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© 2007 American Society for Nutrition J. Nutr. 137:2080-2086, September 2007

Nutrition and Disease

Low Dietary Boron Reduces Parasite (Nematoda) Survival and Alters Cytokine Profiles but the Infection Modifies Liver Minerals in Mice1,2

Annie-Claude Bourgeois3, Marilyn E. Scott3, Kebba Sabally3,4 and Kristine G. Koski4,*

3 Institute of Parasitology and 4 School of Dietetics and Human Nutrition, McGill University (Macdonald Campus), Ste-Anne de Bellevue, Quebec, Canada H9X 3V9

* To whom correspondence should be addressed. E-mail: kris.koski{at}mcgill.ca.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Although boron (B) is an essential trace mineral, any interactions that it may have with gastrointestinal (GI) nematode infections are unknown. This study explored whether low dietary B would: 1) alter survival or reproduction of Heligmosomoides bakeri (Nematoda); 2) modify the resulting cytokine response to this parasitic infection; or 3) influence liver mineral concentrations in the infected host. Balb/c mice were fed either a low-B (0.2 µg B/g), marginal (2.0 µg B/g), or control (12.0 µg B/g) diet. Diets commenced 3 wk before a primary infection and were fed for 4 wk (primary infection protocol) and 8–9 wk (challenge infection protocol). Mice were killed 6 d post-primary infection (d6ppi), or dewormed then reinfected (challenge infection protocol) and killed 14 or 21 d post-challenge infection (d14pci or d21pci, respectively). Low and marginal dietary B intakes impaired survival of the parasite, reduced intestinal inflammation, and modulated a broad range of cytokines and chemokines despite similar liver B concentrations in diet groups. Compared with control mice, cytokine production was lower following low and marginal B intakes at d6ppi but was elevated at d21pci. Serum alkaline phosphatase was higher at d6ppi than at d14pci and d21pci. Compared with d14pci, liver zinc, iron, and B concentrations were reduced at d21pci when worm numbers were also lower, whereas concentrations of sodium, potassium, molybdenum, chromium, and sulfur were higher. This study shows that parasite survival and cytokine and inflammatory responses are modified by dietary B intake but indicates that a GI nematode infection alters liver mineral concentrations.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Malnutrition and gastrointestinal (GI)5 nematode infections co-occur and contribute globally to morbidity and mortality in humans and animals (1). Recent reports have highlighted the possibility that trace element deficiencies may affect nematode survival and reproduction (2–4). Infection-induced mineral redistribution may also modify host defenses, benefit the infectious agent, and promote its survival (5–7).

During the past 25 y, data has accumulated to indicate that boron (B) is an essential trace element for animals and humans (8,9). B plays a role in glycolysis, enzyme activity and respiratory burst (8), mineral-mineral interactions (10), structural integrity of membranes (11), and cell-cell communication in bacteria (12). Supplemental B accelerates angiogenesis and increases TNF{alpha} in cultured human fibroblasts (13), antibody concentrations in rats (14), and cytokines in pigs but downregulates porcine inflammatory responses (15). B deficiency, however, impairs gametogenesis, embryo development, and/or larval maturation in fish (16), amphibians (17), and rodents (18). Our laboratory recently reported toxic effects of in vitro exposure to B in both free-living and parasitic stages of the GI nematode Heligmosomoides bakeri (19).

This study was designed to investigate the effects of low or marginal intakes of dietary B and stage of infection on nutritional, parasitological, and immunological outcomes during an H. bakeri (Nematoda) infection in mice. Our first objective was to investigate whether low dietary B would promote establishment, survival, and reproduction of the parasite, as reported for zinc and selenium deficiency (20,21), or reduce worm burdens, as reported for molybdenum deficiency (4). The other objective was to determine whether liver mineral concentrations or production of cytokines would be altered by low dietary B during the time course of this nematode infection.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Experimental design. The study was designed as a 3 x 3 factorial with main effects of B (low, 0.2 µg B/g; marginal, 2.0 µg B/g; or control, 12.0 µg B/g diet) and infection history [d 6 post-primary infection (d6ppi) or d 14 or d 21 post-challenge infection (d14pci or d21pci, respectively]. d6ppi was chosen because this day measures establishment and at this stage of a primary infection, larvae are still embedded in the intestine; at d 14 following a challenge infection protocol, larvae emerge from the intestine into the lumen and from d14pci to d21pci are under active expulsion if host defenses are activated. Outcomes included measures of nutritional status [food intake, body weight gain, feed efficiency, serum isoenzymes of alkaline phosphatase (ALP), and liver mineral concentrations], a panel of chemokines and cytokines, and parasitological data (larval and adult worm numbers and net egg output).

