FEMS Pathogens and Disease, 74, 2016, ftv096
doi: 10.1093/femspd/ftv096
Advance Access Publication Date: 23 October 2015
Current Opinion
CURRENT OPINION
Microbiota–mitochondria inter-talk: consequence for
microbiota–host interaction
Yann Saint-Georges-Chaumet1 and Marvin Edeas1,2,∗
1
Microbiota Mitochondria task force, Microbiota platform, Paris, France and 2 University of Paris 13 - Biotech
Biopole, Paris, France
∗
Corresponding author: University of Paris 13 - Biotech Biopole, Paris, France. Tel: +33155047755. E-mail: [email protected]
One sentence summary: The unknown but important role of mitochondria during the host–microbiota interaction may be crucial for the design of new
strategies for the management of microbiota-associated diseases.
Editor: Nicholas Carbonetti
ABSTRACT
New discoveries in metagenomics and clinical research have highlighted the importance of the gut microbiota for human
health through the regulation of the host immune response and energetic metabolism. The microbiota interacts with host
cells in particular by intermingling with the mitochondrial activities. This mitochondria–microbiota cross-talk is intriguing
because mitochondria share many common structural and functional features with the prokaryotic world. Several studies
reported a correlation between microbiota quality and diversity and mitochondrial function. The mitochondrial production
of reactive oxygen species (ROS) plays an important role during the innate immune response and inflammation, and is
often targeted by pathogenic bacteria. Data suggest that excessive mitochondrial ROS production may affect ROS signaling
induced by the microbiota to regulate the gut epithelial barrier. Finally, the microbiota releases metabolites that can directly
interfere with the mitochondrial respiratory chain and ATP production. Short chain fatty acids have beneficial effects on
mitochondrial activity. All these data suggest that the microbiota targets mitochondria to regulate its interaction with the
host. Imbalance of this targeting may result in a pathogenic state as observed in numerous studies. The challenge to find
new treatments will be to find strategies to modulate the quality and diversity of the microbiota rather than acting on
microbiota metabolites and microbiota-related factors.
Keywords: microbiota; mitochondria; oxidative stress; inflammation; host–bacteria interaction
MITOCHONDRIA AND MICROBIOTA: AN
INTRIGUING COMMUNE STORY
Recent advances in microbiology and clinical medicine have
shed new light on the importance of the microbiota for human
health. Composed of a thousand different species, representing
1013 cells, the microbiota plays an important role in the development of a functional intestine, and by helping the digestion
of food, provides nutrients for growth and well-being. Colonization of the gut by microorganisms is also necessary for the regulation of a well-balanced immune system (Kamada and Núñez
2014). The gut microbiota interacts with the enteric nervous sys-
tem and may modulate brain activities (Cryan and Dinan 2012;
Foster and McVey Neufeld 2013). Interestingly, several studies
have reported the important role of mitochondria during the
host/microbiota cross-talk (Walker et al. 2014; Zorov et al. 2014;
Lobet, Letesson and Arnould 2015). The aim of this paper is to
highlight the particular role of mitochondria during this process.
Common structure and function
Intriguingly, despite this role, mitochondria and bacterial members of microbiota share many features. Not surprisingly, these
common features are probably due to the probable prokaryotic
Received: 27 August 2015; Accepted: 15 October 2015
C FEMS 2015. All rights reserved. For permissions, please e-mail: [email protected]
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FEMS Pathogens and Disease, 2016, Vol. 74, No. 1
Figure 1. Microbiota and pathogenic bacteria target host cell through ROS regulation and DNA insertion. Commensal and pathogenic bacteria release factors that
modulate cell ROS concentration by acting on mitochondrial activity. Pathogenassociated molecular patterns activate the pattern recognition receptors (PRR)
and induce mitochondrial ROS production and nuclear gene expression. In parallel, commensal bacteria release formylated protein recognized by the formylated protein receptor (FPR) that activates NADPH oxidase (NOX) and increases
cytoplasmic ROS that are sensed by redox sensor proteins. High ROS production
is able to trigger an inflammatory response and increases cell oxidative stress.
