Microbiota in health and diseases

Chen Z., Xiao C.

Type 2 diabetes (T2D) is a chronic metabolic disease characterized by hyperglycemia due to insulin resistant. Mounting evidence has correlated T2D to alterations in the composition of gut microbiota. Accordingly, targeting the gut microbiota has become an emerging strategy to benefit the T2D management. To get a better insight into the rationale for targeting gut microbiota in T2D treatment, we herein reviewed the change of gut microbiota composition in T2D, factors shaping gut microbiota, and potential mechanisms about contribution of gut microbiota to T2D pathogenesis.At present, it has become possible to use intestinal microorganism capsules, bacteria liquid and other preparations to carry out FMT for the treatment and intervention of T2D with insulin resistance and immune-mediated Type 1 diabetes(T1D).

Han Y., Jia Z., Shi J., Wang W., He K.

Introduction: With the outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the interaction between the host and SARS-CoV-2 was widely studied. However, it is unclear whether and how SARS-CoV-2 infection affects lung microflora, which contribute to COVID-19 complications. Methods: Here, we analyzed the metatranscriptomic data of bronchoalveolar lavage fluid (BALF) of 19 COVID-19 patients and 23 healthy controls from 6 independent projects and detailed the active microbiota landscape in both healthy individuals and COVID-19 patients. Results: The infection of SARS-CoV-2 could deeply change the lung microbiota, evidenced by the α-diversity, β-diversity, and species composition analysis based on bacterial microbiota and virome. Pathogens (e.g., Klebsiella oxytoca causing pneumonia as well), immunomodulatory probiotics (e.g., lactic acid bacteria and Faecalibacterium prausnitzii, a butyrate producer), and Tobacco mosaic virus (TMV) were enriched in the COVID-19 group, suggesting a severe microbiota dysbiosis. The significant correlation between Rothia mucilaginosa, TMV, and SARS-CoV-2 revealed drastic inflammatory battles between the host, SARS-CoV-2, and other microbes in the lungs. Notably, TMV only existed in the COVID-19 group, while human respirovirus 3 (HRV 3) only existed in the healthy group. Our study provides insights into the active microbiota in the lungs of COVID-19 patients and would contribute to the understanding of the infection mechanism of SARS-CoV-2 and the treatment of the disease and complications. Conclusion: SARS-COV-2 infection deeply altered the lung microbiota of COVID-19 patients. The enrichment of several other pathogens, immunomodulatory probiotics (lactic acid or butyrate producers), and TMV in the COVID-19 group suggests a complex and active lung microbiota disorder.

Wu Y., Xu H., Tu X., Gao Z.

Hypertension is a significant risk factor for cardiovascular and cerebrovascular diseases, and its development involves multiple mechanisms. Gut microbiota has been reported to be closely linked to hypertension. Short-chain fatty acids (SCFAs)—the metabolites of gut microbiota—participate in hypertension development through various pathways, including specific receptors, immune system, autonomic nervous system, metabolic regulation and gene transcription. This article reviews the possible mechanisms of SCFAs in regulating blood pressure and the prospects of SCFAs as a target to prevent and treat hypertension.

Klünemann M., Andrejev S., Blasche S., Mateus A., Phapale P., Devendran S., Vappiani J., Simon B., Scott T.A., Kafkia E., Konstantinidis D., Zirngibl K., Mastrorilli E., Banzhaf M., Mackmull M., et. al.

Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping of the interactions between drugs and bacteria has only started recently1 and the main underlying mechanism proposed is the chemical transformation of drugs by microorganisms (biotransformation). Here we investigated the depletion of 15 structurally diverse drugs by 25 representative strains of gut bacteria. This revealed 70 bacteria–drug interactions, 29 of which had not to our knowledge been reported before. Over half of the new interactions can be ascribed to bioaccumulation; that is, bacteria storing the drug intracellularly without chemically modifying it, and in most cases without the growth of the bacteria being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using click chemistry, thermal proteome profiling and metabolomics. We find that duloxetine binds to several metabolic enzymes and changes the metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the composition of the community through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioural response of Caenorhabditis elegans to duloxetine. Together, our results show that bioaccumulation by gut bacteria may be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, probably in an individual manner. An analysis of the interactions between 15 drugs and 25 gut bacterial strains shows that bioaccumulation of drugs within bacterial cells is another mechanism through which gut microorganisms can alter drug availability and efficacy.

