The gastrointestinal microbiome in critical illness: A Clinician's guide to mechanisms, emerging tools, and therapeutic questions

ABSTRACTSeasonal influenza outbreaks represent a large burden for the health care system as well as the economy. While the role of the microbiome has been elucidated in the context of various diseases, the impact of respiratory viral infections on the human microbiome is largely unknown. In this study, swine was used as an animal model to characterize the temporal dynamics of the respiratory and gastrointestinal microbiome in response to an influenza A virus (IAV) infection. A multi-omics approach was applied on fecal samples to identify alterations in microbiome composition and function during IAV infection. We observed significantly altered microbial richness and diversity in the gastrointestinal microbiome after IAV infection. In particular, increased abundances of Prevotellaceae were detected, while Clostridiaceae and Lachnospiraceae decreased. Moreover, our metaproteomics data indicated that the functional composition of the microbiome was heavily affected by the influenza infection. For instance, we identified decreased amounts of flagellin, correlating with reduced abundances of Lachnospiraceae and Clostridiaceae, possibly indicating involvement of a direct immune response toward flagellated Clostridia during IAV infection. Furthermore, enzymes involved in short-chain fatty acid (SCFA) synthesis were identified in higher abundances, while metabolome analyses revealed rather stable concentrations of SCFAs. In addition, 16S rRNA gene sequencing was used to characterize effects on the composition and natural development of the upper respiratory tract microbiome. Our results showed that IAV infection resulted in significant changes in the abundance of Moraxellaceae and Pasteurellaceae in the upper respiratory tract. Surprisingly, temporal development of the respiratory microbiome structure was not affected.IMPORTANCE Here, we used swine as a biomedical model to elucidate the impact of influenza A H1N1 infection on structure and function of the respiratory and gastrointestinal tract microbiome by employing a multi-omics analytical approach. To our knowledge, this is the first study to investigate the temporal development of the porcine microbiome and to provide insights into the functional capacity of the gastrointestinal microbiome during influenza A virus infection.

Are Proton Pump Inhibitors Affecting Intestinal Microbiota Health?

BackgroundThe gastrointestinal microbiome is an important component of the human body and is closely related to human health and disease. This study describes the hotspots of the human gastrointestinal microbiome research and its evolution in the past decade, evaluates the scientific cooperation network, and finally predicts the field’s future development trend using bibliometric analysis and a visualized study.MethodsWe searched the original articles from January 2010 to February 2021 in the Scopus database using the term “gastrointestinal microbiome” and its synonyms. CiteSpace was used to construct country and author co-occurrence map; conduct journal, citation cocitation analysis, and reference co-citation knowledge map; and form a keywords co-occurrence map, a clustering knowledge map, timeline view of keywords, and burst term map.ResultA total of 4444 documents published from January 2010 to February 2021 were analysed. In approximately the past decade, the number of articles on the human gastrointestinal microbiome has increased rapidly, and the research topics focus on different populations, research methods, and detection methods. All countries and regions in the world, led by the US, are studying the human gastrointestinal microbiome, and many research teams with close cooperation have been formed. The research has been published extensively in microbiology journals and clinical medicine journals, and the highly cited articles mainly describe the relationship between gastrointestinal microorganisms and human health and disease. Regarding the research emphasis, researchers' exploration of the human gastrointestinal microbiome (2011–2013) was at a relatively macro and superficial stage and sought to determine how the gastrointestinal microbiome relates to humans. From 2014 to 2017, increasingly more studies were conducted to determine the interaction between human gastrointestinal flora and various organs and systems. In addition, researchers (2018–2021) focused on the gastrointestinal microbial community and the diversity of certain types of microbes.ConclusionOver time, the scope of the research on the clinical uses of the gastrointestinal microbiome gradually increased, and the contents were gradually deepened and developed towards a more precise level. The study of the human gastrointestinal microbiome is an ongoing research hotspot and contributes to human health.

