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. 2020 Oct 24;367(20):fnaa163. doi: 10.1093/femsle/fnaa163

Campylobacter jejuni persistently colonizes gnotobiotic altered Schaedler flora C3H/HeN mice and induces mild colitis

Meghan Wymore Brand 1, Orhan Sahin 2, Jesse M Hostetter 3, Julian Trachsel 4, Qijing Zhang 5, Michael J Wannemuehler 6,✉
PMCID: PMC7657340  PMID: 33098301

ABSTRACT

Campylobacter jejuni is a major cause of food-borne human bacterial gastroenteritis but animal models for C. jejuni mediated disease remain limited because C. jejuni poorly colonizes immunocompetent, conventionally-reared (Conv-R) mice. Thus, a reliable rodent model (i.e. persistent colonization) is desirable in order to evaluate C. jejuni-mediated gastrointestinal disease and mechanisms of pathogenicity. As the nature and complexity of the microbiota likely impacts colonization resistance for C. jejuni, Conv-R and gnotobiotic C3H/HeN mice were used to evaluate the persistence of C. jejuni colonization and development of disease. A total of four C. jejuni isolates readily and persistently colonized ASF mice and induced mild mucosal inflammation in the proximal colon, but C. jejuni did not stably colonize nor induce lesions in Conv-R mice. This suggests that the pathogenesis of C. jejuni is influenced by the microbiota, and that ASF mice offer a reproducible model to study the influence of the microbiota on the ability of C. jejuni to colonize the gut and to mediate gastroenteritis.

Keywords: Campylobacter jejuni, campylobacteriosis, altered Schaedler flora, colitis, microbiota, gnotobiotic

Gnotobiotic, ASF mice offer a useful model to evaluate the impact of persistent, host-pathogen interactions including the unique opportunity to evaluate bacterial provocateurs including C. jejuni that contribute to IBD.

INTRODUCTION

Campylobacter jejuni is a major cause of human bacterial gastroenteritis worldwide with increasing case prevalence in developed countries (Skirrow 1994; Kaakoush et al. 2015). Campylobacter-induced gastroenteritis is usually self-limiting, but some patients progress to develop Guillain–Barre syndrome, an autoimmune disease mediated by adaptive immune responses to C. jejuni antigens (Kaakoush et al. 2015). Inflammatory bowel disease, functional gastrointestinal (GI) disorders such as irritable bowel syndrome (IBS) and other GI conditions have been associated with GI colonization by different species of Campylobacter (Kaakoush et al. 2015; Axelrad et al. 2019; Scallan Walter et al. 2019). Campylobacter jejuni naturally colonizes the GI tract of poultry, and poultry meat serves as a vector for transmission to humans, along with contaminated milk, water and other animal meat products (Skirrow 1994; Kaakoush et al. 2015). In addition to its food-borne disease significance, C. jejuni also has a veterinary impact as it causes abortion in small ruminants, and human transmission may occur through contact with infected animals (Skirrow 1994; Kaakoush et al. 2015).

Despite the public health significance of C. jejuni, disease models for campylobacteriosis are limited. Susceptibility to Campylobacter colonization in poultry abattoir workers has been demonstrated to be dependent on the species composition of the host's microbiome (Dicksved et al. 2014). Campylobacter jejuni poorly colonizes immunocompetent mice harboring a conventional microbiota and it rarely induces intestinal disease suggesting that the murine microbiota exhibits colonization resistance towards C. jejuni (Chang and Miller 2006; Bereswill et al. 2011; Stahl, Graef and Vallance 2017; Mousavi, Bereswill and Heimesaat 2020). To study C. jejuni colonization, investigators have used mice with a humanized or limited microbiota, serially passaged C. jejuni in mice, employed antibiotic pre-treatment to reduce the resident microbiota, or used dietary fat manipulation to successfully establish C. jejuni colonization (Chang and Miller 2006; Mansfield, Schauer and Fox 2008; Bell et al. 2009; Bereswill et al. 2011; Haag et al. 2012; Stahl et al. 2014). Some immunodeficient mouse models, including IL-10−/−, TLR- and NF-κB-deficient and SCID mice, have been persistently colonized with C. jejuni resulting in varying severities of GI inflammation (Chang and Miller 2006; Mansfield et al. 2007; Mansfield, Schauer and Fox 2008; Bell et al. 2009; Bereswill et al. 2011; Stahl et al. 2014; Heimesaat et al. 2017). Murine models utilizing a combination of these factors have also demonstrated colonization, with varying levels of disease (Stahl et al. 2014; Sun et al. 2018; Brooks et al. 2019; Schmidt et al. 2019; Mousavi, Bereswill and Heimesaat 2020). Because of the unreliability of rodent models, non-human primates, neonatal swine and ferrets have been used for studying Campylobacter-induced disease (Skirrow 1994; Mansfield, Schauer and Fox 2008).