Furthermore, cell stress can trigger mitochondrial and bacterial DNA insertion
in the nuclear genome leading to alteration of cellular gene expression. (1) Arrow 1: mitochondrial DNA insertion into the nucleus. (2) Arrow 2: bacterial DNA
insertion into the nucleus.
origin of mitochondria. Based on the endosymbiotic theory, the
ancestor of mitochondria is a member of the alphaproteobacteria phylum that developed a symbiotic relationship with the
eukaryotic ancestor cell (Degli Esposti et al. 2014). For example,
degraded mitochondrial proteins or mitochondrial DNA can activate formylated protein receptors (FPRs) in the way that microbial formylated proteins do to signal alien proteins in eukaryotic
cells (Neish 2013). Both bacterial and mitochondrial membranes
can be degraded through similar autophagic systems. Mitochondrial and bacterial ribosomes are more related to each other than
either is to eukaryotic ribosomes and are both sensitive to antibiotics (Kalghatgi et al. 2013). Some bacterial proteins can be
imported into the host mitochondria due to the similarity of
the mitochondrial targeting sequence and bacterial cytoplasmic
protein targeting sequence (Lucattini, Likic and Lithgow 2004).
The membranes of both are maternally inherited because the
microbiota of the newborn is derived from the mother’s microbiota and male mitochondria are eliminated during ovocyte fertilization.
Mitochondrial and microbiota DNA both colonize the
nuclear genome
The insertion of bacterial and mitochondrial DNA may continuously happened in the nuclear genome of the host cell. Several
reports have described the presence of DNA of mitochondrial
and bacterial origin in the nuclear genome (Fig. 1). Mitochondrial
DNA insertion (also called nuclear DNA sequences of mitochondrial origin, or NUMTs) has been well documented (Ricchetti,
Tekaia and Dujon 2004). Transfer of mitochondrial DNA into
the nucleus continues to occur in human cells during repair of
DNA double-strand breaks. Mitochondrial DNA integrates preferentially into coding or regulating regions, increasing mutation
rates and favoring cancer or the inflammatory response (Ric-
chetti, Tekaia and Dujon 2004). A recent study showed that bacterial DNA sequences can be found in human somatic cells and
are enriched in cancer cells (Riley et al. 2013). The mechanism
associated with these particular insertions remains unknown.
However, other examples of bacterial DNA insertion within the
nuclear genome has been previously documented. For example, Agrobacterium tumefaciens injects DNA provoking plant tumor growth and changes in host cell metabolism (Gelvin 2003).
These changes induce optimal growth conditions for bacteria.
Additionally, studies have demonstrated the ability of Bartonella
henselae to integrate its plasmid into human cells in vitro through
its type IV secretion system and induce the formation of benign
tumors in blood vessels (Schröder et al. 2011). The strong and
constant promiscuity of bacteria with host cells is known to favor oxidant stress. One can hypothesize that increased oxidant
stress may favor nuclear DNA alteration. Subsequent repair may
favor bacterial and mitochondrial DNA insertion. Whether these
mechanisms of mitochondria and/or microbiota DNA integration in the nuclear genome of eukaryotic cells are similar or not
is still unclear. However, such insertions may induce mutations,
at least in somatic tissue, and may provoke cancer as previously
observed.
A mitochondria–microbiota inter-talk may be crucial
for human health
Several reports show that syndromes like obesity, diabetes mellitus, Crohn’s disease or even autism and depression are associated with specific microbiota composition, in particular the
differential level of Bacteroides and Firmicutes phyla (Prakash
et al. 2011). The mechanisms regulating microbiota quality and
diversity are clearly multifactorial, including diet, presence of
pathogens, resistance to stress or general health conditions.
Several observations have shed light on interactions between
mitochondrial function and microbiota quality and diversity.
A recent report assessed the association of single nucleotide
polymorphism (SNP) of mitochondrial DNA haplogroups and
their association with specific microbiotal composition (Ma et al.
