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. 2023 Nov 17;5(2):167–171. doi: 10.3168/jdsc.2023-0402

Effects of a multispecies direct-fed microbial on gastrointestinal permeability during feed restriction in a growing heifer model

BM Goetz 1, MA Abeyta 1, S Rodriguez-Jimenez 1, J Opgenorth 1, JL McGill 2, KA Bryan 3, LH Baumgard 1,*
PMCID: PMC10928422  PMID: 38482117

Graphical Abstract

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Summary Production livestock experience unavoidable feed restriction (FR) that can increase gastrointestinal tract (GIT) permeability. Direct-fed microbials (DFM) are commonly fed to production livestock to benefit gut health, immunomodulation, and production. Thus, the objectives were to evaluate the effects of a 4-strain DFM on GIT permeability during FR in heifers.

Highlights

  • •

    Feed restriction alters metabolism and hindgut fermentation.

  • •

    Feed restriction causes GIT permeability.

  • •

    Circulating inflammatory biomarkers increased during feed restriction.

Abstract:

The objectives were to evaluate the effects of a 4-strain direct-fed microbial (DFM) on gastrointestinal tract (GIT) permeability and inflammation during feed restriction (FR) in heifers. Holstein heifers (n = 32; mean ± standard deviation; 295 ± 25 kg body weight; 287 ± 17 d of age) were used in an experiment conducted in 2 replicates (16/replicate). Heifers were randomly assigned to 1 of 2 top-dressed dietary treatments: (1) control (CON; 10 g/d dried lactose; n = 16) or (2) DFM containing a commercial blend of Lactobacillus animalis, Propionibacterium freudenreichii, Bacillus licheniformis, and Bacillus subtilis at 11.8 × 109 cfu/d (PRO; 10 g/d 4-strain DFM; n = 16). The trial consisted of 2 experimental periods (P): P1 (14 d) served as baseline for P2 (5 d), when all heifers were restricted to 40% of their P1 dry matter intake (DMI). On P1 d 12 and P2 d 2 and 5, GIT permeability was evaluated using oral chromium (Cr)-EDTA. By design, FR decreased DMI (60%) and body weight (∼18 kg) in all heifers. Regardless of treatment, during FR, all heifers had decreased circulating glucose, β-hydroxybutyrate, insulin, and l-lactate (4, 14, 45, and 19%, respectively), but increased nonesterified fatty acids, serum amyloid A, and haptoglobin (3.0-, 1.7-, and 5.0-fold, respectively). Circulating white blood cells, neutrophils, lymphocytes, and basophils decreased (4, 7, 5, and 6%, respectively), whereas eosinophils increased (41%) during P2 irrespective of dietary treatment. Circulating IFN-γ inducible protein-10 increased (23%) during FR compared with P1 regardless of treatment. Plasma Cr area under the curve increased in all heifers on d 2 and 5 (10 and 14%, respectively) of P2 relative to P1, but this was unaltered by dietary treatment. In summary, FR compromised GIT barrier function and stimulated an inflammatory response, but this did not appear to be ameliorated by PRO.

There are a variety of circumstances and stressors (i.e., transportation, weaning, heat stress) in animal agriculture that are accompanied with insufficient feed intake or short-term feed restriction (FR). Whereas reduced substrate availability has obvious negative consequences on productivity, increasing evidence suggests that gastrointestinal tract (GIT) barrier dysfunction and the ensuing immune activation are at least partly responsible for the suboptimal phenotype (Zhang et al., 2013; Kvidera et al., 2017a,c). Hyperpermeability of the GIT allows for infiltration of luminal pathogens, and other antigens into the splanchnic tissues, portal vasculature, and possibly systemic circulation (Mani et al., 2012). This GIT barrier dysfunction and subsequent immune activation is catabolically costly as nutrients are directed to fueling an immune response instead of productive purposes (Johnson, 2012; Kvidera et al., 2017b).

