Biochimica et Biophysica Acta 1856 (2015) 86–90

Contents lists available at ScienceDirect

Biochimica et Biophysica Acta

journal homepage: www.elsevier.com/locate/bbacan

Review

Gut bacteria and cancer
Susan E. Erdman a,⁎, Theofilos Poutahidis a,b
a
Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States
b
Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, 54124, Greece

a r t i c l e i n f o a b s t r a c t

Article history: Microbiota on the mucosal surfaces of the gastrointestinal (GI) tract greatly outnumbers the cells in the human
Received 20 April 2015 body. Effects of antibiotics indicate that GI tract bacteria may be determining the fate of distal cancers. Recent
Accepted 24 May 2015 data implicate dysregulated host responses to enteric bacteria leading to cancers in extra-intestinal sites. Together
Available online 4 June 2015
these findings point to novel anti-cancer strategies aimed at promoting GI tract homeostasis.
© 2015 Published by Elsevier B.V.
Keywords:
Enteric
Microbes
Breast cancer
Mammary cancer
Immune system
Neutrophils
Regulatory T cells

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
1.1. Cancer development is a multi-factorial process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
2. Our gut reactions: a balancing act that shapes systemic immune tone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
3. Cancer and inflammation: interleukin-6 and neutrophils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
4. It starts earlier in life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

1. Introduction microbial passengers may unveil novel targets for cancer prevention
and therapy.
Breast cancer is the most frequently diagnosed cancer in women
[1–3]. It has been known for some time that antibiotics and anti-
inflammatory drug therapy, such as aspirin, alter relative risks for breast 1.1. Cancer development is a multi-factorial process
cancer in women [4–6]. However, the etiopathogenic factors leading to
breast malignancy are not well understood [5,7,8]. During studies of Cancers of tissues including the colon and breast are attributable to
gastrointestinal (GI) tract inflammation, it was discovered that certain complex interactions between cells surviving genetic damage and
gut commensal bacteria trigger not only colonic tumors but also mam- their micro- and macro-environments [13–16]. This continuous inter-
mary and prostate gland tumors in susceptible mouse models [9,10]. play eventually leads to the formation of indestructible cancer cell
More recently, human milk-borne microbes were found to inhibit mam- clones through a natural selection process [14]. Immune and stromal
mary neoplasms in predisposed mice [11], with effects transcending cells, cytokines, proteases and hormones are now acknowledged as
several generations [12]. This raises the intriguing possibility that our major environmental contributors in the natural history of cellular ma-
lignant transformations [13,14]. Consequently, the immune system sta-
⁎ Corresponding author. tus [17], the metabolic profile [18] and the psychological condition of
E-mail address: serdman@mit.edu (S.E. Erdman). the host [19], which influence each other at the whole organism level,

http://dx.doi.org/10.1016/j.bbcan.2015.05.007
0304-419X/© 2015 Published by Elsevier B.V.
S.E. Erdman, T. Poutahidis / Biochimica et Biophysica Acta 1856 (2015) 86–90 87