Beneficial roles of gastrointestinal and urinary microbiomes in kidney stone prevention via their oxalate-degrading ability and beyond

Human health is intricately intertwined with the composition and function of the trillions of microorganisms that make up the gastrointestinal (GI) microbiome. The GI microbiome is essentially a microbial organ that provides metabolic, immunologic, and protective functions for the host. Habitual diet, changes in macronutrient composition, and consumption of nondigestible dietary fibers have all been shown to impact the human GI microbiome. Intriguingly, the impact of diet on the microbiome may be related not only to what humans eat but also to the timing of food consumption. Emerging preclinical research suggests that gut microbes experience diurnal rhythms, and the health effects of eating patterns, including time-restricted feeding and meal frequency, may be related to the GI microbiome. Herein, the complex connections among circadian rhythms, eating behaviors, the GI microbiome, and health are reviewed, highlighting the need for additional translational research in this area.

The recognition of the profound impact of the human gastrointestinal microbiome (GM) on human autoimmune diseases has gradually increased thanks to deeper research efforts. As a systemic autoimmune disease, primary Sjögren's syndrome (pSS) cannot be completely cured. Human studies have revealed that GM species and diversity are altered in patients with pSS compared with healthy individuals. Animal studies have provided possible mechanisms for the association between pSS and GM. The potential role of GM in pSS is exerted through several mechanisms. GM dysbiosis leads to increased intestinal permeability, which increases the risk of GM antigen exposure and activates specific autoreactive T lymphocytes via "molecular mimicry". In addition, GM antigen exposure and intestinal immune tolerance loss caused by GM dysbiosis together induce chronic local gut mucosal inflammation, which deteriorates to systemic chronic non-specific inflammation with the circulation of pro-inflammatory lymphocytes and cytokines. These factors eventually activate autoreactive B lymphocytes and lead to pSS. If GM plays a key role in the pathogenesis of pSS, clarifying the underlying mechanisms will be helpful for the development of new therapies targeting GM for dry eye associated with pSS. This review summarizes the latest knowledge about the relationship between GM and pSS, with the aim of contributing to future research and to the development of new clinical applications.

e20542 Background: Human gastrointestinal microbiome (GM) plays a role in food digestion, drug metabolism and protection against infections. We systematically reviewed the outcomes for multiple myeloma (MM) patients (pts) and its changes in GM diversity (GMD) with regimen-related toxicities. Methods: After a systematic search of PubMed, Embase, Web of Science, Cochrane, and Clinicaltrials.gov (until 01/12/2020), 9 out of 135 studies met our inclusion criteria. Results: GM changes were studied in 1343 pts. 1070 pts received Autologous (Auto) and 119 pts received Allogeneic (Allo) hematopoietic cell transplantation (HCT). 1. Impact of Induction without HCT: Higher levels of Eubacterium hallii and Faecalibacterium prausnitzii in 16 (MM) minimal residual disease (MRD) –ive pts and lower levels in 18 (MM) MRD +ive pts were noted (Pianko 2019). 2. Impact of HCT and microbiome: 1142 pts (MM = 1011) were studied; day+15 samples showed reduction of Bacteroidetes in Auto-HCT compared with Allo-HCT pts. Pts with graft versus host disease (GVHD) harbored more Firmicutes, Proteobacteria and less Bacteroidetes than pts without GVHD (Chiusolo 2015). Day+30 fecal samples (FS) revealed increase in Proteobacteria, Clostridium difficile and decrease in Firmicutes, Fusarium in FS while oral samples (OrS) showed increase in Firmicutes and decrease in Proteobacteria and Glomerella. Increased gastrointestinal adverse effects (AEs) (40%) correlated with decreased GMD especially in pts with ulcerative oral mucositis (OM) (Alexa 2019, El-Jurdi 2019, Apewokin 2015). At 3 years, Allo-HCT pts with highest GMD manifested least treatment-related mortality (TRM) (9%) and vice versa (Taur 2014). 3. Impact of Post-HCT Lactobacillus Probiotics (LBP) or Antibiotics: Improvement in AEs with LBP was statistically insignificant (Gorshein 2017, Giammarco 2016). Pts showed better clinical outcomes with ciprofloxacin and metronidazole (Cp-M) (n = 68) than Ciprofloxacin (n = 66) alone; i.e. overall survival (49% vs 42%), increased number of FS without anaerobic bacteria (53% vs 23%), GVHD (25% vs 50%), OM (82% vs 92%) (Beelen 1999). Conclusions: Treatment for MM alters microbiome diversity. Increased diversity was associated with fewer gastrointestinal AEs. Improvement in AEs with LBP was statistically insignificant. Post-HCT use of Cp-M showed better overall survival.