    Mice. Four-week-old female Balb/c mice (Charles River) were housed individually (22–25°C;14-/10-h- light/-dark cycle) in Nalgene cages (Fisher Scientific) with stainless steel covers and floor grids to prevent coprophagy; all cages, covers, grids, bottles, and feeders were acid-washed prior to use. Mice, acclimatized to the control diet for 3 d, were weighed and randomized to 1 of 3 experimental diets. Food was weighed daily, body weight was measured weekly, and feed efficiency (g weight gain/g intake) was estimated over 3 phases of the study (21 d prior to infection to d6ppi, d6ppi to d14pci, and d14pci to d21pci).

    Diets. The semipurified diets, obtained from Curtiss Hunt (USDA, Agricultural Research Service, Human Nutrition Research Center, Grand Forks, ND), were stored at –20°C. The basal diet consisted of acid-washed ground corn, high-protein casein, corn oil, and adequate amounts of all vitamins and minerals (Table 1) with the exception of B. A low-B diet was designed to contain 0.2 µg B/g, a concentration shown by Hunt (22) to induce B deficiency in rodents but sufficient for reproduction in uninfected mice (18); marginal (2.0 µg B/g) and control (12.0 µg B/g) diets were also supplemented with orthoboric acid (22). The marginal diet contained B in amounts found in diets containing fruits and vegetables (23); the concentration in the control diet was similar to that found in commercial mouse nonpurified diet (22). Mice killed during the primary infection (d6ppi) were fed their respective diets for 4 wk, whereas mice killed during the challenge infection (d14pci or d21pci) were fed experimental diets for 8 wk or 9 wk, respectively.


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  		TABLE 1 Composition of diets

 
    Parasites. H. bakeri (=Heligmosomoides polygrus and Nematospiroides dubius) is commonly used as a laboratory mouse model for a GI nematode infection. These ingested infective larvae migrate through the intestinal wall and live in the serosal musculature as fourth stage larvae (L4) for a week before they migrate back through the intestinal wall into the lumen of the duodenum where the adult nematodes coil around the villi (24). A first or "primary" infection of naïve animals leads to a long-term chronic infection, whereas a secondary "challenge" infection following drug treatment to remove the primary infection stimulates immunity that delays development of the challenge infection and results in expulsion of the worms from the intestine in the feces within 3–4 wk (25,26). Infective third stage larvae (L3) were obtained by culturing the feces of stock CD1 mice (Charles River) on moist filter paper for 1 wk. Cultured larvae were suspended in deionized water and kept at 4°C for 2 wk prior to infection of experimental mice (20).

    Protocol. Balb/c mice (n = 68) were given a primary infection by gavage with 150 L3 suspended in 20 µL deionized water 3 wk following dietary restriction, as previous studies in infected mice had shown trace element deficiency after this time (20,27). Between 6 and 8 mice were killed (Ketamine/Xylazine 50/5 mg/kg body weight) on d6ppi to assess parasite establishment. The remaining mice were dewormed (175 mg/kg pyrantel pamoate, Combantrin, Pfizer) on d9ppi and d14ppi. On d21ppi, these mice (n = 7–8 per diet group) were challenged with a second infection of 300 L3. To estimate net egg production (28), a 24-h stool sample was collected on d15pci from mice subsequently killed on d21pci. At necropsy (d6ppi, d14pci, d21pci), blood was collected by cardiac puncture and serum was frozen at –20°C for later ALP and cytokine analyses. The number of L4 in the serosal musculature at d6ppi and the adult male:female ratio in the intestinal lumen (d14pci and d21pci) were recorded and intestinal wet weight was measured (d14pci and d21pci) as a crude index of intestinal inflammation. Livers were frozen (–80°C) for later mineral analyses. All procedures were approved by the McGill Animal Care Committee in accordance with the Guidelines of the Canadian Council on Animal Care (29).