Gnotobiotic (i.e. altered Schaedler flora, ASF) and conventionally-reared (Conv-R) C3H/HeN mice were utilized to demonstrate that colonization by C. jejuni is differentially influenced by the complexity of the microbiota (Wymore Brand et al. 2015). The ASF is a well-described community of eight bacterial strains that stably colonize the murine GI tract, and is composed of Lachnospiraceae strain 356 (ASF356), Lactobacillus intestinalis (ASF360), Lactobacillus murinus (ASF361), Mucispirillum schaedleri (ASF457), Eubacterium plexicaudatum(ASF492), Colidextribacter strain 500 (ASF500), Schaedlerella arabinosiphila (ASF502) and Parabacteroides goldsteinii (ASF519), and is reviewed in Wymore Brand et al. 2015 though some nomenclature has since been revised. As a community, the ASF has been stably maintained in our gnotobiotic mouse colony for two decades and have been shown to be functionally similar to a conventional microbiota while lacking proteobacteria (Wymore Brand et al. 2015; Biggs et al. 2017). Previous data with this model demonstrates that an adherent invasive Escherichia coli LF82 persistently colonizes these mice, while LF82 is not maintained in Conv-R mice (Carvalho et al. 2009; Henderson et al. 2015). It has also been demonstrated that both Helicobacter bilis and Brachyspira hyodysenteriae persistently colonize ASF mice resulting in typhlocolitis (Jergens et al. 2006). Thus, it was hypothesized that C. jejuni, a member of the epsilon-proteobacteria, would readily colonize ASF mice and induce mucosal inflammation. The results of this study indicate that four strains of C. jejuni persistently colonized and induced mild histopathological lesions in the GI tract of ASF mice. This observation supports the concept that immunocompetent, ASF-colonized mice are more readily colonized by C. jejuni than Conv-R mice and will provide a useful model to study the influence of the microbiota on C. jejuni colonization and pathogenesis.

MATERIALS AND METHODS

Animals

Adult gnotobiotic C3H/HeN mice harboring the ASF were bred, raised and maintained in Trexler plastic isolators until challenge with C. jejuni (Wymore Brand et al. 2015). Conv-R, specific pathogen-free (SPF) C3H/HeN mice were obtained from Envigo (Madison, WI). Separate groups of ASF and Conv-R C3H/HeN mice remained free of C. jejuni and served as non-colonized controls. All animals were housed and maintained in the Iowa State University Laboratory Animal Resource facility on a filtered air unit (Innovive, San Diego, CA) and were maintained on an irradiated diet (2919 Teklad, Envigo, Madison, WI) and sterile water for the duration of the experiment. All mouse experiments were performed according to the requirements of the Iowa State University Institutional Animal Care and Use Committee.