Direct-fed microbials (DFM) are widely used in ruminant nutrition in an attempt to improve health, feed efficiency, and production (Buntyn et al., 2016). Traditionally, DFM have been classified as lactic acid producing (LAB), lactic acid utilizing (LUB), rumen bacteria, fungi, or yeast (McAllister et al., 2011). Feeding LAB is thought to increase lactic acid production, which helps promote the growth of LUB, and ultimately improves the rumen environment through decreased lactic acid and increased propionate production (Krehbiel et al., 2003). Further, DFM consisting of a combination of LAB and LUB, such as Lactobacillus acidophilus and Propionibacterium freudenreichii, have been used to favorably alter the ruminal environment leading to improved performance (Boyd et al., 2011), but this is not always consistent (Raeth-Knight et al., 2007; Philippeau et al., 2017). Spore-forming bacteria such as Bacillus spp. have gained attention because they are thermotolerant and environmentally stable; thus, they are resilient and adaptable to harsh environmental and intestinal conditions (Hong et al., 2005). Though mechanistically unclear, Bacillus spp. appear to competitively exclude pathogens, improve nutrient absorption, modulate immune function, and improve GIT microbial balance (Hong et al., 2005; Dong et al., 2020). The multifactorial and complementary effects of Bacillus spp. fed in combination with Lactobacillus and Propionibacterium may create a synergistic relationship that could improve GIT health and barrier function resulting in increased performance. Therefore, study objectives were to evaluate the effect of a 4-strain DFM supplement on inflammatory markers, metabolism, and GIT permeability during FR in a ruminant model.

All procedures were approved by the Iowa State University Institutional Animal Care and Use Committee. Holstein heifers (n = 32; mean ± SD; 295 ± 25 kg of BW; 287 ± 17 d of age) were used in an experiment conducted in 2 replicates (16 animals/replicate). Heifers were randomly assigned to 1 of 2 top-dressed dietary treatments: (1) control (CON; 10 g/d dried lactose; n = 16) or (2) DFM containing a commercial blend of Lactobacillus animalis, Propionibacterium freudenreichii, Bacillus licheniformis, and Bacillus subtilis at 11.8 × 109 cfu/d on a lactose carrier (PRO; 10 g/d 4-strain DFM; Chr. Hansen Inc., Milwaukee, WI; n = 16). Heifers were housed in individual crates (182 × 79 cm) equipped with a waterer and feed and were allowed 5 d to acclimate to housing conditions. After acclimating to their new surroundings, the trial consisted of 2 experimental periods (P) during which treatments were administered daily. Period 1 (14 d) served as baseline and heifers were implanted with jugular catheters on d 10 as we have previously described (Kvidera et al., 2017a; Horst et al., 2020) and catheters were maintained until the end of P2. During P2 (5 d), all heifers were feed restricted (FR) to 40% of their average daily ad libitum feed intake during P1. The severity of FR was selected based upon our previous lactating dairy cow models (Kvidera et al., 2017c; Horst et al., 2020). Treatments were provided twice daily and mixed with a ground corn carrier (50 g/feeding; 100 g/d).

Heifers were fed a diet that was formulated to meet or exceed the predicted nutrient requirements (NRC, 2001). The diet consisted primarily of 52.0% alfalfa hay, 37.2% corn silage, 4.9% corn gluten pellets, 4.7% soybean meal, and 1.2% vitamin and mineral mix, and the chemical composition on a DM basis was 14.6% starch, 16.4% CP, 36.8% amylase-treated NDF (aNDF), 29.0% ADF, and NEL was 1.49 Mcal/kg of DM. Heifers were fed ad libitum twice daily (0630 and 1830 h) during acclimation and P1. During P2, the daily feed allowance was divided into 3 equal portions (0630, 1230, and 1830 h) to minimize the metabolic effects of gorging. Rectal temperature and respiration rate were measured twice daily (0600 and 1800 h) and were condensed into daily averages. Body weight was obtained on acclimation d 1, P1 d 1, 7, 10, and 14, and P2 d 5.