2014). The study shows that among SNPs of 89 European subjects, polymorphism in ND5, CYTB genes or the D-LOOP region
are strongly associated with specific microbiota composition.
Moreover, some mitochondrial disorders have been associated
with increased rate of infection (Walker et al. 2014). Patients
with mitochondrial neurogastrointestinal encephalomyopathy
or carnitine palmitoyltransferase 1A deficiency are more prone
to bacterial infection than the general population (Garone,
Tadesse and Hirano 2011; Gessner et al. 2013). A new example of mitochondria–microbiota functional interaction has been
recently published: rats fed with human milk compared with
cow’s milk or donkey’s milk display higher energy efficiency
associated with change in quality and diversity of their microbiota (Trinchese et al. 2015). These modification of mitochondrial energy metabolism are associated with an increased
production of butyrate known to be produced by microbiota
and to enter the TCA cycle (see paragraph below). This suggests that diet can modulate mitochondrial function related depending on the quality and diversity of microbiota. All these
data suggest that mitochondria play an important role during the interaction of the microbiota with the host cell. Moreover, mitochondrial activity may be an important factor that
modulates microbiota diversity and quality, probably due to
the role of mitochondria during the inflammatory and immune
responses.
Saint-Georges-Chaumet and Edeas
REACTIVE OXYGEN SPECIES (ROS) SIGNALING
– A KEYSTONE OF THE IMMUNE SYSTEM AND
INFLAMMATION – INVOLVES
MITOCHONDRIAL FUNCTIONS
Immune system and mitochondria
ROS cell concentration is determinant for the innate immune
response. Mitochondria are the main source of cellular ROS and
its concentration is directly correlated to the activity of the electron transfer chain. Depending on its level in the cell, the ROS
concentration can induce cell proliferation and differentiation,
cytokine release, or cell death by apoptosis.
Pathogenic bacteria release lipopolysaccharides (LPS),
flagelin, lipoteichoic acid, lipoprotein or other toxins, known
as pathogen-associated molecular patterns (PAMPs), which
the host cell recognizes by means of the pattern recognition
receptor (PRR) system through different pathways (Fig. 1). Four
different classes of PRR receptors sense the microbiota’s factors: Tol-like receptor (TLR), Rig-1-like receptor (RLR), Nod-like
receptor (NLR) and C-type lectin receptor (CLR). They generate
downstream signals and induce activation of the nuclear factor
(NF)-κB pathway and inflammatory response to release of
pro-inflammatory cytokines and antibacterial factors (Weissig
and Guzman-Villanueva 2015). NLR and TLR tend to increase
reactive oxygen species (ROS) production by the mitochondrial
respiratory chain. In macrophages, LPS via TLR pathways
reduce the expression of uncoupling protein 2 (UCP2) and
increase the activity of the electron transfer chain resulting in
an increase in mitochondrial ROS production (Emre and Nübel
2010). Furthermore, activation of TLR induces the translocation
of the proteinTRAF6 into mitochondria and its subsequent
association with ECSIT (evolutionarily conserved signaling
intermediate in Toll). This protein increases mitochondrial
electron transfer chain assembly and the resultant increase
of mitochondrial ROS production (West et al. 2011). The most
described member of the NLR family is NLRP3. Activation of this
protein, partly by mitochondrial ROS, induces its re-localization
from endoplasmic reticulum to mitochondria and allows the
activity of the inflammosome (Lobet, Letesson and Arnould
2015).
Activation of the adaptive immune system generally increases ATP production in both lymphocytes B and T, in order to
switch from quiescent state to proliferation and differentiated
states. In lymphocyte T, this higher ATP production is usually
due to high glycolytic activity and mitochondrial fatty acid oxidation associated with a reduction of electron transfer chain
gene expression (Walker et al. 2014). This high glycolytic activity
related to the Warburg effect allows the high production of different precursors involved in the biosynthesis of NADPH, amino
acids, nucleotides and fatty acids. On the other hand, stimulation of lymphocyte B leads to the upregulation of both glycolysis
and oxidative phosphorylation in order to allow the production
of IgG or IgA antibodies.
