The Interplay between Immune System and Microbiota in Inflammatory Bowel Disease: A Narrative Review

The importance of the gut microbiota in human health is currently well established. It contributes to many vital functions such as development of the host immune system, digestion and metabolism, barrier against pathogens or brain–gut communication. Microbial colonization occurs during infancy in parallel with maturation of the host immune system; therefore, an adequate cross-talk between these processes is essential to generating tolerance to gut microbiota early in life, which is crucial to prevent allergic and immune-mediated diseases. Inflammatory bowel disease (IBD) is characterized by an exacerbated immune reaction against intestinal microbiota. Changes in abundance in the gut of certain microorganisms such as bacteria, fungi, viruses, and archaea have been associated with IBD. Microbes that are commonly found in high abundance in healthy gut microbiomes, such as F. prausnitzii or R. hominis, are reduced in IBD patients. E. coli, which is usually present in a healthy gut in very low concentrations, is increased in the gut of IBD patients. Microbial taxa influence the immune system, hence affecting the inflammatory status of the host. This review examines the IBD microbiome profile and presents IBD as a model of dysbiosis.     

Aryl Hydrocarbon Receptor (AhR) Activation by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Dose-Dependently Shifts the Gut Microbiome Consistent with the Progression of Non-Alcoholic Fatty Liver Disease

Gut dysbiosis with disrupted enterohepatic bile acid metabolism is commonly associated with non-alcoholic fatty liver disease (NAFLD) and recapitulated in a NAFLD-phenotype elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. TCDD induces hepatic fat accumulation and increases levels of secondary bile acids, including taurolithocholic acid and deoxycholic acid (microbial modified bile acids involved in host bile acid regulation signaling pathways). To investigate the effects of TCDD on the gut microbiota, the cecum contents of male C57BL/6 mice orally gavaged with sesame oil vehicle or 0.3, 3, or 30 µg/kg TCDD were examined using shotgun metagenomic sequencing. Taxonomic analysis identified dose-dependent increases in Lactobacillus species (i.e., Lactobacillus reuteri). Increased species were also associated with dose-dependent increases in bile salt hydrolase sequences, responsible for deconjugation reactions in secondary bile acid metabolism. Increased L. reuteri levels were further associated with mevalonate-dependent isopentenyl diphosphate (IPP) biosynthesis and o-succinylbenzoate synthase, a menaquinone biosynthesis associated gene. Analysis of the gut microbiomes from cirrhosis patients identified an increased abundance of genes from the mevalonate-dependent IPP biosynthesis as well as several other menaquinone biosynthesis genes, including o-succinylbenzoate synthase. These results extend the association of lactobacilli with the AhR/intestinal axis in NAFLD progression and highlight the similarities between TCDD-elicited phenotypes in mice to human NAFLD.     

Dioscin Alleviates Cisplatin-Induced Mucositis in Rats by Modulating Gut Microbiota,Enhancing Intestinal Barrier Function and Attenuating TLR4/NF-κB Signaling Cascade

Cisplatin-based chemotherapy causes intestinal mucositis, which causes patients immense suffering and hinders the process of cancer treatment. Dioscin is a natural steroid saponin that exhibits strong anti-inflammatory and immunomodulatory properties. Herein, we investigate the protective effect of dioscin on cisplatin induced mucositis in rats from the perspective of gut microbiota and intestinal barrier. We established a rat model of intestinal mucositis by tail vein injection of cisplatin, and concurrently treated with dioscin oral administration. Parameters, such as body weight, diarrheal incidence, and D-Lactate levels, were assessed in order to evaluate the effects of dioscin on intestinal mucositis in rats. Furthermore, biological samples were collected for microscopic gut microbiota, intestinal integrity, and immune inflammation analyses to elucidate the protective mechanisms of dioscin on intestinal mucositis. The results revealed that administration of dioscin significantly attenuated clinical manifestations, histological injury and inflammation in mucositis rats. Besides this, dioscin markedly inhibited the gut microbiota dysbiosis induced by cisplatin. Meanwhile, dioscin partially alleviated junctions between ileum epithelial cells and increased mucus secretion. Moreover, dioscin effectively inhibited the TLR4-MyD88-NF-κB signal transduction pathway and reduced the secretion of subsequent inflammatory mediators. These results suggested that dioscin effectively attenuated cisplatin-induced mucositis in part by modulating the gut microflora profile, maintaining ileum integrity and inhibiting the inflammatory response through the TLR4-MyD88-NF-κB pathway.     