Fresh fecal samples were obtained via manual rectal extraction daily (0600 h) from P1 d 11 through P2 d 5. To ensure accuracy, 50 g of fecal matter was diluted with 50 g of distilled water and homogenized (Lab-Blender Stomacher 80, Seward Ltd.) before pH was determined as previously described (Branstad et al., 2017). Fecal samples were sent to a commercial laboratory (Dairyland Laboratories Inc., Arcadia, WI) for analysis of starch using a YSI Biochemistry analyzer (Yellow Springs Instrument Inc.).

Intestinal barrier function was evaluated using the paracellular permeability marker chromium (Cr)-EDTA on P1 d 12 and P2 d 2 and 5 as previously described (Wood et al., 2015). For each challenge, beginning at 0600 h a 180 mM solution of Cr-EDTA (0.1 g/kg BW; Amado et al., 2019) was dosed into the rumen using an oral drench system. Blood was collected hourly from 0 to 12 h, and at 18, 24, and 36 h relative to Cr-EDTA administration into a tube containing K2EDTA (Becton, Dickinson and Co., reference no. 368381; plasma for trace element analysis). Plasma was harvested following centrifugation at 1,500 × g for 15 min at 4°C and subsequently frozen at −20°C until analysis. Samples obtained at 0, 1, 2, 4, 8, 12, 18, and 24 h relative to Cr-EDTA administration were submitted to the Iowa State University Veterinary Diagnostics Laboratory for Cr analysis.

Unless otherwise specified, blood samples for metabolite and inflammatory biomarker analysis were obtained on d 12 and 14 of P1 and d 1, 3, and 5 of P2 at 0600 h immediately before feeding. Two blood tubes were collected, one tube contained K2EDTA (BD, Franklin Lakes, NJ; for plasma collection) and the other a silicone clot activator (BD; for serum collection).

Samples for complete blood count analysis were collected at 0600 h on d 12 and 14 of P1 and daily during P2. Blood (3 mL) was collected from the jugular catheter and placed into a tube containing K2EDTA (Becton, Dickinson and Co.) and stored at 4°C before submitting to the Iowa State University's Department of Veterinary Pathology for analysis.

Plasma insulin, nonesterified fatty acids (NEFA), BUN, glucose, BHB, l-lactate, serum amyloid A (SAA), haptoglobin (Hp), and lipopolysaccharide binding protein (LBP) concentrations were determined using commercially available kits according to manufacturers' instructions.

A MILLIPLEX Bovine Cytokine/Chemokine 15-plex kit (BCYT1–33K-PXBK15; EMD Millipore Corporation) utilizing antibodies to bovine IFN-γ, IL-1α, IL-1β, IL-4, IL-6, IL-8, IL-10, IL-17A, macrophage inflammatory protein (MIP)-1α, IL-36 receptor antagonist, IFN-γ inducible protein (IP)-10, macrophage chemo-attractant protein (MCP)-1, MIP-1β, tumor necrosis factor (TNF)-α, and vascular endothelial growth factor (VEGF)-A was used to evaluate serum samples. The assay was performed according to the manufacturer's instructions. Concentrations of IL-1α, IL-1β, IL-4, IL-6, IL-17A, MIP-1α, and TNF-α were below detectable limits.

Area under the curve (AUC) for circulating Cr was calculated by linear trapezoidal summation between successive pairs of Cr-EDTA concentration and time coordinates and the 24-h AUC calculation are reported.

Data were evaluated for normality and variables that required natural logarithmic transformation were back transformed for interpretation (i.e., SAA and Hp). Data were analyzed using the MIXED procedure of SAS version 9.4 (SAS Institute Inc., Cary, NC). The model included treatment, period, their interaction, and replicate as fixed effects. Heifer nested within treatment was included as a random effect. Plasma Cr AUC during both P1 and P2 were analyzed together to fully characterize the time effect (so each of the 3 challenge days could be statistically compared). For both models, initial BW was used as the covariate.