could be viewed as external determinants of the perturbed ecosystem of of cancer in distal tissues. However, the bacterial translocation due to
abnormal cells with neoplastic potential. the compromised intestinal integrity caused by cancer treatment thera-
Studies in animal models of cancer increased the understanding of the pies has been shown to augment anti-tumor immunity networks of ac-
multistep evolution of dysplasia and pre-neoplasia to cancer [11,20–22]. tivated myeloid cells and T-lymphocytes. This beneficial effect was lost
Several of these studies have also highlighted the fact that early neoplastic in germ-free mice or animals treated with antibiotics. Therefore, in this
lesions are less autonomous in their growth than previously thought [11, setting, bacterial translocation worked synergistically to certain cancer
22–26]. Instead, their thriving and evolution depends on their micro- and therapeutic regimens [32,33,56,58]. This discrepancy is not surprising.
macro-environment [13–15,17,27,28]. This finding raises interesting The divergent effects of translocating bacteria-induced systemic im-
possibilities for cancer prevention. Indeed, accidental gene mutations oc- mune responses on neoplastic disease outcomes reflect the multiface-
curring during the lifetime of a human being are countless [15,29]. There- ted relationship of inflammation with cancer.
fore, most people develop focal dysplastic and pre-neoplastic lesions Taken together, there is abundant evidence that bacteria modulate
during their lifetimes. These lesions rarely develop into cancer. However, cancer development and growth. Finding that bowel bacteria or their
co-existing local or systemic smoldering inflammatory disturbances of products promote a competent, healthy immune system provides an
homeostasis have a trophic effect on them, promote their development, explanation for perplexing increases in cancers arising from epithelia
and greatly increase the chances of carcinogenesis [15,17,23]. in colon, breast and other sites in countries with more stringent hygiene
Taken together these recent conceptual advances in tumor biology practices [23,59]. Along similar lines, chronic antibiotic therapy may dis-
suggest that immune system elements, hormones and psychosomatic rupt constructive bacterial processes, ultimately leading to higher rates
factors may determine the fate of pre-neoplastic lesions towards pro- of breast cancer in women [4]. Systemic NSAID therapy has been linked
gression to cancer through interrelated mechanisms. This raises an im- with significant decreases in several types of cancer [60–63]. Thus, ways
portant question whether effective modalities that could contribute in which gut microbiota stimulate inherent host homeostatic properties
towards shaping an overall systemic homeostatic, non-tumor promot- are an attractive target for systemic good health approaches using pro-
ing status may exist. biotic bacteria or microbial product vaccines.
Recent findings using mouse models suggest this may be possible. It
appears that supplementation with certain gastrointestinal bacteria ini- 3. Cancer and inflammation: interleukin-6 and neutrophils
tiates multifaceted systemic events that overlap with basic pro-
carcinogenic signaling [12,27,28,30–34]. In this case, bacteria apparent- In the context of cancer, inflammation is widely believed to repre-
ly suppress the evolution of early neoplastic lesions to cancer in epithe- sent the body's fight against tumor cells [64,65]. Other data, however,
lia locating distally from the gut, such as those of mammary gland, by suggests just the opposite; chronic smoldering inflammation may be a
down-regulating the systemic inflammatory index in the form of pro- cause of cancer and is a powerful stimulus for tumor growth and inva-
inflammatory cytokine levels and inflammatory cells [11]. Beneficial sion [66–68]. These opposing observations are not easily reconciled,
Firmicutes bacteria including Lactobacillus spp. are likewise able in and are most easily comprehended in the context of immune balance,
mice to interrupt metabolic disorders such as obesity and induce a re- with cancer arising during dysregulated attempts by the host animal
productive fitness-matching hormonal milieu with youthful testoster- to restore homeostasis after an insult.
one, free thyroxin (T4), and oxytocin levels [35–37]. Interestingly, Several lines of evidence support that pathogenic GI tract microbiota
these same hormones have been connected with healthful mentality stimulate certain innate immune cells to enhance tumor formation
and anxiolytic effects [38–40]. As pivotal elements of the gut throughout the body [9,22,69–74]. In order to identify the key immune
microbiota-brain axis, certain gastrointestinal tract bacteria are being cell players, prior studies have built upon reciprocal systemic relation-
introduced as psychobiotics due to their potential to counteract depres- ships existing between neutrophils, mast cells and macrophages with
sion and promote a sense of well-being [41]. cells of adaptive immunity [70,75–81]. During homeostasis, these im-
mune networks are persistently down-regulated by anti-inflammatory
2. Our gut reactions: a balancing act that shapes systemic activities of CD4+ TREG that bestow intestinal homeostasis [9,52,69]. In
immune tone this context, a weakened TREG-mediated inhibitory loop imparts carcino-
genic consequences of elevated IL-6 and possibly IL-17, leading to more
The GI tract encompasses the largest surface of the human body frequent inflammation-associated distal cancers [82]. In this context, neu-
where microbial products interact with the immune system. It has trophils have been identified in animal models as an important factor in
become clear that balance of systemic health is routinely enforced by ac- cancer initiation and development [24–26,70,83–88]. A distant neoplastic
tivities of CD4+ T regulatory (TREG) cells along mucosal surfaces. These effect of a commensal gut microbe was recently shown in FVB-Tg(C3-1-
lymphocytes have evolved to play a sophisticated balancing act of TAg)cJeg/JegJ mammary tissue by a neutrophil-mediated mechanism
allowing host protective immune responses during acute inflammatory [75]. Importantly, systemic interplay between microbes, IL-6, and neutro-
responses, while later regaining suppressive roles that limit deleterious phils was recently shown in human patients with breast cancer [77].
pathological sequelae of chronic smoldering inflammation [42–44]. Re- To the same extent that pathogenic gut bacteria can lead to carcino-
cent evidence highlights the important developmental and functional genic events in distant tissues, it appears that beneficial bacteria may in-
associations of intestinal microbiota with TREG cells [45–48]. Both hibit or even suppress carcinogenesis. A prototype beneficial microbe
in vitro data and lymphocyte titration experiments in preclinical models Lactobacillus reuteri was recently shown to rescue mice from age-
have revealed that homeostatic potency of TREG [ie., ability of TREG to re- associated obesity and the deleterious IL-6 and IL-17-rich smoldering
store homeostasis after environmental insults] is modulated by prior in- systemic inflammatory obese status [10]. Obesity has been linked with
testinal bacterial challenges [9,23,49–55]. These studies on TREG cells postmenopausal mammary cancer [89–91]; thus, it was subsequently
complement other data showing an array of different effects of gut bac- examined and shown that beneficial Lactobacillus sp. microbes inhibit
teria on systemic innate and adaptive immunity [56] thus solidifying a obesity-associated mammary carcinogenesis in mice [75]. Interestingly,
pivotal role for gut microbiota in shaping systemic immune tone and re- the same anti-neoplastic effect occurred in the Her-2/Neu mouse, a ge-
sponses [Fig. 1]. netically engineered mouse model of mammary cancer, in which the as-
Disruptive events in the GI tract also increase risk for microbial sociation between immunity and mammary carcinogenesis is less
translocations [57] together with systemic immune cell trafficking. Mi- obvious. This animal model is transgenic for ErbB2 Epidermal Growth
crobial translocation from gut to mammary tissue has been postulated Factor [EGF] receptor and over-produces the protein HER-2; a condition
in breast cancer etiopathogenesis [74]. The subsequent increase of the that occurs in up to 30% of breast cancer patients and carries a poor
systemic inflammatory index would be expected to increase likelihood prognosis [20].
88 S.E. Erdman, T. Poutahidis / Biochimica et Biophysica Acta 1856 (2015) 86–90

