoral microbiota shapes and regulates the tumor immune microenvironment. Here, we summarize the latest advancements on the role of the intratumoral microbiota in cancer immunity, exploring the potential mechanisms through which immune functions are influenced by intratumoral microbiota within and outside the gut barrier. We also discuss the impact of the intratumoral microbiota on the response to cancer immunotherapy and its clinical applications, highlighting future research directions and challenges in this field. We anticipate that the valuable insights into the interactions between cancer immunity and the intratumoral microbiota provided in this review will foster the development of microbiota-based tumor therapies.

Cracking the type 1 diabetes code: Genes, microbes, immunity, and the early life environment.

Type 1 diabetes (T1D) results from a complex interplay of genetic predisposition, immunological dysregulation, and environmental triggers, that culminate in the destruction of insulin-secreting pancreatic ß cells. This review provides a comprehensive examination of the multiple factors underpinning T1D pathogenesis, to elucidate key mechanisms and potential therapeutic targets. Beginning with an exploration of genetic risk factors, we dissect the roles of human leukocyte antigen (HLA) haplotypes and non-HLA gene variants associated with T1D susceptibility. Mechanistic insights gleaned from the NOD mouse model provide valuable parallels to the human disease, particularly immunological intricacies underlying ß cell-directed autoimmunity. Immunological drivers of T1D pathogenesis are examined, highlighting the pivotal contributions of both effector and regulatory T cells and the multiple functions of B cells and autoantibodies in ß-cell destruction. Furthermore, the impact of environmental risk factors, notably modulation of host immune development by the intestinal microbiome, is examined. Lastly, the review probes human longitudinal studies, unveiling the dynamic interplay between mucosal immunity, systemic antimicrobial antibody responses, and the trajectories of T1D development. Insights garnered from these interconnected factors pave the way for targeted interventions and the identification of biomarkers to enhance T1D management and prevention strategies.

Hit me baby one more time with microbial IPA.

The immune system is imprinted by gut microbes in early life. In this issue of Immunity, Perdijk et al. show that dysregulation of airway epithelial function by neonatal antibiotic treatment can be reversed by supplementation with a depleted microbial metabolite.

Immunomodulation aspects of gut microbiome-related interventional strategies in colorectal cancer.

Colorectal cancer (CRC), the third most common cancer worldwide, develops mainly due to the accumulation of genetic and epigenetic changes over many years. Substantial evidence suggests that gut microbiota plays a significant role in the initiation, progression, and control of CRC, depending on the balance between beneficial and pathogenic microorganisms. Nonetheless, gut microbiota composition by regulating the host immune response may either promote or inhibit CRC. Thus, modification of gut microbiota potentially impacts clinical outcomes of immunotherapy. Previous studies have indicated that therapeutic strategies such as probiotics, prebiotics, and postbiotics enhance the intestinal immune system and improve the efficacy of immunotherapeutic agents, potentially serving as a complementary strategy in cancer immunotherapy. This review discusses the role of the gut microbiota in the onset and development of CRC in relation to the immune response. Additionally, we focus on the effect of strategies manipulating gut microbiome on the immune response and efficacy of immunotherapy against CRC. We demonstrate that manipulation of gut microbiome can enhance immune response and outcomes of immunotherapy through downregulating Treg cells and other immunosuppressive cells while improving the function of T cells within the tumor; however, further research, especially clinical trials, are needed to evaluate its efficacy in cancer treatment.

Microbiota and plasticity of antigen-presenting ILC3s: impact on antitumor immune response.