By design, FR decreased DMI (60%) and BW in all heifers (∼18 kg) compared with P1 (P < 0.01; Table 1) and these were unaffected by treatment (P > 0. 43). Relative to P1, fecal pH and DM increased (0.28 units and 4%, respectively) during FR (P ≤ 0.05), but no differences between treatments were detected (P > 0.33). Fecal starch content was unaffected by diet or time (P > 0.38; Table 1).

Table 1.

Effect of probiotic supplementation on production and metabolism during feed restriction (FR) in a ruminant model

Parameter P11
 P21
 SEM P-value
CON PRO CON PRO Trt Per Trt × Per
DMI, kg/d 7.9 8.0 3.2 3.2 0.2 0.76 <0.01 0.58
Rectal temperature, °C 38.6a 38.6a 38.4b 38.5ab <0.1 0.35 <0.01 0.02
Respiration rate, bpm2 41 42 36 37 1 0.46 <0.01 0.77
BW, kg 308 303 289 285 4 0.43 <0.01 0.24
Fecal pH 6.98 6.95 7.28 7.23 0.03 0.33 <0.01 0.59
Fecal DM, % 16.4 16.2 17.2 16.8 0.4 0.50 0.05 0.82
Fecal starch, % DM 0.46 0.48 0.42 0.34 0.10 0.74 0.38 0.62
Metabolism
 Glucose, mg/dL 95.0 92.3 91.1 89.2 1.6 0.26 <0.01 0.67
 NEFA, μEq/L 100 99 400 401 11 0.97 <0.01 0.94
 BHB, mM 0.55 0.53 0.46 0.47 0.02 0.82 <0.01 0.26
 BUN, mg/dL 10.1 9.9 9.8 9.9 0.3 0.91 0.35 0.43
 Insulin, μg/L 1.01a 0.89a 0.48b 0.56b 0.06 0.76 <0.01 0.03
 l-Lactate, μmol/L 0.43 0.44 0.35 0.34 0.02 0.99 <0.01 0.44
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a,b

Values within a row with differing superscript letters indicate a significant interaction (P ≤ 0.05).

1

P1 and P2 = experimental periods (Per) 1 and 2. During P1, all heifers were fed ad libitum. During P2, all heifers were FR to 40% of their ad libitum feed intake. Trt = treatment: CON = 10 g/d dried lactose (n = 16); PRO = 10 g/d Lactobacillus animalis, Propionibacterium freudenreichii, Bacillus licheniformis, and Bacillus subtilis supplemented at 11.8 × 109 cfu/head per day (n = 16).

2

bpm = breaths per minute.

Circulating glucose, BHB, insulin, and l-lactate decreased (4, 14, 45, and 19%, respectively), and NEFA increased (3.0-fold) during FR regardless of dietary treatment (P < 0.01; Table 1). Blood urea nitrogen concentrations did not differ due to treatment or time (P > 0.35).

Circulating white blood cells, neutrophils, lymphocytes, and basophils decreased (4, 7, 5, and 6%, respectively), whereas eosinophils, hemoglobin, and hematocrit increased (41, 2, and 2%, respectively) during P2 regardless of dietary treatment (P ≤ 0.01; Table 2). Circulating monocytes and platelets were unchanged with treatment or time (P ≥ 0.09). Overall, SAA and Hp concentrations increased (1.7- and 5.0-fold, respectively) during P2 compared with P1 (P < 0.01; Table 2), but neither variable was influenced by dietary treatment (P > 0.13). Circulating LBP did not differ due to treatment or time (P ≥ 0.06). Circulating IP-10 increased (23%) during FR compared with P1 regardless of treatment (P = 0.03; Table 2), but IFN-γ, IL-8, IL-10, IL-36, MCP-1, MIP-1β, and VEGF-A were not altered by treatment or time (P > 0.12).

Table 2.