A healthy gastrointestinal (GI) microbiome has been shown to be essential for proper nutrient absorption and metabolism, maintenance of intestinal epithelial integrity and osmolarity, gut immunomodulation, and overall health. One of the most effective ways to promote a healthy GI microbiome is through dietary interventions, such as the addition of prebiotics. Prebiotics are substrates that are selectively utilized by the host GI microbiome through fermentation to confer a health benefit. However, research on prebiotics in companion animals is limited, especially in growing animals. Thus, this study was conducted to assess the effects of a novel prebiotic fiber blend on key parameters related to intestinal health and growth in puppies. Twenty-two puppies at least 4 months of age but not older than 10 months were fed a commercially available dry food during a prefeed period, and then fed a similarly formulated test food with the addition of the prebiotic fiber blend for a minimum of 90 days. Serum and fecal samples were collected at the end of the prefeed period and throughout the test period. Puppies fed the test food grew as expected for puppies of this age. Complete blood count and serum chemistry analyses were clinically normal for all animals. Fecal score increased linearly, fecal moisture decreased linearly, and pH exhibited a cubic trend throughout the study duration. There was a linear increase in short-chain fatty acids throughout the study, which is associated with favorable digestive and overall health. The inflammatory cytokine interleukin-7 decreased linearly and interleukin-18 trended towards linear decrease. This study showed that puppies continued to grow and develop normally, and experienced serum and stool characteristics indicative of improved GI health when fed a growth food fortified with a novel prebiotic fiber blend. Furthermore, these results contribute to the overall understanding of the effects of prebiotics on the GI health of growing companion animals.

Swine are a major reservoir of an array of zoonotic Salmonella enterica subsp. enterica lineage I serovars including Derby, Typhimurium, and 4,[5],12:i:- (a.k.a. Monophasic Typhimurium). In this study, we assessed the gastrointestinal (GI) microbiome composition of pigs in different intestinal compartments and the feces following infection with specific zoonotic serovars of S. enterica (S. Derby, S. Monophasic, and S. Typhimurium). 16S rRNA based microbiome analysis was performed to assess for GI microbiome changes in terms of diversity (alpha and beta), community structure and volatility, and specific taxa alterations across GI biogeography (small and large intestine, feces) and days post-infection (DPI) 2, 4, and 28; these results were compared to disease phenotypes measured as histopathological changes. As previously reported, only S. Monophasic and S. Typhimurium induced morphological alterations that marked an inflammatory milieu restricted to the large intestine in this experimental model. S. Typhimurium alone induced significant changes at the alpha- (Simpson’s and Shannon’s indexes) and beta-diversity levels, specifically at the peak of inflammation in the large intestine and feces. Increased community dispersion and volatility in colonic apex and fecal microbiomes were also noted for S. Typhimurium. All three Salmonella serovars altered community structure as measured by co-occurrence networks; this was most prominent at DPI 2 and 4 in colonic apex samples. At the genus taxonomic level, a diverse array of putative short-chain fatty acid (SCFA) producing bacteria were altered and often decreased during the peak of inflammation at DPI 2 and 4 within colonic apex and fecal samples. Among all putative SCFA producing bacteria, Prevotella showed a broad pattern of negative correlation with disease scores at the peak of inflammation. In addition, Prevotella 9 was found to be significantly reduced in all Salmonella infected groups compared to the control at DPI 4 in the colonic apex. In conclusion, this work further elucidates that distinct swine-related zoonotic serovars of S. enterica can induce both shared (high resilience) and unique (altered resistance) alterations in gut microbiome biogeography, which helps inform future investigations of dietary modifications aimed at increasing colonization resistance against Salmonella through GI microbiome alterations.