    Serum analysis of ALP. Duplicate serum samples were analyzed using the Promega AttoPhos AP Fluorescent Substrate system; these kits use 2'-[2-benzothiazoyl]-6'- hydroxybenzothiazole phosphate, a substrate that is more sensitive than the traditional substrate p-nitrophenylphosphate (30). Quantification of intestinal and liver-bone-kidney (LBK) ALP isoenzymes was based on the fact that both are heat labile, but the intestinal isoenzyme is inhibited by L-phenylalanine (2.5 mmol/L) and LBK by L-homoarginine (10 mmol/L) (31). Absorbance readings using the Wallac fluorometer, set at 430–440 nm for the excitation filter and 550–560 nm for the emission filter, were recorded. The final concentration for each isoenzyme was determined.

    Liver analysis of minerals. Liver samples (~1 g) and bovine muscle standard reference material (RM 8414) were weighed in acid-washed 15-mL Teflon tubes. After adding 4 mL of ultrapure trace metal grade HNO3, each capped tube was allowed to stand for 24 h at room temperature in a Thermolyne dry bath incubator (Fisher). Thereafter, samples were acid-digested for 8 h (50°C, 30 min; 60°C, 30 min; 75°C, 1 h; 85°C, 1 h; 100°C, 1 h; 110°C, 4 h) based on a modification of the method performed by Chan et al. (32). Digested samples were diluted 4 times with double deionized water for analysis by inductively coupled plasma-optical emission spectroscopy (Perkin-Elmer Elan 5300) with axial light emission for detection.

    Screening assay for cytokine pattern. Within each diet group and at each time point, 2 serum samples (each pooled from 2 mice) were screened for 31 cytokines and chemokines (RayBio Mouse Cytokine Antibody Array, Raybiotech). Each membrane, exposed to Kodak X-omat AR film and developed using a film processor (Kodak, no. M35A), was digitized and the OD of each spot was read by densitometry (Versa Doc Imaging system, Biorad). Net intensity was calculated by subtracting background intensity around each spot from the intensity of the spot itself. Net intensity of the positive control on each membrane was assigned a value of 100 and the intensity of the negative control a value of 0; relative intensity was then interpolated and the calculated relative intensities of the 2 membranes from the same dietary group and time point were averaged. At each time point, cytokine production for mice fed low or marginal diets was compared with cytokine production of control mice according to methods of Klein and colleagues (33). Cytokines that increased 50–100% were considered upregulated (+) and those that increased by >100% were considered as more upregulated ({uparrow}). Cytokines that decreased by 33–50% were considered downregulated (–) and those that decreased >50% were considered more downregulated ({downarrow}).

    Statistical analysis. All data were normally distributed using skewness and kurtosis measures and were analyzed using SAS version 9.1. Main effects of B (low, marginal, or control diets) or stage of infection (d6ppi, d14pci, or d21pci) on body weight and weight gain, food intake, and feed efficiency were tested by 2-way ANOVA for significant main effects of diet, time, and diet x time interactions using the general linear models option. Additionally, 1-way ANOVA was also performed on these data because of confounding by age and length of exposure to the diets as a result of infection protocols. Both 1- and 2-way ANOVA are reported for body weight and weight gain, food intake, and feed efficiency. For other variables (liver minerals, ALP, and intestinal wet weight), if there was no significant main effect of either diet (low, marginal, or control) or stage of infection (d6ppi, d14, or d21pci), these data were pooled and analyzed; post hoc significance was determined using Scheffé test. Pearson correlations relating worm burdens with intestinal weight and concentrations of liver minerals were also performed. In all cases, P < 0.05 was significant. Cytokine screening arrays were qualitatively assessed following standard procedures (33).