Pathogenic bacteria target mitochondria
Interaction of the host cell with pathogenic bacteria induces
several effects depending on the cell type (colonocyte, dendritic cell, macrophage. . . ) and the PRR system that is activated.
However, mitochondria are often targeted by pathogenic bacteria. For example Listeria infection is associated with fragmentation of the mitochondrial network (Lebreton, Stavru and Cossart 2015). To overcome the mitochondrial effect on the immune
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response, numerous bacterial species of microbiota tend to directly reduce mitochondrial ROS production (Lobet, Letesson
and Arnould 2015). Mycobacterium tuberculosis downregulates the
LPS-mediated signaling pathway. Other microbial toxins can upregulate the activity of the detoxification enzyme mitochondrial
superoxide dismutase (MnSOD), which results in a lower ROS
content and reduces host cell apoptosis, as observed in Ehrlichia
chaffeensis (Liu et al. 2012).
Microbiota ROS signaling modulates the gut epithelial
barrier
The presence of commensal bacteria is crucial to reduce the effect of pathogenic bacteria. Pathogenic bacteria must compete
with commensal bacteria for dietary products and commensal
bacteria boost the immune system (for review see Kamada and
Núñez 2014). Furthermore, commensal bacteria are an important regulator of the gut epithelial barrier function. Luminal bacteria produce and release small formylated peptides that bind
to the formyl peptide receptor. These receptors form a distinct
class of PRR, located in the apical surface of gut epithelia. Activation of this receptor triggers the production of superoxide anion
by NADPH oxidase 1 (NOX1). This results in an increased level
of cellular ROS, independently of mitochondria, and induces
the activity of redox sensor regulatory proteins. These proteins
modulate signaling pathways, cell motility, immune suppression and epithelial cell proliferation (for review see Neish and
Jones 2014). These activities are necessary to ensure epithelial
barrier function and to induce anti-inflammatory cytokines such
as IL-10.
Interestingly mitochondrial ROS may also be involved in the
regulation of the gut epithelial barrier. First, mitochondria also
release protein or nucleotides that can activate the FPRs. Secondly, induced mitochondrial dysfunction, using dinitrophenol,
affects epithelial barrier dysfunction allowing transepithelial
flux of Escherichia coli (Wang et al. 2014). Moreover, addition of
mitochondria-targeted antioxidant suppresses epithelial barrier
dysfunction. These results suggest that dinitrophenol increases
mitochondrial ROS production and directly affects epithelial barrier function leading to a state of gut inflammation. In addition,
the resultant gut inflammation is associated with structurally
abnormal mitochondria in patient tissue (Nazli et al. 2004).
Altogether these data suggest that mitochondria are a key
element in the regulation of the immune system and inflammatory process in particular through the production of ROS and its
downstream effect on cell gene expression.
METABOLITES PRODUCED BY GUT
MICROBIOTA MODULATE ENERGY
METABOLISM
H2 S and NO released by the microbiota are inhibitors of
mitochondrial host respiratory chain
The most direct evidence of a mitochondrial–microbiota interaction came from a study about metabolites produced by intestinal flora. Leschelle et al. have shown that several enteric bacteria
(E. coli, Salmonella) can produce a large quantity of hydrogen sulfide (H2 S) due to the degradation of sulfur amino acids in the gut.
An elevated concentration of H2 S is known to inhibit cytochrome
oxidase, one of the major complexes of the mitochondrial respiratory chain (Fig. 2) (Leschelle et al. 2005). However, small concentrations of H2 S may have a positive effect on mitochondrial
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FEMS Pathogens and Disease, 2016, Vol. 74, No. 1
Figure 2. Microbiota release metabolites that promote or decrease mitochondrial energy metabolism. Nitric oxide (NO) is able to inhibit the tricarboxylic
acid cycle (TCA) by reducing acetyl-CoA production. In addition high production
of hydrogen sulfide (H2 S) by the microbiota inhibit complex IV of the electron
transfer chain (ETC). In contrast, short chain fatty acids (SCFAs), in particular
butyrate, are able to fuel the TCA cycle. In parallel, SCFAs can induce release of
anti-inflammatory IL-10 cytokines and signaling hormone GLP-1 to reduce energy intake.