HEALTH DISEASE
Earlier microbe Bone
exposures induce marrow
protective TREG cells

Spleen

TREG cells Gut microbes
inhibit pathogenic CANCER stimulate pathogenic
systemic inflammation systemic inflammation
TREG
cells
Lymph node

Gut homeostasis Gut mucosal disruption
inhibits microbe with microbe
translocation translocation

Fig. 1. A proposed model of gut microbe-induced extra-intestinal carcinogenesis. Humans infected with pathogenic gut bacteria are at increased risk for inflammation and cancer. The
compromised intestinal epithelial barrier during pathogenic infection leads to translocation of bacteria thereby triggering systemic activation of immune cells, culminating in an elevated
septic and systemic inflammatory index and to cancer in distant sites such as breast tissue. Immunocompetent hosts have efficient T regulatory (Treg) cell responses in response to mi-
crobial challenges that help restore gut epithelial homeostasis.

4. It starts earlier in life bottle-feeding may compromise host ability to navigate future mucosal
challenges. It is promising that administration of similar beneficial bac-
Recently, much attention has been focused on the possibility that teria later in life may serve to prevent enteric inflammation [95,96] as
modulating intestinal flora early in life may provide life-long protection well as a wide variety of inflammation-associated systemic disorders
against cancer. Prior work [9,51,52,74,92] supports a model whereby [97]. For example, as a consequence of eating L. reuteri, aged mice
prior enteric infections serve to suppress gut inflammation, consistent displayed superb integumentary health with increased wound healing
with the observations of Belkaid and Rouse (2005) involving immune capacity, and resisted age-associated thyroid and testicular involution
competency and TREG cells [50]. More recent evidence highlights the im- [10,98]. Dosing mice orally with L. reuteri isolated from human milk
portance of intestinal microbiota during maturation of the immune sys- was proven sufficient to down-regulate systemic inflammatory cyto-
tem [45–48]. Data from preclinical models has substantiated this notion kines and neutrophil accumulations [37,98], in addition to lowered
that host ability to restore homeostasis after environmental insults is risk for mammary cancer [78], in mouse models.
modulated by prior intestinal bacterial exposures [9,23,49–55]. This According to recent studies, diet and dietary microbes may have
makes sense involving a paradigm proposed by Kuchroo and co- transgenerational cancer consequences involving integrated immune
workers [93,94] showing that ability of TREG to enforce homeostasis and hormonal factors [99]. De Assis et al. have shown that descendant
and inhibit immune-mediated diseases depending upon levels of in- generations of female rats fed a high-fat diet or exposed to estrogen dur-
flammation, and IL-6 in particular. In this paradigm, elevated levels of ing pregnancy are more prone to carcinogen-induced mammary cancer.
IL-6 trigger a T helper type (Th)-17 host response that contributes to In those studies, the increased sensitivity to mammary chemical carci-
worsening systemic disease conditions. Taken together, these observa- nogenesis was epigenetically inherited, since offspring rats had an al-
tions link the immune system, gastrointestinal infections, and seeming- tered mammary tissue DNA methylation pattern [99]. Interestingly,
ly divergent downstream phenotypes: allergies, autoimmune disease, both treatments used to achieve this epigenetically-regulated effect
and cancer. These observations suggest that TREG may do more than connect with pivotal elements of one proposed gut-centric mechanism
block constructive anti-cancer responses [64,65]. Following this reason- of remote cancer risk control involving gut microbiota and regulatory T-
ing, a model in which childhood infections protect from inflammatory cells. High fat diets have been shown to alter gut microbial communities
diseases later in life, TREG cell biology may help explain unanswered in both rodents [98,99] and human beings [100]. In mice, high-fat diet
questions of cancer risk and modern lifestyle. and the related obesity-type gut microbiota coincide with reduced
During early life in mammals, the immune system programming numbers of TREG cells in both mesenteric and mammary lymph nodes
process is chaperoned by milk-borne lactic acid bacteria that apparently [78,98]. In the offspring with maternal estrogen changes, the prenatal
serve to protect nursing infants by stimulating anti-inflammatory cyto- exposure to estrogens disrupts T-cell differentiation in the thymus and
kine IL-10 and TREG cells along naïve mucosal surfaces. Modern lifestyle has long-term effects in its immune system [103] including reduced
practices that remove natural exposures due to Caesarian births and TREG cells [104]. Disrupted thymic maturation of suppressive CD4+ T
S.E. Erdman, T. Poutahidis / Biochimica et Biophysica Acta 1856 (2015) 86–90 89

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