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Food intake and body weights. Initial body weights were similar (Table 2) and cumulative food intake did not differ among the dietary groups; consequently, body weight gains did not differ (Table 2). On the other hand, stage of infection significantly affected daily weight gain, food intake per day, and feed efficiency, whereas dietary B intake affected only feed efficiency (Table 2).


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  		TABLE 2 Effects of low and marginal intake of B in H. bakeri (Nematoda) on food intake, body weight gain, and feed efficiency in mice1

 
    Parasite survival and reproduction. Worm burdens were measured to determine whether low or marginal dietary B intake influenced parasite establishment following a primary infection in previously uninfected mice (d6ppi) or survival following the challenge reinfection protocol (d14pci and d21pc). The numbers of L4 at d6ppi were 18.3 and 25.1% lower in mice fed low and marginal diets, respectively, compared with those fed the control diet. Moreover, the proportion that developed into adults at d14pci was also lower for both low and marginal diets (Fig. 1A). B did not modify the parasite sex ratio at either d14pci or d21pci or net egg production at d15pci (data not shown).


Figure 1
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  		FIGURE 1  Impact of dietary B deficiency on establishment (L4 at d6ppi) and survival of adult worms (d14pci and d21pci) in mice infected with H. bakeri for primary and challenge infection protocols (A) and wet weight of the intestines after challenge infection (B). Values are means ± SEM, n = 68. Means at a time without a common letter differ, P < 0.0001 (Scheffé test).

 
    Serum ALP. Both intestinal and LBK ALP were higher at d6ppi when the L4 stage was embedded in the intestinal wall than at d14pci when adults emerged into the intestine and at d21pci during active parasite expulsion (Table 3).


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  		TABLE 3 Concentrations of ALP isoenzymes in serum and liver mineral concentrations (per g wet wt) in H. bakeri-infected mice at d6ppi and d14pci and d21pci1

 
    Liver mineral concentrations. Dietary B intakes did not alter concentrations of any liver minerals, including liver B (data not shown). In contrast, infection protocols did. During the challenge infection, there were decreased B, iron, and zinc but increased chromium, molybdenum, potassium, sodium, and sulfur from d14pci to d21pci (Table 3). In addition, calcium, phosphorus, and zinc concentrations were lower at d6ppi than at d14pci (Table 3).

For the challenge-infected mice (d14pci and d21pci), there were positive correlations between adult worm numbers and zinc (r = 0.40; P < 0.01), B (r = 0.43; P < 0.007), and iron (r = 0.36; P < 0.03) but negative correlations for molybdenum (r = –0.46; P < 0.004) and sulfur (r = –0.38; P < 0.02).

    Indicators of immunity and inflammation. Intestinal wet weight was used as an index of intestinal inflammation (Fig. 1B). At d14pci, intestinal wet weight was higher in control mice than in the other 2 groups (Fig. 1B) and was positively correlated with worm burdens when analyzed across all diet groups (r = 0.81; P < 0.0001). In contrast at d21pci, wet weights did not differ among diet groups and were not correlated with worm burden.

Mouse cytokine arrays were used as a qualitative index to determine whether cytokines and chemokines were generally upregulated or downregulated when each was compared with mice fed the control diet (Table 4). At d6ppi, levels of 30 of 31 cytokines were >50% lower in mice consuming the low-B diet, whereas only 1 cytokine was not reduced by at least 33% [soluble TNF-receptor type I (STNF-RI)]. This generalized downregulation was also evident in mice fed the marginal diet, although fewer cytokines (25/31) were affected. During the challenge infection, the opposite pattern was observed, especially at d21pci. Mice consuming low- and marginal-B diets had >100% increase in 23 of 31 cytokines. Only IL-5 and STNF-RI were unaffected by dietary B restriction.