Sulaiman I., Chung M., Angel L., Tsay J.J., Wu B.G., Yeung S.T., Krolikowski K., Li Y., Duerr R., Schluger R., Thannickal S.A., Koide A., Rafeq S., Barnett C., Postelnicu R., et. al.

Respiratory failure is associated with increased mortality in COVID-19 patients. There are no validated lower airway biomarkers to predict clinical outcome. We investigated whether bacterial respiratory infections were associated with poor clinical outcome of COVID-19 in a prospective, observational cohort of 589 critically ill adults, all of whom required mechanical ventilation. For a subset of 142 patients who underwent bronchoscopy, we quantified SARS-CoV-2 viral load, analysed the lower respiratory tract microbiome using metagenomics and metatranscriptomics and profiled the host immune response. Acquisition of a hospital-acquired respiratory pathogen was not associated with fatal outcome. Poor clinical outcome was associated with lower airway enrichment with an oral commensal (Mycoplasma salivarium). Increased SARS-CoV-2 abundance, low anti-SARS-CoV-2 antibody response and a distinct host transcriptome profile of the lower airways were most predictive of mortality. Our data provide evidence that secondary respiratory infections do not drive mortality in COVID-19 and clinical management strategies should prioritize reducing viral replication and maximizing host responses to SARS-CoV-2. Analysis of lower respiratory tract microbiome of mechanically ventilated COVID-19 patients rules out a role for secondary respiratory infections as drivers of increased mortality.

Wingfield B., Lapsley C., McDowell A., Miliotis G., McLafferty M., O’Neill S.M., Coleman S., McGinnity T.M., Bjourson A.J., Murray E.K.

A growing body of evidence supports an important role for alterations in the brain-gut-microbiome axis in the aetiology of depression and other psychiatric disorders. The potential role of the oral microbiome in mental health has received little attention, even though it is one of the most diverse microbiomes in the body and oral dysbiosis has been linked to systemic diseases with an underlying inflammatory aetiology. This study examines the structure and composition of the salivary microbiome for the first time in young adults who met the DSM-IV criteria for depression (n = 40) and matched controls (n = 43) using 16S rRNA gene-based next generation sequencing. Subtle but significant differences in alpha and beta diversity of the salivary microbiome were observed, with clear separation of depressed and healthy control cohorts into distinct clusters. A total of 21 bacterial taxa were found to be differentially abundant in the depressed cohort, including increased Neisseria spp. and Prevotella nigrescens, while 19 taxa had a decreased abundance. In this preliminary study we have shown that the composition of the oral microbiome is associated with depression in young adults. Further studies are now warranted, particuarly investigations into whether such shifts play any role in the underling aetiology of depression.

Vyhnalova T., Danek Z., Gachova D., Linhartova P.B.

Dysbiosis in the oral environment may play a role in the etiopathogenesis of oral squamous cell carcinoma (OSCC). This review aims to summarize the current knowledge about the association of oral microbiota with OSCC and to describe possible etiopathogenetic mechanisms involved in processes of OSCC development and progression. Association studies included in this review were designed as case–control/case studies, analyzing the bacteriome, mycobiome, and virome from saliva, oral rinses, oral mucosal swabs, or oral mucosal tissue samples (deep and superficial) and comparing the results in healthy individuals to those with OSCC and/or with premalignant lesions. Changes in relative abundances of specific bacteria (e.g., Porphyromonas gingivalis, Fusobacterium nucleatum, Streptococcus sp.) and fungi (especially Candida sp.) were associated with OSCC. Viruses can also play a role; while the results of studies investigating the role of human papillomavirus in OSCC development are controversial, Epstein–Barr virus was positively correlated with OSCC. The oral microbiota has been linked to tumorigenesis through a variety of mechanisms, including the stimulation of cell proliferation, tumor invasiveness, angiogenesis, inhibition of cell apoptosis, induction of chronic inflammation, or production of oncometabolites. We also advocate for the necessity of performing a complex analysis of the microbiome in further studies and of standardizing the sampling procedures by establishing guidelines to support future meta-analyses.

Chen J., Vitetta L.

