Host mitochondria influence gut microbiome diversity: A role for ROS

Yardeni, Tal; Tanes, Ceylan; Bittinger, Kyle; Mattei, Lisa M.; Schaefer, Patrick; Singh, Larry N.; Wu, Gary D.; Murdock, Deborah G.; Wallace, Douglas C.

doi:10.1126/scisignal.aaw3159

Cited by 129 publications

(110 citation statements)

References 58 publications

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“…This may amplify the effect of eATP on tight junctions. On the other hand, it has been shown that functional changes in mitochondria directly change the microbiome [103] and intestinal epithelial cell and mucosal function at the host-microbe interface [104]. The inhibition of mitochondrial function by systemic eATP shown in this study might therefore be a direct cause of intestinal epithelial cell functional changes that lead to chronic changes in the microbial ecology of the gut.…”

Section: Microbiomementioning

confidence: 61%

Metabolic and Behavioral Features of Acute Hyperpurinergia and the Connection to Autism Spectrum Disorder

Zolkipli‐Cunningham

Naviaux

Nakayama

et al. 2020

Preprint

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Background. Since 2012, studies in mice, rats, and humans have suggested that abnormalities in purinergic signaling may be a final common pathway for many genetic and environmental causes of autism spectrum disorder (ASD). The current study in mice was conducted to characterize the bioenergetic, metabolomic, breathomic, and behavioral features of acute hyperpurinergia triggered by systemic injection of the purinergic agonist and danger signal, extracellular ATP (eATP). Methods. Responses were studied in C57BL/6J mice with ASD-like behaviors in the maternal immune activation (MIA) model and controls. Basal metabolic rates, respiratory exchange ratios (RER = VCO2/VO2), and locomotor activity were measured in CLAMS cages. Plasma metabolomics measured 401 metabolites. Breathomics measured 98 volatile organic compounds. Results. A 0.5 µmol/g dose of ATP dropped whole body oxygen consumption by 74% ± 6% (mean ± SEM, 5,303 to 1,382 ml/kg/hr, p<0.0001) and rectal temperature by 6.2˚ ± 0.3˚C (p<0.0001) in 30 minutes. Over 200 metabolites from 37 different biochemical pathways where changed. MIA animals were hypersensitive to the metabolic and behavioral responses triggered by eATP and poly(IC). Breathomic and metabolomic analysis revealed changes in folate-methylation-1-carbon, purines, pyrimidines, acyl-carnitines, glycolysis, aromatic and branch-chain amino acids, Krebs cycle, glutathione, urea cycle, phospholipids, sphingolipids, eicosanoids, cholesterol, bile acids, vitamins, and microbiome metabolism similar to children with ASD. Limitations. The responses to ATP were studied in only a single genetic strain of mice (C57BL/6J). Although similar to metabolic results reported in FVB mice and a small clinical trial in children with ASD, the generalizability of these results to larger studies in humans is unknown. The chronic effects of repeated postnatal ATP exposures were not tested. Conclusions. Acute hyperpurinergia produced metabolic and behavioral changes in mice that were similar to those found in children with ASD. These behaviors and metabolic changes were associated with mitochondrial functional changes that were profound but reversible.

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Section: Microbiomementioning

confidence: 61%

Metabolic and Behavioral Features of Acute Hyperpurinergia and the Connection to Autism Spectrum Disorder

Zolkipli‐Cunningham

Naviaux

Nakayama

et al. 2020

Preprint

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“…This increase in O 2 may provide a potential mechanistic explanation for changes in microbiome associated with GVHD and IBD. The change in O 2 levels might lead to dysbiosis with loss of microbial diversity, decrease in commensals such as obligate anaerobes and shift towards to aerobes and pathobionts in the microbiome of patients with GVHD and IBD 43 44 45 46 47 48 49 50 51 52 53 54 55 .…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Complex II In Intestinal Epithelial Cells Regulates T-cell Mediated Immunopathology