Growing evidence highlights the pivotal role of RORγt-innate lymphoid cells (ILCs) in the establishment of antitumor immune response and in enhancing tumor sensitivity to immunotherapy. Noteworthy, type 3 ILCs (ILC3s) have been recently acknowledged as an important class of antigen-presenting cells (APCs) in the context of host-microorganism interactions shaping the adaptive immune response in the intestinal mucosa. Although a broad range of mouse models has led to significant progress in untangling the role of ILC3s as APCs, the outcome of major histocompatibility complex (MHC)-dependent ILC-T cell crosstalk in colorectal cancer (CRC) remains underexplored in human. Moreover, expression of MHCII is confined to ILC3 subset, endowed with lymphoid tissue-inducing properties, that adopts tissue-specific fates and functions. Intestinal microbiota could dictate the plasticity of antigen-presenting ILC3s and we here summarize our current understanding of the functions of these cells in both mouse and human CRC discussing the role of microbiota as a key modulator of their tumor-suppressive activity.

Multiple effects of dietary supplementation with Lactobacillus reuteri and Bacillus subtilis on the growth, immunity, and metabolism of largemouth bass (Micropterus salmoides).

Probiotics play an essential role in the largemouth bass (Micropterus salmoides) aquaculture sector. They aid the fish in sickness prevention, intestinal structure improvement, food absorption, and immune system strengthening. In this experiment, Bacillus subtilis (BS, 107 CFU/g) and Lactobacillus reuteri (LR, 107 CFU/g) were added to the feed and then fed to M. salmoides for 35 days. The effects of two probiotics on the growth, immunity, and metabolism of M. salmoides organisms were studied. The results revealed that the BS group significantly increased the growth rate and specific growth rate of M. salmoides, while both the BS and LR groups significantly increase the length of villi M. salmoides intestines. The BS group significantly increased the levels of AKP, T-AOC, and CAT in the blood of M. salmoides, as well as AKP levels in the intestine. Furthermore, the BS group significantly increased the expression of intestinal genes Nrf2, SOD1, GPX, and CAT, while significantly decreasing the expression of the keap1 gene. M. salmoides gut microbial analysis showed that the abundance of Planctomycetota was significantly different in both control and experimental groups. Analyzed at the genus level, the abundance of Citrobacter, Paracoccus, Luedemannella， Sphingomonas, Streptomyces and Xanthomonas in the both control and experimental groups were significantly different. The BS group's differentially expressed genes were predominantly enriched in oxidative phosphorylation pathways in the intestine, indicating that they had a good influence on intestinal metabolism and inflammation suppression. In contrast, differentially expressed genes in the LR group were primarily enriched in the insulin signaling and linoleic acid metabolism pathways, indicating improved intestine metabolic performance. In conclusion, B. subtilis and L. reuteri improve the growth and health of M. salmoides, indicating tremendous potential for enhancing intestinal metabolism and providing significant application value.

Gut microbiota and immunosenescence in cancer.

Cancer is generally defined as a disease of aging. With aging, the composition, diversity and functional characteristics of the gut microbiota occur changes, with a decline of beneficial commensal microbes triggered by intrinsic and extrinsic factors (e.g., diet, drugs and chronic health conditions). Nowadays, dysbiosis of the gut microbiota is recognized as a hallmark of cancer. At the same time, aging is accompanied by changes in innate and adaptive immunity, known as immunosenescence, as well as chronic low-grade inflammation, known as inflammaging. The elevated cancer incidence and mortality in the elderly are linked with aging-associated alterations in the gut microbiota that elicit systemic metabolic alterations, leading to immune dysregulation with potentially tumorigenic effects. The gut microbiota and immunosenescence might both affect the response to treatment in cancer patients. In-depth understanding of age-associated alterations in the gut microbiota and immunity will shed light on the risk of cancer development and progression in the elderly. Here, we describe the aging-associated changes of the gut microbiota in cancer, and review the evolving understanding of the gut microbiota-targeted intervention strategies. Furthermore, we summarize the knowledge on the cellular and molecular mechanisms of immunosenescence and its impact on cancer. Finally, we discuss the latest knowledge about the relationships between gut microbiota and immunosenescence, with implications for cancer therapy. Intervention strategies targeting the gut microbiota may attenuate inflammaging and rejuvenate immune function to provide antitumor benefits in elderly patients.