Effect of probiotic supplementation on immune metrics during feed restriction (FR)

Parameter P11
 P21
 SEM P-value
CON PRO CON PRO Trt Per Trt × Per
Complete blood count
 WBC,2 × 103/μL 10.7 10.2 10.3 9.7 0.4 0.26 <0.01 0.46
 Neutrophils, × 103/μL 3.5 3.1 3.2 3.0 0.2 0.17 0.01 0.36
 Platelets, × 103/μL 309 321 300 306 23 0.79 0.28 0.79
 Monocytes, × 103/μL 0.53 0.51 0.50 0.49 0.03 0.71 0.09 0.72
 Lymphocytes, × 103/μL 6.16 6.00 5.97 5.57 0.28 0.48 <0.01 0.06
 Eosinophils, × 103/μL 0.35 0.35 0.47 0.52 0.06 0.75 <0.01 0.43
 Basophils, × 103/μL 0.13 0.12 0.12 0.11 0.01 0.57 0.01 0.24
 Hemoglobin, g/dL 10.8 10.8 11.1 10.9 0.2 0.62 <0.01 0.23
 Hematocrit, % 28.3 28.2 28.9 28.6 0.4 0.75 <0.01 0.35
Acute phase protein3
 LBP, μg/mL 0.91 0.80 0.87 1.16 0.13 0.57 0.13 0.06
 SAA, μg/mL 170 93 305 388 72 0.62 <0.01 0.12
 Haptoglobin, μg/mL 0.21 0.23 0.75 2.35 0.31 0.13 <0.01 0.19
Cytokine4
 IFN-γ, pg/mL 7.5 7.2 8.8 10.8 2.2 0.73 0.23 0.58
 IL-8, μg/L 33.0 12.9 16.7 10.6 8.2 0.15 0.24 0.38
 IL-10, pg/mL 181 162 162 140 34 0.59 0.49 0.94
 IL-36, pg/mL 658 564 551 497 74 0.42 0.12 0.72
 IP-10, pg/mL 2,120 2,505 2,670 3,032 273 0.23 0.03 0.96
 MCP-1, pg/mL 1,047 894 1,092 1,084 104 0.52 0.14 0.36
 MIP-1β, pg/mL 231 249 198 185 45 0.96 0.13 0.63
 VEGF-A, pg/mL 280 241 332 232 49 0.21 0.62 0.48
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1

P1 and P2 = experimental periods (Per) 1 and 2. During P1, all heifers were fed ad libitum. During P2, all heifers were FR to 40% of their ad libitum feed intake. Trt = treatment: CON = 10 g/d dried lactose (n = 16); PRO = 10 g/d Lactobacillus animalis, Propionibacterium freudenreichii, Bacillus licheniformis, and Bacillus subtilis supplemented at 11.8 × 109 cfu/head per day (n = 16).

2

WBC = white blood cells.

3

LBP = lipopolysaccharide binding protein; SAA = serum amyloid A.

4

IP = IFN-γ inducible protein; MCP = macrophage chemo-attractant protein; MIP = macrophage inflammatory protein; VEGF = vascular endothelial growth factor.

Plasma Cr AUC increased similarly in all heifers on d 2 and 5 (10 and 14%, respectively) of P2 compared with P1 (P < 0.01; Figure 1) but was unaffected (P > 0.58) by dietary treatment.

Figure 1.

Figure 1

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Plasma Cr area under the response curve (AUC) in Holstein heifers fed either 10 g/d dried lactose as a control (CON; n = 16) or 10 g/d of Lactobacillus animalis, Propionibacterium freudenreichii, Bacillus licheniformis, and Bacillus subtilis supplemented at 11.8 × 109 cfu/head per day (PRO; n = 16). Trt = treatment. During period 1, heifers were fed ad libitum, and during period 2 they were feed restricted to 60% of their period 1 intake. Intestinal barrier function was evaluated using a 180 mM solution of Cr-EDTA (0.1 g/kg of BW) that was dosed into the rumen using an oral drench system. Error bars indicate SE, and superscript letters indicate the significant day effect.