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  		TABLE 4 Comparison with control diet of cytokine profiles in H. bakeri-infected mice fed either low- or marginal-B diet12

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
Key results from this initial investigation exploring the impact of low dietary B intake in a GI nematode-infected host revealed several novel findings. First, both parasite establishment during the primary infection and survival of adult worms during the challenge infection were impaired. We conclude that B, which is found in nematode tissues (34), may be required for parasite survival, as has been demonstrated for a variety of vertebrate species (10). Another intriguing observation was that most cytokines decreased during the primary infection, but they increased during the challenge infection such that most of them in challenged mice fed the low-B diets doubled, whereas fewer were elevated in mice fed the marginal diet. These findings suggest that, in addition to modulation of TNF{alpha} and IFN{gamma} (15), B may play a broader role in immunological and inflammatory processes than previously suggested (9). The final observation was that shifts in liver mineral concentrations during the course of the experiment were not due to reduced dietary intake of B but may have resulted from infection-induced alterations in mineral absorption or redistribution, as has been previously shown for viral infections (5–7).

Different parasitic stages of H. bakeri induce distinctive pathologies that are associated with either the tissue dwelling or intestinal phases of the infection. During a primary infection, tissue damage, including cellular infiltration and hemorrhaging, arises on d6–7ppi as the larvae emerge from the gut and migrate to the lumen (35,36); in contrast, the immune response during the challenge infection results in elevated Th2 cytokine production and fluid leakage peaking at d14pci (37,38) that expel the adult worms normally coiled around villi of the duodenum (24). In support of these immunological and inflammatory responses, we observed elevated serum concentrations of both intestinal and LBK ALP at d 6 of a primary infection. Although ALP can be produced by hookworm nematodes (39), the nematode-induced hepatitis described during a primary infection (35) most likely caused the elevated serum LBK ALP. The liver has recently been characterized as a nonlymphoid organ involved in the generation and/or accumulation of Th2 cells during an H. bakeri primary infection (40) and it has been proposed that migrating apoptotic effector cells may also accumulate in the liver before being eliminated (41). Thus, liver and intestinal ALP responses, as well as the correlation between intestinal wet weight and worm burden at d14pci, are consistent with dose-dependent inflammatory responses that were unaffected by dietary B. Thus, this inflammation may have contributed to the redistribution of liver minerals in our nematode-infected mice, as is the case with other infections (5–7).

As reviewed by Ilback et al. (7), no study to our knowledge has tracked mineral changes in tissues during a GI nematode infection. We found positive correlation of worm burdens with increased liver concentrations of B, iron, and zinc and negative correlation with liver concentrations of molybdenum and sulfur. Liver iron concentrations were significantly higher at d14pci compared with d21pci, but both were within the normal range reported for uninfected Balb/c mice (7). H bakeri do not feed on blood (24) and only induce temporary hemorrhaging when the larvae migrate from the serosal musculature to the intestinal lumen (42). Thus, it is not surprising that liver iron concentrations did not fall. The elevated liver zinc at d14pci suggests active zinc sequestration, possibly as a result of increased production of metallothionein during the infection (43,44) or the presence of a zinc-finger protein, such as BCL-6, involved in regulation of Th2-induced inflammation (45). The return to normal liver zinc concentrations (7) at d21pci implies that liver sequestration of zinc is transitory. Our observation that liver B was also elevated at d6ppi and d14pci is consistent with its probable involvement in phagocytosis and its regulatory role in glycolysis during active inflammation (8). B has also been reported to accelerate destruction of reactive oxygen species (9,46,47). Because infection with H. bakeri induces reactive oxygen species production (48), the higher liver concentrations would be necessary during infection.

The lower liver concentrations of potassium, sodium, molybdenum, chromium, and sulfur at d14pci compared with d21pci may result from impaired absorption of these macro- and microminerals when adult worm numbers are high, just prior to their expulsion from the GI tract. Malabsorption has been reported to be directly related to the severity and duration of H. bakeri infection (49). Decreased sodium and potassium absorption 7 d after a primary H. bakeri infection (49) and reduced jejunal enterocyte Na,K ATPase and sodium transport at the time of peak numbers of the GI nematode Nippostrongylus brasiliensis have been observed (50). That malabsorption and increased epithelial cell permeability (51) could account for the lower liver concentrations of potassium and sodium at d14pci and of molybdenum, chromium, or sulfur at d21pci must be considered.