respiratory chain activity. Some bacteria are able to reduce H2 S
into sulfide. Sulfide can be metabolized by the colonocyte mitochondrial respiratory chain via the sulfide quinone reductase
(Goubern et al. 2007). These data show that the microbiota can
directly regulate oxidative phosphorylation activity depending
on the level of H2 S present in the colon. It also suggests that the
presence of bacteria in the gut microbiota able to produce sulfide from H2 S may be a target to improve bacteria–mitochondria
cross-talk and helpful for the treatment of metabolic disease.
Interestingly, nitric oxide (NO) also impaired energy
metabolism by reducing acetyl-CoA production. NO is produced
by the host during inflammation due to L-arginine conversion
or nitrite reduction. Recent data showed that NO can also be
produced by microbiota. Interestingly, dietary thiol compounds
may increase H2 S production and in combination with nitrate
contribute to NO production (Vermeiren et al. 2012). High NO
production in the gut may affect host mitochondrial activity
and favor bacterial infection as previously explained.
Based on these data, the release of metabolites by microbiota
is dependent on the diet of the subjects and the composition
of the microbiota. These results highlighted the importance of
dietary compounds to regulate microbiota activity that in turn
modulates mitochondrial energy metabolism.
The microbiota’s release of short chain fatty acids
positively regulates gut function and homeostasis
In a similar way, recent studies have shown that the microbiota
produced short chain fatty acids (SCFAs) such as butyrate or propionate from the fermentation of dietary fiber (Kumar et al. 2009).
Interestingly, butyrate is known to be used as a source of carbon by colonocytes. Indeed, butyrate can enter the TCA cycle
to reduce NAD+ to NADH, a donor of the mitochondrial electron transfer chain (Fig. 2). Notably, butyrate can be used as the
only source of carbon by colonocyte mitochondria even in the
presence of glucose (Donohoe et al. 2011). Moreover, butyrate not
only regulates mitochondrial activity but also promotes release
of signaling hormones such as GLP-1 that favor a lower food intake (Yadav et al. 2013). In line with this observation, the addition of butyrate to a high fat diet given to mice prevents the induced obesity generally observed (Lin et al. 2012). The receptor
FFAR3 has been identified as a SCFA receptor expressed in GLP1-secreting endocrine L cells. The diversity and quality of the
microbiota and the degree of methylation of the FFAR3 promoter
were significantly lower in the obese and type 2 diabetic patients
compared to lean individuals (Remely et al. 2014). These data
demonstrate a correlation between a higher body mass index
and a lower methylation of FFAR3 promoter. In addition it has
been reported that butyrate and propionate promote the generation of peripheral regulatory T-cells (Furusawa et al. 2013). Butyrate and propionate are known to inhibit histone deacetylase.
The presence of SCFAs enhances histone H3 acetylation in the
promoter of the Foxp3 locus and reduces the development of
colitis.
These previous data suggest that short chain fatty acids not
only induce the release of hormones that reduce food intake,
but also seem to increase metabolic rate and regulate the immune system and inflammation. This example highlights the
mitochondria–microbiota direct interaction for the regulation of
energy metabolism.
CONCLUSION
The role of mitochondria during the host microbiota cross-talk
is essential in order to modulate the innate immune response.
Microbiota species tend to control mitochondrial activity in order to favor interaction and infection. Indeed, the response of
the host cell toward the presence of microbiota is dependent on
the presence of factors released by the microbiota that will increase (SCFAs. . . ) or decrease (NO; MnSOD. . . ) mitochondrial activity and ROS production. Unknown mechanisms by a variety
of metabolites originating from the microbiota may be relevant
for mitochondrial homeostasis and remain to be discovered. The
balance between these factors may trigger an adequate host
response. Differences in microbiota quality and diversity have
been associated with several diseases including bowel inflammatory disease and obesity (Turnbaugh et al. 2006; Sartor and
Mazmanian 2012). Alternatively, based on current available data,
bacterial species can also trigger insertion of bacterial or mitochondrial DNA within the host genome and induce mutation of
the somatic cell independently of mitochondria.