The Role of Leaky Gut in Nonalcoholic Fatty Liver Disease: A Novel Therapeutic Target

The liver directly accepts blood from the gut and is, therefore, exposed to intestinal bacteria. Recent studies have demonstrated a relationship between gut bacteria and nonalcoholic fatty liver disease (NAFLD). Approximately 10–20% of NAFLD patients develop nonalcoholic steatohepatitis (NASH), and endotoxins produced by Gram-negative bacilli may be involved in NAFLD pathogenesis. NAFLD hyperendotoxicemia has intestinal and hepatic factors. The intestinal factors include impaired intestinal barrier function (leaky gut syndrome) and dysbiosis due to increased abundance of ethanol-producing bacteria, which can change endogenous alcohol concentrations. The hepatic factors include hyperleptinemia, which is associated with an excessive response to endotoxins, leading to intrahepatic inflammation and fibrosis. Clinically, the relationship between gut bacteria and NAFLD has been targeted in some randomized controlled trials of probiotics and other agents, but the results have been inconsistent. A recent randomized, placebo-controlled study explored the utility of lubiprostone, a treatment for constipation, in restoring intestinal barrier function and improving the outcomes of NAFLD patients, marking a new phase in the development of novel therapies targeting the intestinal barrier. This review summarizes recent data from studies in animal models and randomized clinical trials on the role of the gut–liver axis in NAFLD pathogenesis and progression.     

Butyrate and the Fine-Tuning of Colonic Homeostasis: Implication for Inflammatory Bowel Diseases

This review describes current evidence supporting butyrate impact in the homeostatic regulation of the digestive ecosystem in health and inflammatory bowel diseases (IBDs). Butyrate is mainly produced by bacteria from the Firmicutes phylum. It stimulates mature colonocytes and inhibits undifferentiated malignant and stem cells. Butyrate oxidation in mature colonocytes (1) produces 70–80% of their energetic requirements, (2) prevents stem cell inhibition by limiting butyrate access to crypts, and (3) consumes oxygen, generating hypoxia and maintaining luminal anaerobiosis favorable to the microbiota. Butyrate stimulates the aryl hydrocarbon receptor (AhR), the GPR41 and GPR109A receptors, and inhibits HDAC in different cell types, thus stabilizing the gut barrier function and decreasing inflammatory processes. However, some studies indicate contrary effects according to butyrate concentrations. IBD patients exhibit a lower abundance of butyrate-producing bacteria and butyrate content. Additionally, colonocyte butyrate oxidation is depressed in these subjects, lowering luminal anaerobiosis and facilitating the expansion of Enterobacteriaceae that contribute to inflammation. Accordingly, gut dysbiosis and decreased barrier function in IBD seems to be secondary to the impaired mitochondrial disturbance in colonic epithelial cells.     

Human Gut Microbiota in Health and Selected Cancers

The majority of the epithelial surfaces of our body, and the digestive tract, respiratory and urogenital systems, are colonized by a vast number of bacteria, archaea, fungi, protozoans, and viruses. These microbiota, particularly those of the intestines, play an important, beneficial role in digestion, metabolism, and the synthesis of vitamins. Their metabolites stimulate cytokine production by the human host, which are used against potential pathogens. The composition of the microbiota is influenced by several internal and external factors, including diet, age, disease, and lifestyle. Such changes, called dysbiosis, may be involved in the development of various conditions, such as metabolic diseases, including metabolic syndrome, type 2 diabetes mellitus, Hashimoto’s thyroidis and Graves’ disease; they can also play a role in nervous system disturbances, such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and depression. An association has also been found between gut microbiota dysbiosis and cancer. Our health is closely associated with the state of our microbiota, and their homeostasis. The aim of this review is to describe the associations between human gut microbiota and cancer, and examine the potential role of gut microbiota in anticancer therapy.     