The gut microbiota is well known to exert multiple benefits on human health including protection from disease causing pathobiont microbes. It has been recognized that healthy intestinal microbiota is of great importance in the pathogenesis of COVID-19. Gut dysbiosis caused by various reasons is associated with severe COVID-19. Therefore, the modulation of gut microbiota and supplementation of commensal bacterial metabolites could reduce the severity of COVID-19. Many approaches have been studied to improve gut microbiota in COVID-19 including probiotics, bacterial metabolites, and prebiotics, as well as nutraceuticals and trace elements. So far, 19 clinical trials for testing the efficacy of probiotics and synbiotics in COVID-19 prevention and treatment are ongoing. In this narrative review, we summarize the effects of various approaches on the prevention and treatment of COVID-19 and discuss associated mechanisms.

Li Q., Gao B., Siqin B., He Q., Zhang R., Meng X., Zhang N., Zhang N., Li M.

Cardiovascular disease is the main cause of death worldwide, and traditional cardiovascular risk factors cannot fully explain the occurrence of the disease. In recent years, the relationship between gut microbiota and its metabolites and cardiovascular disease has been a hot study topic. The changes in gut microbiota and its metabolites are related to the occurrence and development of atherosclerosis, myocardial infarction, heart failure, and hypertension. The mechanisms by which gut microbiota and its metabolites influence cardiovascular disease have been reported, although not comprehensively. Additionally, following ingestion, flavonoids are decomposed into phenolic acids that are more easily absorbed by the body after being processed by enzymes produced by intestinal microorganisms, which increases flavonoid bioavailability and activity, consequently affecting the onset of cardiovascular disease. However, flavonoids can also inhibit the growth of harmful microorganisms, promote the proliferation of beneficial microorganisms, and maintain the balance of gut microbiota. Hence, it is important to study the relationship between gut microbiota and flavonoids to elucidate the protective effects of flavonoids in cardiovascular diseases. This article will review the role and mechanism of gut microbiota and its metabolites in the occurrence and development of atherosclerosis, myocardial infarction, heart failure, and hypertension. It also discusses the potential value of flavonoids in the prevention and treatment of cardiovascular disease following their transformation through gut microbiota metabolism.

Li L., Zhang Y., Liu X., Meng X., Zhao R., Ou L., Li B., Xing T.

Periodontitis is a type of systemic immune inflammation that is caused by the complex infection of a variety of microorganisms in the subgingival plaque and the imbalance of the microbial ecological environment in the mouth. Periodontitis and chronic kidney disease (CKD) share many risk factors, such as obesity, smoking, and age. A growing body of data supports a strong correlation between periodontitis and kidney disease. Evidence supports the role of periodontal inflammation and elevated serum inflammatory mediators in renal atherosclerosis, renal deterioration, and end-stage renal disease (ESRD) development. Periodontitis is a risk factor for kidney disease. However, to our knowledge, there are few studies detailing the possible link between periodontitis and CKD. This review summarizes the possible mechanisms underlying periodontitis and CKD. More importantly, it highlights novel and potential pathogenic factors for CKD, including bacteria, pro-inflammatory mediators and oxidative stress. However, most research on the relationship between periodontitis and systemic disease has not determined causality, and these diseases are largely linked by bidirectional associations. Future research will focus on exploring these links to contribute to new treatments for CKD.

Cunningham M., Vinderola G., Charalampopoulos D., Lebeer S., Sanders M.E., Grimaldi R.

There is substantial demand for gut health products incorporating probiotics and prebiotics. They are being delivered as ingredients in an increasing range of different product formulations. While new delivery matrices are assessed for their potential impact on cell viability and prebiotic degradation, it is unknown whether they should be expected to independently alter the clinical effect of a given probiotic and prebiotic. We provide an overview of preclinical and clinical data to examine the degree to which probiotic and prebiotic efficacy may be altered by processing and incorporation into various delivery matrices. We also consider the impact of inter-individual host factors on product efficacy. We further review regulatory positions across the globe on substantiation of prebiotic and probiotic efficacy in the final product format. In vitro data suggest that the delivery matrix may interact with prebiotic and probiotic functions via various physicochemical interactions with molecular and cellular structures and changes in cellular expression. However, direct evidence to suggest these changes have a significant in vivo impact is very limited. Indeed, meta-analyses suggest a robustness of effect across delivery matrices. Regulatory expectations vary among regions, but scope typically exists for adequate scientific justification to translate probiotic or prebiotic evidence across product formats. Early evidence suggests host factors such as diet, health and microbiome status are likely to play an important role in an individual's response to a given probiotic and prebiotic. • Probiotic and prebiotic formulation changes can affect in vitro functionality. • Meta-analyses suggest a robustness of effect across different formulations. • Host microbiome, health status and meal context may influence clinical benefit. • Regulators expect scientific rationale for use of evidence across products formats. • Performance mapping can be used to assess potential matrix-related effects.