C. jejuni colonization

Campylobacter jejuni was cultured on Mueller–Hinton (MH) agar (BD Difco, Fisher Scientific, Waltham, MA) in microaerophilic conditions (5% oxygen, 10% carbon dioxide and 85% nitrogen) at 42°C. A total of four strains of C. jejuni were utilized, including two human isolates (81–176 and NCTC 11168) and two abortifacient ovine isolates (IA3902 and IA5908) which are also human pathogens (Parkhill et al. 2000; Hofreuter et al. 2006; Sahin et al. 2008; Wu et al. 2013; Lashley et al. 2019). Separate groups of mice (n = 7–8) were inoculated once with one of the four strains (5 × 108 colony forming units, CFU, in 0.2 mL) by oral gavage. Colonization experiment with C. jejuni 81–176 was repeated an additional time with mice sacrificed at 3 and 7 weeks after colonization (n = 8 for each timepoint). Data from the two experiments were combined for reporting the results.

Culture from feces and liver

Colonization persistence of C. jejuni was evaluated by measuring fecal CFU using serial dilution of fecal pellets in MH broth and inoculation of MH agar supplemented with Preston Campylobacter selective supplement (polymixin B, rifampicin, trimethroprim, cycloheximide; ThermoScientific, Waltham, MA) and Campylobacter growth supplements (sodium pyruvate, sodium metabisulphate, ferrous sulphate; ThermoScientific, Waltham, MA). Plates were incubated for 48 h at 42°C under microaerophilic conditions before counting CFU. At necropsy, a piece of liver (about 0.5 g) was homogenized in 2.0 mL of MH broth and 100 µL was inoculated onto a MH agar plate containing the same supplements described above.

Histopathological analysis

Mice were euthanized at 3 or 7 weeks post-colonization. Proximal colon samples were collected at necropsy, routinely processed and embedded in paraffin, sectioned and stained with hematoxylin and eosin. Tissues were blindly scored by a pathologist (JMH) as previously described, using a scale of 0–5 for ulceration, inflammation, edema, stromal collapse and gland hyperplasia, and a sum score of those individual parameters (Haarberg et al. 2015).

Statistical analysis

Prism 6 software (GraphPad Software, San Diego, CA) was used for all statistical calculations. All data were evaluated by the Kruskal–Wallis test with Dunn's multiple comparisons test or the Mann–Whitney test.

RESULTS

Multiple strains of C. jejuni persistently colonize ASF mice

All four strains of C. jejuni persistently colonized ASF mice for 7 weeks (107–109 CFU/g feces) while C. jejuni CFU in fecal samples from Conv-R mice decreased throughout the 7-week study (Fig. 1). Strains 11168, IA5908 and IA3902 maintained colonization levels between 108 and 109 CFU/g feces, while the CFU of strain 81–176 decreased to approximately 107 CFU/g feces after day 21 (Fig. 1A). On a repeat colonization experiment, C. jejuni 81–176 colonization levels were maintained at 107–108 CFU/g feces in ASF mice with no evidence of decrease as observed in the first study (data shown for 81–176 is pooled from the two individual experiments). In the Conv-R C3H/HeN mice, CFU for C. jejuni 81–176 increased between days 3 and 7 post-inoculation (∼107 CFU/g feces), but decreased to 105 by the end of the 7-week study At necropsy, one to two colonies of C. jejuni were additionally recovered from the liver of one ASF mouse colonized with IA 3902 and two ASF mice colonized with 11168 (data not shown).

Figure 1.

Figure 1.

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Multiple strains of C. jejuni persistently colonize ASF mice. Gnotobiotic C3H/HeN mice harboring the ASF were colonized with one of four strains of C. jejuni and monitored for fecal shedding, reported as CFUs/g feces, for 7 weeks (A and B). Conventionally-reared (SPF) C3H/HeN mice were also colonized with C. jejuni 81–176 and monitored for fecal shedding for 7 weeks (B). Symbols indicate P ≤ 0.05 in comparison to 81–176: ^11168, #IA 3902, *IA 5908 (A). In comparison to 81–176 in SPF mice: *P ≤ 0.05, **P ≤ 0.01 (B). mean ± SEM