Consistent with these effects, it is tempting to think that targeting the microbiota could be useful to manage intestinal ROS,
oxidative stress, inflammation and metabolic anomalies due to
the alteration of the microbiota as we previously reported (Edeas
and Weissig 2013; Weissig and Edeas 2015a,b). The perspective
will be to modulate the quality and diversity of the microbiota
of each person rather than acting on the microbiota metabolites and the microbiota-related factors (NO, H2 S, SCFAs). Probiotics, diet or fecal transplantation are new emerging strategies
to modulate the quality and diversity of the microbiota.
FUNDING
This project is supported by the World Mitochondria Society.
Saint-Georges-Chaumet and Edeas
Conflict of interest. None declared.
REFERENCES
Cryan JF, Dinan TG. Mind-altering microorganisms: the impact
of the gut microbiota on brain and behaviour. Nat Rev Neurosci 2012;13:701–12.
Degli Esposti M, Chouaia B, Comandatore F, et al. Evolution of
mitochondria reconstructed from the energy metabolism of
living bacteria. PLoS One 2014;9:e96566.
Donohoe DR, Garge N, Zhang X, et al. The microbiome and butyrate regulate energy metabolism and autophagy in the
mammalian colon. Cell Metab 2011;13:517–26.
Edeas M, Weissig V. Targeting mitochondria: strategies, innovations and challenges: The future of medicine will come
through mitochondria. Mitochondrion 2013;13:389–90.
Emre Y, Nübel T. Uncoupling protein UCP2: when mitochondrial
activity meets immunity. FEBS Lett 2010;584:1437–42.
Foster JA, McVey Neufeld K-A. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci
2013;36:305–12.
Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbederived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013;504:446–50.
Garone C, Tadesse S, Hirano M. Clinical and genetic spectrum
of mitochondrial neurogastrointestinal encephalomyopathy.
Brain 2011;134:3326–32.
Gelvin SB. Agrobacterium-mediated plant transformation: the biology behind the “gene-jockeying” tool. Microbiol Mol Biol Rev
2003;67:16–37.
Gessner BD, Gillingham MB, Wood T, et al. Association of a genetic variant of carnitine palmitoyltransferase 1A with infections in Alaska Native children. J Pediatr 2013;163:1716–21.
Goubern M, Andriamihaja M, Nübel T, et al. Sulfide, the first inorganic substrate for human cells. FASEB J 2007;21:1699–706.
Kalghatgi S, Spina CS, Costello JC, et al. Bactericidal antibiotics
induce mitochondrial dysfunction and oxidative damage in
mammalian cells. Sci Transl Med 2013;5:192ra85.
Kamada N, Núñez G. Regulation of the immune system by the
resident intestinal bacteria. Gastroenterology 2014;146:1477–
88.
Kumar A, Wu H, Collier-Hyams LS, et al. The bacterial fermentation product butyrate influences epithelial signaling via reactive oxygen species-mediated changes in cullin-1 neddylation. J Immunol 2009;182:538–46.
Lebreton A, Stavru F, Cossart P. Organelle targeting during
bacterial infection: insights from Listeria. Trends Cell Biol
2015;25:330–8.
Leschelle X, Goubern M, Andriamihaja M, et al. Adaptative
metabolic response of human colonic epithelial cells to the
adverse effects of the luminal compound sulfide. Biochim Biophys Acta 2005;1725:201–12.
Lin HV, Frassetto A, Kowalik EJ, et al. Butyrate and propionate
protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One 2012;7:e35240.
Liu H, Bao W, Lin M, et al. Ehrlichia type IV secretion effector ECH0825 is translocated to mitochondria and curbs ROS
and apoptosis by upregulating host MnSOD. Cell Microbiol
2012;14:1037–50.
Lobet E, Letesson J-J, Arnould T. Mitochondria: a target for bacteria. Biochem Pharmacol 2015;94:173–85.