Yang I., Arthur R.A., Zhao L., Clark J., Hu Y., Corwin E.J., Lah J.

Inflammation and immune mechanisms are believed to play important roles in Alzheimer's disease pathogenesis. Research supports the link between poor oral health and Alzheimer's disease. Periodontal disease and dental caries represent the two most common infections of the oral cavity. This study focused on a precursor to Alzheimer's disease, mild cognitive impairment (MCI). Using 16S rRNA sequencing, we characterized and compared the oral microbiome of 68 older adults who met the criteria for MCI or were cognitively normal, then explored relationships between the oral microbiome, diagnostic markers of MCI, and blood markers of systemic inflammation. Two taxa, Pasteurellacae and Lautropia mirabilis were identified to be differentially abundant in this cohort. Although systemic inflammatory markers did not differentiate the two groups, differences in five cerebrospinal fluid inflammatory mediators were identified and had significant associations with MCI. Because inflammatory markers may reflect CNS changes, pursuing this line of research could provide opportunities for new diagnostic tools and illuminate mechanisms for prevention and mitigation of Alzheimer's disease.

Furuyama N., Sircili M.P.

Gram-negative bacteria produce outer membrane vesicles (OMVs) with 10 to 300 nm of diameter. The contribution of OMVs to bacterial pathogenesis is a topic of great interest, and their capacity to be combined with antigens impact in the future to the development of vaccines.

Tsay J.J., Wu B.G., Sulaiman I., Gershner K., Schluger R., Li Y., Yie T., Meyn P., Olsen E., Perez L., Franca B., Carpenito J., Iizumi T., El-Ashmawy M., Badri M., et. al.

Abstract In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs, and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB–IV tumor–node–metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I–IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB–IV disease. In addition, this lower airway microbiota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers. Significance: Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis. See related commentary by Zitvogel and Kroemer, p. 224. This article is highlighted in the In This Issue feature, p. 211

Zhou A., Lei Y., Tang L., Hu S., Yang M., Wu L., Yang S., Tang B.

The gut microbiota plays a crucial role in the development of the immune system and confers benefits or disease susceptibility to the host. Emerging studies have indicated the gut microbiota could affect pulmonary health and disease through cross talk between the gut microbiota and the lungs. Gut microbiota dysbiosis could lead to acute or chronic lung disease, such as asthma, tuberculosis, and lung cancer. In addition, the composition of the gut microbiota may be associated with different lung diseases, the prevalence of which also varies by age.

Okunlola F.O., Okunlola A.R., Adetuyi B.O., Soliman M.E., Alexiou A., Papadakis M., Fawzy M.N., El-Saber Batiha G.

Liu X., Mei L., Wang J., Liu X., Yang Y., Wu Z., Ji Y.

Liu Z., Qin X., Zhang B., Nong K., Chen W., Yang Z., Lang W., Liu X., Li L., Wang X., Shi H., Zhang H.

Sliti A., Kim R., Lee D., Shin J.

Akpoghelie P.O., Edo G.I., Ali A.B., Yousif E., Zainulabdeen K., Owheruo J.O., Isoje E.F., Igbuku U.A., Essaghah A.E., Makia R.S., Ahmed D.S., Umar H., Alamiery A.A.

Garg G., Trisal A., Singh A.K.

de Lange M., Yarosh V., Farell K., McDonnell C., Patil R., Hawthorn I., Jung M., Wenje S., Steinert J.R.

Mallick K., Khodve G., Ruwatia R., Banerjee S.

Mondal T., Chattopadhyay D., Mondal P.S., Das S., Mondal A., Das A., Samanta S., Saha T.

Shuhan D., Yunpeng D., Haiyang W., Wenhan Y., Ai W., Liu li

Zhou Y., Zhang L., Lin L., Liu Y., Li Q., Zhao Y., Zhang Y.

Abavisani M., Tafti P., Khoshroo N., Ebadpour N., Khoshrou A., Kesharwani P., Sahebkar A.

Cheng B., Feng H., Li C., Jia F., Zhang X.

Mehta I., Juneja K., Nimmakayala T., Bansal L., Pulekar S., Duggineni D., Ghori H.K., Modi N., Younas S.

Tulio E.F., Lucini F., de Lima A.C., Garoni Martins do Carmo N.D., Barbosa M.D., de Almeida de Souza G.H., Rossato L.