The Role of Gut Microbiota in an Ischemic Stroke

The intestinal microbiome, the largest reservoir of microorganisms in the human body, plays an important role in neurological development and aging as well as in brain disorders such as an ischemic stroke. Increasing knowledge about mediators and triggered pathways has contributed to a better understanding of the interaction between the gut-brain axis and the brain-gut axis. Intestinal bacteria produce neuroactive compounds and can modulate neuronal function, which affects behavior after an ischemic stroke. In addition, intestinal microorganisms affect host metabolism and immune status, which in turn affects the neuronal network in the ischemic brain. Here we discuss the latest results of animal and human research on two-way communication along the gut-brain axis in an ischemic stroke. Moreover, several reports have revealed the impact of an ischemic stroke on gut dysfunction and intestinal dysbiosis, highlighting the delicate play between the brain, intestines and microbiome after this acute brain injury. Despite our growing knowledge of intestinal microflora in shaping brain health, host metabolism, the immune system and disease progression, its therapeutic options in an ischemic stroke have not yet been fully utilized. This review shows the role of the gut microflora-brain axis in an ischemic stroke and assesses the potential role of intestinal microflora in the onset, progression and recovery post-stroke.     

Effects of Microbiota Imbalance in Anxiety and Eating Disorders: Probiotics as Novel Therapeutic Approaches

Anxiety and eating disorders produce a physiological imbalance that triggers alterations in the abundance and composition of gut microbiota. Moreover, the gut–brain axis can be altered by several factors such as diet, lifestyle, infections, and antibiotic treatment. Diet alterations generate gut dysbiosis, which affects immune system responses, inflammation mechanisms, the intestinal permeability, as well as the production of short chain fatty acids and neurotransmitters by gut microbiota, which are essential to the correct function of neurological processes. Recent studies indicated that patients with generalized anxiety or eating disorders (anorexia nervosa, bulimia nervosa, and binge-eating disorders) show a specific profile of gut microbiota, and this imbalance can be partially restored after a single or multi-strain probiotic supplementation. Following the PRISMA methodology, the current review addresses the main microbial signatures observed in patients with generalized anxiety and/or eating disorders as well as the importance of probiotics as a preventive or a therapeutic tool in these pathologies.     

How Microbes Affect Depression: Underlying Mechanisms via the Gut–Brain Axis and the Modulating Role of Probiotics

Accumulating evidence suggests that the gut microbiome influences the brain functions and psychological state of its host via the gut–brain axis, and gut dysbiosis has been linked to several mental illnesses, including major depressive disorder (MDD). Animal experiments have shown that a depletion of the gut microbiota leads to behavioral changes, and is associated with pathological changes, including abnormal stress response and impaired adult neurogenesis. Short-chain fatty acids such as butyrate are known to contribute to the up-regulation of brain-derived neurotrophic factor (BDNF), and gut dysbiosis causes decreased levels of BDNF, which could affect neuronal development and synaptic plasticity. Increased gut permeability causes an influx of gut microbial components such as lipopolysaccharides, and the resultant systemic inflammation may lead to neuroinflammation in the central nervous system. In light of the fact that gut microbial factors contribute to the initiation and exacerbation of depressive symptoms, this review summarizes the current understanding of the molecular mechanisms involved in MDD onset, and discusses the therapeutic potential of probiotics, including butyrate-producing bacteria, which can mediate the microbiota–gut–brain axis.     