Persistent colonization of C. jejuni induces mild colonic inflammation

Colons of ASF mice colonized with C. jejuni for 7 weeks had higher histopathological scores (P ≤ 0.05) than C. jejuni colonized Conv-R mice and the lesions were characterized by increased inflammatory cell infiltrate and stromal collapse (Fig. 2). In contrast, ASF mice colonized for only 3 weeks presented with total histopathological scores intermediate between control ASF mice and ASF mice colonized for 7 weeks. Both Conv-R control and C. jejuni-colonized Conv-R mice were histologically similar to control ASF mice (i.e. no evidence of histological lesions). At 7 weeks post-colonization, the inflammatory infiltrate in the proximal colon of C. jejuni colonized ASF mice was characterized by the presence of mononuclear cells and some polymorphonuclear leukocytes. Although it was not statistically significant, colonic tissue sections also exhibited moderate glandular hyperplasia in comparison to control ASF mice. Regardless of the time point and C. jejuni strain, the cecum and distal ileum of the ASF mice did not show evidence of inflammation following colonization (data not shown).

Figure 2.

Figure 2.

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ASF-colonized mice have mild colonic inflammation following persistent C. jejuni 81–176 colonization. The tissues were evaluated in a blinded fashion by a board-certified pathologist (JMH). The total histopathological score (A) is the summation of multiple parameters (see Materials and Methods) including the inflammatory cell infiltrate (B) and stromal collapse (C). Photomicrographs (D) are representative of H&E stained sections of proximal colons from C. jejuni 81–176 colonized ASF and SPF mice. *P < 0.05 compared to control ASF. mean ± SEM.

DISCUSSION

In previous studies, Conv-R mice were shown to be poorly colonized by Campylobacter, though pretreatment of various Conv-R mouse strains with antibiotics has been demonstrated to enhance C. jejuni colonization (Chang and Miller 2006; Bereswill et al. 2011; Stahl et al. 2014). In a previous study, using C3H mice with a limited microbiota, the CFU of C. jejuni dropped below the limit of detection by 20 weeks post-colonization (Chang and Miller 2006). Together, these studies suggest that the nature and complexity of the microbiota impacts colonization resistance for C. jejuni. Unlike most limited microbiota and antibiotic-treated mice, the ASF community has been demonstrated to be metabolically representative of a conventional microbiota and is a better representative microbiota than randomly selected consortia (Biggs et al. 2017). Thus, the ASF microbiota may be more relevant for pathogenesis studies than other models with a limited microbial community. In this study, four separate C. jejuni isolates, including two human isolates and two abortifacient ovine isolates, were shown to persistently colonize ASF mice (107–109 CFU/g feces) for at least 7 weeks. The CFU of C. jejuni 81–176 appeared to decrease over time in the initial experiment, but on a subsequent experiment, there was no apparent decrease in fecal CFU over time. Unlike most prior colonization studies in Conv-R immunosufficient mice, the Conv-R mice in this study did maintain C. jejuni 81–176 throughout the study time period, though the CFU significantly decreased over time. These data suggest that gnotobiotic mice harboring the ASF microbiota permit persistent colonization by C. jejuni unlike Conv-R mice.

As is characteristic of C. jejuni, the isolates used in this study were not host adapted to mice. In a previous study using IL-10−/− mice, serial passage of C. jejuni through mice resulted in enhanced colonization and pathogenicity (Bell et al. 2009). Short term serial passage (2 week colonization, 5 passages) of C. jejuni 81–176 through ASF mice did not result in the development of more severe disease or increased colonization in the immunologically competent, ASF mice (data not shown).

Following oral inoculation, C. jejuni IA3902 and 11168 were isolated from the liver of ASF mice indicating that live C. jejuni had entered the portal circulation (data not shown). Bacteremia with C. jejuni has previously been demonstrated in murine models and human infections (Skirrow 1994; Kaakoush et al. 2015). As has been observed in sheep, the ability of these C. jejuni isolates to enter the systemic circulation may provide an opportunity to develop an abortion model in ASF mice, as IA 3902 is a C. jejuni isolate from an ovine abortion case (Sahin et al. 2008; Wu et al. 2013). This is notable as isolation from the liver was performed 7 weeks post-colonization without any other disturbance to the epithelial barrier (e.g. use of dextran sulfate sodium, DSS). Orally administered C. jejuni IA3092 has previously been associated with abortion in pregnant guinea pigs, an established model for C. jejuni -mediated abortion and it has been demonstrated to have an affinity for the murine reproductive tract (Skirrow 1994; Burrough et al. 2009; Lashley et al. 2019).