Fujiwara

Mathew

Kovalenko

et al. 2020

Preprint

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Keywords: mitochondria, succinate dehydrogenase, bone marrow transplantation, graft-versus-host 22 disease, intestinal epithelium 23 24 25Summary 26Intestinal epithelial cell (IEC) damage by T cells contributes to alloimmune, autoimmune and iatrogenic 27 diseases such as graft-versus-host disease (GVHD), inflammatory bowel disease (IBD) and immune 28 checkpoint blockade (ICB) mediated colitis, respectively. Despite significant advances in understanding 29 the aberrant biology of T cells in these diseases, little is known about how the fundamental biological 30 processes of the target IECs influence the disease severity. Here, through analyses of metabolic 31 pathways of IECs, we identified disruption of oxidative phosphorylation without a concomitant change 32 in glycolysis and an increase in succinate levels in several distinct in vivo models of T cell mediated 33 mediated gastrointestinal graft-versus-host disease (GI-GVHD) often have similar symptoms and cause 50 significant morbidity and mortality 1 5 6 . Although the pathophysiology of each of these diseases is a 51 complex interplay of the environmental and genetic factors, T cell mediated damage of IECs plays a 52 vital role in the cause and severity of all of these conditions. Immunosuppression with corticosteroids, 53 and anti-cytokine therapies have shown good results with adverse effects, but are still incomplete 5 7 8 . 54The biology and treatments of these diseases are often understood and targeted from the immune cell 55 3 and inflammation perspective, but the pathogenesis and severity from host IEC target cell perspective 56 remain undefined. 57 58 Emerging data in recent years have brought into focus the central role of immune cell metabolism in the 59 regulation of intestinal inflammatory diseases. APCs, including macrophages and dendritic cells, and T 60 cells show changes in metabolic programming, including morphological alterations in mitochondria, 61transitioning from glycolysis dependence (pro-inflammatory macrophages and effector T cells) to 62 oxidative phosphorylation (OXPHOS) dependence (anti-inflammatory macrophages and memory T 63 cells) 9 10 11 and regulate intestinal T cell mediated diseases such as GI GVHD and IBD. However, 64whether the metabolism of the targets of these pathogenic T cells in these diseases, the IECs, are 65 perturbed or reprogrammed, and if so, whether this has an impact on the disease severity remains 66 unknown. The mammalian GI tract is a relatively hypoxic region and thus, IECs are uniquely adapted to 67 this hypoxic environment 12 13 . In this study, we aimed to determine the metabolic changes in IECs when 68 they are targeted by pathogenic T effector cells. We found that in the context of pathogenic T cell 69 mediated damage, the IECs demonstrated a reduction in OXPHOS and accumulated succinate as a result 70 of decrease in SDHA, a component of mitochondrial complex II. The reduction of SDHA in IECs 71 aggravated disease severity in multiple T cell mediated models such as the alloimmune mediated GI 72 GVHD, ...

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“…Oxidative stress occurs as a result of an imbalance between reactive oxygen species and the defence system responsible for ROS elimination. Long-term high-fat diet induces oxidative stress in colon [11,12] besides inducing bacterial dysbiosis by changing the redox status [13,14]. Bacteria with higher resistance to oxidative stress (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Although the precise role of gut microbiota in obesity is still unknown, a dietary factor, especially high fat consumption, is considered to play an important role in linking obesity with gut microbiota. High-fat diet is known to increase the levels of oxidative stress in colon [11,12] and affect the composition of colonic microbiota [13,14]. Abdominal fat tissue is also known to directly increase reactive oxygen species (ROS) levels [15,16] Lactobacillus has been reported to show high diversity in resistance to oxidative stress across species [17,18] and strains [19], based on catalase activity.…”

Section: Introductionmentioning

confidence: 99%

High-fat diet-induced oxidative stress links increased colonisation of Lactobacillus sakei with its anti-inflammatory properties in obesity

Lee

Bae

Kim

et al. 2020

Preprint

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Abstract Background: Obesity is one of the major public health problems related to various chronic health conditions, with steadily increasing prevalence worldwide. Lactobacillus provides various benefits to the host body; however, its role in obesity is unknown. Results: In this study, we found higher colonisation of Lactobacillus sakei species in obesity group, which in turn was related to increased reactive oxygen species (ROS) levels induced by higher fat intake. We isolated L. sakei ob4.1 strain from the faeces of one subject with obesity and compared its genetic and molecular features with those of L. sakei DSM 20017 strain. L. sakei ob4.1 showed higher catalase activity, which was regulated by oxidative stress at gene transcriptional levels. L. sakei ob4.1 maintained colon epithelial cell-adhesion ability under ROS stimulation, and live bacteria could decrease colon epithelial inflammation in a dose-dependent manner. Establishing a mouse model revealed high-fat diet-induced colon ROS to be associated with increased colonisation of L. sakei ob4.1 through catalase activity. Four-week supplementation with this strain could reduce colon inflammation effectively, though not so for body weight or ROS levels in high fat-fed mice. Conclusion: We, therefore, concluded that changes in host gut-oxidative stress levels could link high fat-induced obesity to increased colonisation of L. sakei ob4.1 , and this strain could be potent as anti-inflammatory probiotic in obese population with gut inflammation. Keywords Lactobacillus sakei; Obesity; Gut microbiome; Reactive oxygen stress; Inflammation; High fat diet

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Host mitochondria influence gut microbiome diversity: A role for ROS

Cited by 129 publications

References 58 publications

Metabolic and Behavioral Features of Acute Hyperpurinergia and the Connection to Autism Spectrum Disorder

Metabolic and Behavioral Features of Acute Hyperpurinergia and the Connection to Autism Spectrum Disorder

Mitochondrial Complex II In Intestinal Epithelial Cells Regulates T-cell Mediated Immunopathology

High-fat diet-induced oxidative stress links increased colonisation of Lactobacillus sakei with its anti-inflammatory properties in obesity

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