Lower worm numbers in mice fed low dietary B differed from previous reports in which data on deficiencies of zinc, iron, and manganese showed higher parasite numbers in the deficient hosts (20,52,53). To our knowledge, the only known exception prior to our study was molybdenum. Weaned Merino lambs fed less than optimal concentrations of molybdenum had reduced numbers of Trichostrongylus colubriformis and reduced female worm egg output compared with lambs fed an optimal diet (4). We present 3 hypotheses to account for lower worm survival in mice with low or marginal dietary B intakes. Perhaps B activates nematode free-radical scavengers as it does for the host (8). Survival depends in part on the ability of H. bakeri to produce antioxidants (48,54). In fact, the rate of production of catalase, superoxide dismutase, peroxidase, and glutathione-S-transferase (48,54) in H. bakeri increases as oxidative stress in its environment increases. If B is required by the parasite's antioxidant enzymes as it is for host enzymes (8), there may be insufficient B available for the parasite when B in the infected host is differentially drawn to the liver, as indicated by our mineral analysis of liver tissues in our infected mice. Alternatively, B, which mimics the effect of TNF{alpha} in healing and is also a suspected stimulus for this cytokine (13), may also accelerate angiogenesis (13) and, therefore, tissue repair. Thus, a low-B diet may compromise intestinal repair and without adequate villi for attachment, there would be fewer worms at d14pci in mice fed restricted amounts of B. A final possibility is that low or marginal intake of dietary B may impair parasite establishment and survival through its effects on the gut microflora. As proper growth, survival, and reproduction of H. bakeri does not occur when the microfloral environment of the gut is disrupted (55,56) and as borate activates autoinducer-2 (12), which is involved in cell-cell communication in bacteria (57), deprivation of dietary B may impair communication in bacteria, leading to inadequate regulation of the gut microflora and creating an inappropriate environment for both the establishment of L4 and survival of adult parasite in the duodenum. Based on the generalized but differential cytokine responses we observed between the primary and challenge infection, B could also be involved in cell-cell communication necessary for immunological and inflammatory responses. This requires further exploration.

It is important to highlight several unavoidable aspects of the experimental design. The different infection protocols used for our experimental design (d6ppi, d14pci, and d21pci) were confounded by both the length of time the mice were fed the experimental diets (4, 8, and 9 wk, respectively) and by the different ages of mice at necropsy (8, 12, and 13 wk, respectively). However, to produce the challenge infection, mice had to receive a primary infection followed by an anthelmintic-abbreviated immunizing protocol. There was evidence that ALP, which declines with age (58), may have done so in our infected mice. On the other hand, our mineral analysis showed both increased and decreased concentrations over time, which supports differences resulting from our infection protocols and not age of the mice or the length of exposure to the experimental diets.

In summary, our findings are novel in a number of ways. First, they show that low and marginal dietary B intakes impair nematode survival. The impaired nematode survival in mice fed B-restricted diets may result from either impaired development or physiology of the parasite or from an altered microenvironment in the host, both of which merit further exploration. Secondly and equally novel is the finding that low and marginal B intakes downregulated virtually all assayed cytokines during the primary infection but upregulated many of these same cytokines during the challenge infection. We consider this to be very important and worthy of further investigation.


   ACKNOWLEDGMENTS
 
We thank Curtiss Hunt (USDA Human Nutrition Research Center, Grand Forks, ND) for his generous supply of the diets which were critical to the success of this study.


   FOOTNOTES
 
1 Supported by Natural Sciences and Engineering Research Council of Canada Discovery Grants. Research at the Institute of Parasitology is supported by a regroupement stratégique grant from Fonds Québécois de la recherche sur la nature et les technologies. Back

2 Author disclosures: A.-C. Bourgeois, M. E. Scott, K. Sabally, and K. G. Koski, no conflicts of interest. Back

5 Abbreviations used: ALP, alkaline phosphatase; GI, gastrointestinal; L4, stage 4 larvae; LBK, liver-bone-kidney; d6ppi, 6 d post-primary infection; d14pci, 14 d post-challenge infection; STNF-RI, soluble TNF-receptor type I. Back

Manuscript received 27 October 2006. Initial review completed 7 December 2006. Revision accepted 17 June 2007.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 

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