IntroductionThe human gastrointestinal microbiome (GM) has been proposed to be integral in the pathogenesis of Parkinson’s disease (PD). Evidence supports a bidirectional interaction between the brain and the gut that is mediated by the GM. Dysbiosis of the GM is believed to negatively influence vital physiological functions in many diseases.MethodsWe reviewed the literature on changes in human physiological function associated with gut microbial community states in PD. In particular, we evaluated the literature for effects of GM dysbiosis on motor and non-motor features, dietary and lifestyle factors and medication use in PD.ResultsAltered GM profiles in PD have been suggested to disrupt vital signalling pathways within the microbiota-gut-brain axis, integral to regulating physiological digestive function and metabolic homeostasis. Unfavourable variations in the GM have been shown to perturb mood (anxiety/depression), cognition, perception (hallucinations/delusions), gastrointestinal motility, including constipation in PD. Further, varied clinical motor phenotypes, including postural instability and gait disturbance have been attributed to alterations in the GM, in addition to the use of catechol-O-methyltransferase inhibitors, anticholinergics and levodopa. Variations in dietary and lifestyle factors have also been inferred to cause alterations in GM profiles, including caffeine consumption, macronutrient intake, smoking and the effects of ageing and exercise.ConclusionsIt is apparent from the mounting evidence that alterations in the GM are intimately involved in PD pathogenesis. However, the GM can also be modulated by dietary, lifestyle and treatment factors that may influence motor and non-motor features as well as disease progression.

Purpose of ReviewThe aim of this review is to summarize the role of gastrointestinal microbiome (GM) in the development of type 2 diabetes mellitus (T2DM). Besides, we discuss the feasibility of applying FMT in the treatment of T2DM and propose a series of processes to refine the use of FMT in the treatment of T2DM.Recent FindingsT2DM is a metabolic disease which is connected with the GM. According to many researches, GM can produce a variety of metabolites such as bile acid, short chain fatty acids, lipopolysaccharides and trimethylamine oxide which play an important role in metabolism. FMT is a method to regulate GM and has been observed to be effective in the treatment of metabolic diseases such as T2DM in some mouse models and people. However, there is still a lack of direct evidence for the use of FMT in the treatment of T2DM, and the process of FMT is not standardized.SummaryDysregulation of GM is closely related to the development of T2DM. Promoting the conversion of GM in T2DM patients to normal population through FMT can reduce insulin resistance and lower their blood glucose level, which is an optional treatment for T2DM patients in the future. At present, the feasibility and limitations of applying FMT to the treatment of T2DM need to be further studied.

There is growing interest in understanding the complex relationship between psychosocial stress and the human gastrointestinal microbiome (GIM). This review explores the potential physiological pathways connecting these two and how they contribute to a proinflammatory environment that can lead to the development and progression of the disease. Exposure to psychosocial stress triggers the activation of the sympathetic nervous system (SNS) and hypothalamic-pituitary axis (HPA), leading to various physiological responses essential for survival and coping with the stressor. However, chronic stress in susceptible individuals could cause sustained activation of HPA and SNS, leading to immune dysregulation consisting of redistribution of natural killer (NK) cells in the bloodstream, decreased function of T and B cells, and elevation of proinflammatory cytokines such as interleukin-1, interleukin-6, tumor necrotic factor-α, interferon-gamma. It also leads to disruption of the GIM composition and increased intestinal barrier permeability, contributing to GIM dysbiosis. The GIM dysbiosis and elevated cytokines can lead to reciprocal effects and further stimulate the HPA and SNS, creating a positive feedback loop that results in a proinflammatory state underlying the pathogenesis and progression of stress-associated cardiovascular, gastrointestinal, autoimmune, and psychiatric disorders. Understanding these relationships is critical for developing new strategies for managing stress-related health disorders.