ZIP8-Mediated Intestinal Dysbiosis Impairs Pulmonary Host Defense against Bacterial Pneumonia

Pneumococcal pneumonia is a leading cause of morbidity and mortality worldwide. An increased susceptibility is due, in part, to compromised immune function. Zinc is required for proper immune function, and an insufficient dietary intake increases the risk of pneumonia. Our group was the first to reveal that the Zn transporter, ZIP8, is required for host defense. Furthermore, the gut microbiota that is essential for lung immunity is adversely impacted by a commonly occurring defective ZIP8 allele in humans. Taken together, we hypothesized that loss of the ZIP8 function would lead to intestinal dysbiosis and impaired host defense against pneumonia. To test this, we utilized a novel myeloid-specific Zip8KO mouse model in our studies. The comparison of the cecal microbial composition of wild-type and Zip8KO mice revealed significant differences in microbial community structure. Most strikingly, upon a S. pneumoniae lung infection, mice recolonized with Zip8KO-derived microbiota exhibited an increase in weight loss, bacterial dissemination, and lung inflammation compared to mice recolonized with WT microbiota. For the first time, we reveal the critical role of myeloid-specific ZIP8 on the maintenance of the gut microbiome structure, and that loss of ZIP8 leads to intestinal dysbiosis and impaired host defense in the lung. Given the high incidence of dietary Zn deficiency and the ZIP8 variant allele in the human population, additional investigation is warranted to improve surveillance and treatment strategies.     

Mucins Dynamics in Physiological and Pathological Conditions

Maintaining intestinal health requires clear segregation between epithelial cells and luminal microbes. The intestinal mucus layer, produced by goblet cells (GCs), is a key element in maintaining the functional protection of the epithelium. The importance of the gut mucus barrier is highlighted in mice lacking Muc2, the major form of secreted mucins. These mice show closer bacterial residence to epithelial cells, develop spontaneous colitis and became moribund when infected with the attaching and effacing pathogen, Citrobacter rodentium. Furthermore, numerous observations have associated GCs and mucus layer dysfunction to the pathogenesis of inflammatory bowel disease (IBD). However, the molecular mechanisms that regulate the physiology of GCs and the mucus layer remain obscured. In this review, we consider novel findings describing divergent functionality and expression profiles of GCs subtypes within intestinal crypts. We also discuss internal (host) and external (diets and bacteria) factors that modulate different aspects of the mucus layer as well as the contribution of an altered mucus barrier to the onset of IBD.     

The Association between Gut Microbiota and Osteoarthritis: Does the Disease Begin in the Gut?

Some say that all diseases begin in the gut. Interestingly, this concept is actually quite old, since it is attributed to the Ancient Greek physician Hippocrates, who proposed the hypothesis nearly 2500 years ago. The continuous breakthroughs in modern medicine have transformed our classic understanding of the gastrointestinal tract (GIT) and human health. Although the gut microbiota (GMB) has proven to be a core component of human health under standard metabolic conditions, there is now also a strong link connecting the composition and function of the GMB to the development of numerous diseases, especially the ones of musculoskeletal nature. The symbiotic microbes that reside in the gastrointestinal tract are very sensitive to biochemical stimuli and may respond in many different ways depending on the nature of these biological signals. Certain variables such as nutrition and physical modulation can either enhance or disrupt the equilibrium between the various species of gut microbes. In fact, fat-rich diets can cause dysbiosis, which decreases the number of protective bacteria and compromises the integrity of the epithelial barrier in the GIT. Overgrowth of pathogenic microbes then release higher quantities of toxic metabolites into the circulatory system, especially the pro-inflammatory cytokines detected in osteoarthritis (OA), thereby promoting inflammation and the initiation of many disease processes throughout the body. Although many studies link OA with GMB perturbations, further research is still needed.     