Lucattini R, Likic VA, Lithgow T. Bacterial proteins predisposed
for targeting to mitochondria. Mol Biol Evol 2004;21:652–8.
5
Ma J, Coarfa C, Qin X, et al. mtDNA haplogroup and single nucleotide polymorphisms structure human microbiome communities. BMC Genomics 2014;15:257.
Nazli A, Yang P-C, Jury J, et al. Epithelia under metabolic
stress perceive commensal bacteria as a threat. Am J Pathol
2004;164:947–57.
Neish AS. Redox signaling mediated by the gut microbiota. Free
Radic Res 2013;47:950–7.
Neish AS, Jones RM. Redox signaling mediates symbiosis between the gut microbiota and the intestine. Gut Microbes
2014;5:250–3.
Prakash S, Rodes L, Coussa-Charley M, et al. Gut microbiota: next
frontier in understanding human health and development of
biotherapeutics. Biologics 2011;5:71–86.
Remely M, Aumueller E, Merold C, et al. Effects of short
chain fatty acid producing bacteria on epigenetic regulation of FFAR3 in type 2 diabetes and obesity. Gene 2014;537:
85–92.
Ricchetti M, Tekaia F, Dujon B. Continued colonization of the human genome by mitochondrial DNA. PLoS Biol 2004;2:E273.
Riley DR, Sieber KB, Robinson KM, et al. Bacteria-human somatic
cell lateral gene transfer is enriched in cancer samples. PLoS
Comput Biol 2013;9:e1003107.
Sartor RB, Mazmanian SK. Intestinal microbes in inflammatory
bowel diseases. Am J Gastroenterol Suppl 2012;1:15–21.
Schröder G, Schuelein R, Quebatte M, et al. Conjugative DNA
transfer into human cells by the VirB/VirD4 type IV secretion
system of the bacterial pathogen Bartonella henselae. Proc Natl
Acad Sci U S A 2011;108:14643–8.
Trinchese G, Cavaliere G, Canani RB, et al. Human, donkey and cow milk differently affects energy efficiency
and inflammatory state by modulating mitochondrial function and gut microbiota. J Nutr Biochem 2015,
DOI:10.1016/j.jnutbio.2015.05.003.
Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated
gut microbiome with increased capacity for energy harvest.
Nature 2006;444:1027–31.
Vermeiren J, Van de Wiele T, Van Nieuwenhuyse G, et al. Sulfideand nitrite-dependent nitric oxide production in the intestinal tract. Microb Biotechnol 2012;5:379–87.
Walker MA, Volpi S, Sims KB, et al. Powering the immune system:
mitochondria in immune function and deficiency. J Immunol
Res 2014;2014:164309.
Wang A, Keita ÅV, Phan V, et al. Targeting mitochondria-derived
reactive oxygen species to reduce epithelial barrier dysfunction and colitis. Am J Pathol 2014;184:2516–27.
Weissig V, Edeas M. Preface. In: Mitochondrial Medicine. Vol. II Manipulating Mitochondrial Function. Methods in Molecular Biology,
New York, NY: Springer New York, 2015a;1265:v–xiv.
Weissig V, Edeas M. Preface. In: Mitochondrial Medicine. Vol. I Probing Mitochondrial Function. Methods in Molecular Biology, New
York, NY: Springer New York, 2015b;1264:v–xiv.
Weissig V, Guzman-Villanueva D. Nanocarrier-based antioxidant therapy: promise or delusion? Expert Opin Drug Deliv
2015;12:1–8.
West AP, Brodsky IE, Rahner C, et al. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 2011;472:476–80.
Yadav H, Lee J-H, Lloyd J, et al. Beneficial metabolic effects of
a probiotic via butyrate-induced GLP-1 hormone secretion.
J Biol Chem 2013;288:25088–97.
Zorov DB, Plotnikov EY, Silachev DN, et al. Microbiota and mitobiota. Putting an equal sign between mitochondria and bacteria. Biochemistry (Moscow) 2014;79:1017–31.