There is a clear association between the gastrointestinal (GI) microbiome and the development of chronic noncommunicable diseases, providing a rationale for the development of strategies that target the GI microbiota to improve human health. In this article, we discuss the potential of supplementing the human diet with nondigestible fermentable carbohydrates (NDFCs) to modulate the composition, structure, diversity, and metabolic potential of the GI microbiome in an attempt to prevent or treat human disease. The current concepts by which NDFCs can be administered to humans, including prebiotics, fermentable dietary fibers, and microbiota-accessible carbohydrates, as well as the mechanisms by which these carbohydrates exert their health benefits, are discussed. Epidemiological research presents compelling evidence for the health effects of NDFCs, with clinical studies providing further support for some of these benefits. However, rigorously designed human intervention studies with well-established clinical markers and microbial endpoints are still essential to establish (i) the clinical efficiency of specific NDFCs, (ii) the causal role of the GI microbiota in these effects, (iii) the underlying mechanisms involved, and (iv) the degree by which inter-individual differences between GI microbiomes influence these effects. Such studies would provide the mechanistic understanding needed for a systematic application of NDFCs to improve human health via GI microbiota modulation while also allowing the personalization of these dietary strategies.

The human gastrointestinal (gut) microbiome plays a critical role in maintaining host health and has been increasingly recognized as an important factor in precision medicine. High-throughput sequencing technologies have revolutionized -omics data generation, facilitating the characterization of the human gut microbiome with exceptional resolution. The analysis of various -omics data, including metatranscriptomics, metagenomics, glycomics, and metabolomics, holds potential for personalized therapies by revealing information about functional genes, microbial composition, glycans, and metabolites. This multi-omics approach has not only provided insights into the role of the gut microbiome in various diseases but has also facilitated the identification of microbial biomarkers for diagnosis, prognosis, and treatment. Machine learning algorithms have emerged as powerful tools for extracting meaningful insights from complex datasets, and more recently have been applied to metagenomics data via efficiently identifying microbial signatures, predicting disease states, and determining potential therapeutic targets. Despite these rapid advancements, several challenges remain, such as key knowledge gaps, algorithm selection, and bioinformatics software parametrization. In this mini-review, our primary focus is metagenomics, while recognizing that other -omics can enhance our understanding of the functional diversity of organisms and how they interact with the host. We aim to explore the current intersection of multi-omics, precision medicine, and machine learning in advancing our understanding of the gut microbiome. A multidisciplinary approach holds promise for improving patient outcomes in the era of precision medicine, as we unravel the intricate interactions between the microbiome and human health.

Commensal gastrointestinal bacteria resist the expansion of pathogens and are lost during critical illness, facilitating pathogen colonization and infection. We performed a prospective, ICU-based study to determine risk factors for loss of gut colonization resistance during the initial period of critical illness. Rectal swabs were taken from adult ICU patients within 4 hours of admission and 72 hours later, and analyzed using 16S rRNA gene sequencing and selective culture for vancomycin-resistant Enterococcus (VRE). Microbiome data was visualized using principal coordinate analyses (PCoA) and assessed using a linear discriminant analysis algorithm and logistic regression modeling. 93 ICU patients were analyzed. At 72 hours following ICU admission, there was a significant decrease in the proportion of Clostridial Clusters IV/XIVa, taxa that produce short chain fatty acids (SCFAs). At the same time, there was a significant expansion in Enterococcus. Decreases in Cluster IV/XIVa Clostridia were associated with loss of gut microbiome colonization resistance (reduced diversity and community stability over time). In multivariable analysis, both decreased Cluster IV/XIVa Clostridia and increased Enterococcus after 72 hours were associated with receipt of antibiotics. Cluster IV/XIVa Clostridia, although a small fraction of the overall gastrointestinal microbiome, drove distinct clustering on PCoA. During initial treatment for critical illness, there was a loss of Cluster IV/XIVa Clostridia within the distal gut microbiome which associated with an expansion of VRE and with a loss of gut microbiome colonization resistance. Receipt of broad-spectrum antibiotics was associated with these changes.