Small Intestinal Bacterial Overgrowth as Potential Therapeutic Target in Parkinson’s Disease

Increasing evidence suggests that the gut microbiota and the brain are closely connected via the so-called gut–brain axis. Small intestinal bacterial overgrowth (SIBO) is a gut dysbiosis in which the small intestine is abundantly colonized by bacteria that are typically found in the colon. Though not a disease, it may result in intestinal symptoms caused by the accumulation of microbial gases in the intestine. Intestinal inflammation, malabsorption and vitamin imbalances may also develop. SIBO can be eradicated by one or several courses of antibiotics but reappears if the predisposing condition persists. Parkinson’s disease (PD) is a common neurodegenerative proteinopathy for which disease modifying interventions are not available. Sporadic forms may start in the gut years before the development of clinical features. Increased gastrointestinal transit time is present in most people with PD early during the course of the disease, predisposing to gut dysbiosis, including SIBO. The role that gut dysbiosis may play in the etiopathogenesis of PD is not fully understood yet. Here, we discuss the possibility that SIBO could contribute to the progression of PD, by promoting or preventing neurodegeneration, thus being a potential target for treatments aiming at slowing down the progression of PD. The direct symptomatic impact of SIBO and its impact on symptomatic medication are also briefly discussed.     

Lantibiotics Produced by Oral Inhabitants as a Trigger for Dysbiosis of Human Intestinal Microbiota

Lantibiotics are a type of bacteriocin produced by Gram-positive bacteria and have a wide spectrum of Gram-positive antimicrobial activity. In this study, we determined that Mutacin I/III and Smb (a dipeptide lantibiotic), which are mainly produced by the widespread cariogenic bacterium Streptococcus mutans, have strong antimicrobial activities against many of the Gram-positive bacteria which constitute the intestinal microbiota. These lantibiotics also demonstrate resistance to acid and temperature. Based on these features, we predicted that lantibiotics may be able to persist into the intestinal tract maintaining a strong antimicrobial activity, affecting the intestinal microbiota. Saliva and fecal samples from 69 subjects were collected to test this hypothesis and the presence of lantibiotics and the composition of the intestinal microbiota were examined. We demonstrate that subjects possessing lantibiotic-producing bacteria in their oral cavity exhibited a tendency of decreased species richness and have significantly reduced abundance of the phylum Firmicutes in their intestinal microbiota. Similar results were obtained in the fecal microbiota of mice fed with S. mutans culture supernatant containing the lantibiotic bacteriocin Mutacin I. These results showed that lantibiotic bacteriocins produced in the oral cavity perturb the intestinal microbiota and suggest that oral bacteria may be one of the causative factors of intestinal microbiota dysbiosis.     

Candida Administration in Bilateral Nephrectomy Mice Elevates Serum (1→3)-β-D-glucan That Enhances Systemic Inflammation Through Energy Augmentation in Macrophages

Systemic inflammation, from gut translocation of organismal molecules, might worsen uremic complications in acute kidney injury (AKI). The monitoring of gut permeability integrity and/or organismal molecules in AKI might be clinically beneficial. Due to the less prominence of Candida albicans in human intestine compared with mouse gut, C. albicans were orally administered in bilateral nephrectomy (BiN) mice. Gut dysbiosis, using microbiome analysis, and gut permeability defect (gut leakage), which was determined by fluorescein isothiocyanate-dextran and intestinal tight-junction immunofluorescent staining, in mice with BiN-Candida was more severe than BiN without Candida. Additionally, profound gut leakage in BiN-Candida also resulted in gut translocation of lipopolysaccharide (LPS) and (1→3)-β-D-glucan (BG), the organismal components from gut contents, that induced more severe systemic inflammation than BiN without Candida. The co-presentation of LPS and BG in mouse serum enhanced inflammatory responses. As such, LPS with Whole Glucan Particle (WGP, a representative BG) induced more severe macrophage responses than LPS alone as determined by supernatant cytokines and gene expression of downstream signals (NFκB, Malt-1 and Syk). Meanwhile, WGP alone did not induced the responses. In parallel, WGP (with or without LPS), but not LPS alone, accelerated macrophage ATP production (extracellular flux analysis) through the upregulation of genes in mitochondria and glycolysis pathway (using RNA sequencing analysis), without the induction of cell activities. These data indicated a WGP pre-conditioning effect on cell energy augmentation. In conclusion, Candida in BiN mice accelerated gut translocation of BG that augmented cell energy status and enhanced pro-inflammatory macrophage responses. Hence, gut fungi and BG were associated with the enhanced systemic inflammation in acute uremia.     