In this study, C. jejuni colonization of ASF mice resulted in the onset of demonstrable colitis characterized by histopathological lesions including stromal collapse. Human campylobacteriosis has been reported to induce adverse effects from the small intestine through the colon (van Spreeuwel et al. 1985; Skirrow 1994; Kaakoush et al. 2015). Previous murine studies demonstrate disease in the stomach through the colon (Chang and Miller 2006; Mansfield et al. 2007; Bereswill et al. 2011); though in our model, the cecum and ileum did not display evidence of microscopic or macroscopic disease. Some murine models have demonstrated mild colonic inflammation characterized by the infiltration of lymphocytes and neutrophils (Chang and Miller 2006; Bereswill et al. 2011). The histopathologic changes in the colon of ASF mice were more severe after 7 weeks compared to 3 weeks of colonization suggesting that the persistent presence of C. jejuni was critical to the onset of chronic lesions in this mouse model rather than the acute inflammation most frequently described in human disease (van Spreeuwel et al. 1985). This is consistent with mild inflammation induced by E. coli LF82 in this same ASF mouse model after 4 weeks of colonization (Henderson et al. 2015). Though antibiotic administration facilitates colonization of C. jejuni in models using Conv-R mice, no disease is observed unless the mice possess an immunodeficiency such as impaired TLR signaling or lack of regulatory T cells (Bell et al. 2009; Bereswill et al. 2011; Stahl et al. 2014).

Human campylobacteriosis is characterized by polymorphonuclear leukocytes and blood in the stool, with colonic diffuse inflammatory colitis (van Spreeuwel et al. 1985; Kaakoush et al. 2015). The notable histopathologic changes observed at 7 weeks in this study included an increase in inflammatory cell infiltrate (primarily lymphocytic with some neutrophils) and stromal collapse. As the lesions in ASF colonized mice became more severe with time following colonization, this suggests either host mediated immune changes are modulating the disease progression or C. jejuni is becoming more fit as a mouse pathogen.

In conclusion, four disparate C. jejuni strains were demonstrated to persistently colonize and induce mild histopathological changes in the GI tract of gnotobiotic C3H/HeN mice colonized with the ASF. This observation supports the concept that mice harboring a less complex microbiota are more readily colonized by C. jejuni than those with a more complex microbiota. This study demonstrates that the pathogenesis of disease caused by C. jejuni is differentially influenced by the complexity of the microbiota. Furthermore, ASF mice offer a useful model to evaluate the impact of a persistent, host-pathogen interaction as well as the unique opportunity to evaluate colonization factors and pathogenesis of C. jejuni within the context of a microbial community, particularly in the corresponding evaluation of metabolomic, transcriptional and/or genomic changes that could be ascribed to members of the resident microbiota (Wannemuehler et al. 2014).

ACKNOWLEDGEMENTS

The authors wish to acknowledge Mary Jane Long, Anne-Marie Overstreet and Amanda Ramer-Tait for technical support and assistance with experimental protocols.

Contributor Information

Meghan Wymore Brand, Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, 1800 Christensen Drive, Ames, IA 50011, USA.

Orhan Sahin, Department of Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, 1800 Christensen Drive, Ames, IA 50011, USA.

Jesse M Hostetter, Department of Veterinary Pathology, College of Veterinary Medicine, University of Georgia, 501 D. W. Brooks Drive, Athens, GA 30602, USA.

Julian Trachsel, Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, 1800 Christensen Drive, Ames, IA 50011, USA.

Qijing Zhang, Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, 1800 Christensen Drive, Ames, IA 50011, USA.

Michael J Wannemuehler, Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, 1800 Christensen Drive, Ames, IA 50011, USA.

FUNDING

Research reported in this publication was supported in part by the National Institute of General Medicine of the National Institutes of Health under award number R01GM099537.

Conflicts of interest

None declared.

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