Mechanisms by Which Probiotic Bacteria Attenuate the Risk of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the second leading cause of cancer-related deaths worldwide. Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV), alcoholic liver disease (ALD), and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) are the major extrinsic risk factors of HCC development. Genetic background is pivotal in HCC pathogenesis, and both germline mutations and single nucleotide polymorphism (SNP) are intrinsic risk factors of HCC. These HCC risk factors predispose to hepatic injury and subsequent activation of fibrogenesis that progresses into cirrhosis and HCC. Probiotic bacteria can mitigate HCC risk by modulating host gut microbiota (GM) to promote growth of beneficial microbes and inhibit HCC-associated dysbiosis, thus preventing pathogen-associated molecular patterns (PAMPs)-mediated hepatic inflammation. Probiotics have antiviral activities against HBV and HCV infections, ameliorate obesity and risk of NAFLD/NASH, and their antioxidant, anti-proliferative, anti-angiogenic, and anti-metastatic effects can prevent the HCC pathogenesis. Probiotics also upregulate the expression of tumor suppressor genes and downregulate oncogene expression. Moreover, metabolites generated by probiotics through degradation of dietary phytochemicals may mitigate the risk of HCC development. These multiple anticancer mechanisms illustrate the potential of probiotics as an adjuvant strategy for HCC risk management and treatment.     

Regulation of Oxygen Homeostasis at the Intestinal Epithelial Barrier Site

The unique biology of the intestinal epithelial barrier is linked to a low baseline oxygen pressure (pO₂), characterised by a high rate of metabolites circulating through the intestinal blood and the presence of a steep oxygen gradient across the epithelial surface. These characteristics require tight regulation of oxygen homeostasis, achieved in part by hypoxia-inducible factor (HIF)-dependent signalling. Furthermore, intestinal epithelial cells (IEC) possess metabolic identities that are reflected in changes in mitochondrial function. In recent years, it has become widely accepted that oxygen metabolism is key to homeostasis at the mucosae. In addition, the gut has a vast and diverse microbial population, the microbiota. Microbiome–gut communication represents a dynamic exchange of mediators produced by bacterial and intestinal metabolism. The microbiome contributes to the maintenance of the hypoxic environment, which is critical for nutrient absorption, intestinal barrier function, and innate and/or adaptive immune responses in the gastrointestinal tract. In this review, we focus on oxygen homeostasis at the epithelial barrier site, how it is regulated by hypoxia and the microbiome, and how oxygen homeostasis at the epithelium is regulated in health and disease.     

TLR4 Deficiency Affects the Microbiome and Reduces Intestinal Dysfunctions and Inflammation in Chronic Alcohol-Fed Mice

Chronic alcohol abuse causes an inflammatory response in the intestinal tract with damage to the integrity of the mucosa and epithelium, as well as dysbiosis in the gut microbiome. However, the role of gut bacteria in ethanol effects and how these microorganisms interact with the immune system are not well understood. The aim of the present study was to evaluate if TLR4 alters the ethanol-induced intestinal inflammatory response, and whether the response of this receptor affects the gut microbiota profile. We analyzed the 16S rRNA sequence of the fecal samples from wild-type (WT) and TLR4-knockout (TLR4-KO) mice with and without ethanol intake for 3 months. The results demonstrated that chronic ethanol consumption reduces microbiota diversity and causes dysbiosis in WT mice. Likewise, ethanol upregulates several inflammatory genes (IL-1β, iNOS, TNF-α) and miRNAs (miR-155-5p, miR-146a-5p) and alters structural and permeability genes (INTL1, CDH1, CFTR) in the colon of WT mice. Our results further demonstrated that TLR4-KO mice exhibit a different microbiota that can protect against the ethanol-induced activation of the immune system and colon integrity dysfunctions. In short, our results reveal that TLR4 is a key factor for determining the gut microbiota, which can participate in dysbiosis and the inflammatory response induced by alcohol consumption.