As anticipated, the BW loss, increased circulating NEFA, mild hypoglycemia, and marked hypoinsulinemia are consistent with the hallmarks of FR (Kvidera et al., 2017c; Marins et al., 2023). In contrast to lactating cows, which frequently have increased circulating BHB (Horst et al., 2020; Marins et al., 2023), BHB decreased during FR herein and this corroborates other reports in nonlactating ruminants (Zhang et al., 2013). The reduction in circulating ketones is likely a reflection of decreased alimentary ketogenesis in the rumen and large intestine epithelium (Abeyta et al., 2023); however, it further illustrates that NEFA and BHB are not well correlated (McCarthy et al., 2015). Including LAB and LUB in the PRO fed herein is thought to alter fermentation toward propionate production (Philippeau et al., 2017). Increased propionate would then enhance hepatic glucose output, increase pancreatic insulin secretion, and ultimately then decrease adipose tissue mobilization; however, PRO did not affect energetic hormones and metabolites measured herein. It is possible that the high fiber and low starch diet fed may have influenced the effectiveness of PRO, but results from past investigators indicate that increasing starch does not necessarily increase the effectiveness of DFM supplements on lactation performance (Philippeau et al., 2017; Lawrence et al., 2021). Additionally, the severity of FR (60%) may have overwhelmed the capacity for the DFM to effectively demonstrate meaningful modifications of bioenergetics within the context of this model. Regardless, identifying the dietary and physiological opportunities of when DFM supplementation alters postabsorptive metabolism would have pragmatic significance.

Administering Cr-EDTA is a well-established model for measuring GIT barrier function in vivo in monogastrics (Zuckerman et al., 1993) and ruminants (Zhang et al., 2013; Horst et al., 2020). Furthermore, while circulating acute phase proteins are nonspecific markers of immune activation, their pattern of change has been correlated with intestinal permeability measured using the Cr-EDTA technique (Horst et al., 2020). Our Cr AUC data corroborate both ruminants (Zhang et al., 2013; Horst et al., 2020) and monogastrics (Boza et al., 1999) that FR causes GIT hyperpermeability.

The actual mechanism of how and why FR causes leaky gut in multiple species is not clear, but this appears to be a generalized response to stress (Mayorga et al., 2020). In lactating cows and growing steers, the negative effects of FR on GIT barrier function were most pronounced early following FR and progressively improved with time (Zhang et al., 2013; Horst et al., 2020). The temporal result herein suggests GIT permeability did not improve with time as there were no differences in d 2 versus 5 (Figure 1). Reasons for the inconsistences are unclear, but there are key limitations to the Cr-EDTA technique such as how feed intake, passage rate, and renal clearance may influence blood Cr concentrations in addition to measuring Cr in blood versus the traditional urine collection technique (Goetz et al., 2022).

Almost all circulating WBC decreased during FR (Table 2), and this is similar to the decrease observed in previous FR models (Horst et al., 2020). Incidentally, severe and acute decreases in WBC are observed following i.v. LPS administration in cattle and pigs (Kvidera et al., 2017b) and this further strengthens the notion that FR induces an immune response (ostensibly via GIT barrier dysfunction). Interestingly, circulating eosinophils markedly increased (>40%) during FR. The role of eosinophils in GIT inflammation has gained attention (Celi et al., 2019). Typically, eosinophils reside in the intestinal lamina propria and have a defensive role against viral and parasitic pathogens (Filippone et al., 2019), but they also assist in GIT epithelial regrowth (Aceves et al., 2007). Furthermore, circulating acute phase proteins increased during FR, and this agrees with previous reports in ruminants (Kvidera et al., 2017a,c; Horst et al., 2020). The increased acute phase proteins coupled with the changes in WBC provide strong evidence that FR-induced leaky gut caused an immune response. Sometimes FR does not appear to stimulate an immune response (Abeyta et al., 2023; Marins et al., 2023) and reasons for the discrepancies between studies remain unclear, but the duration and magnitude of FR, stage of production, and production priorities may all be contributing factors. As aforesaid, DFM may interact with the postruminal GIT through competitive exclusion, secretion of antimicrobial substances, and immunomodulation (McAllister et al., 2011). The overall intent is to slightly upregulate the immune system and defense mechanisms, but hyperimmune stimulation is not unprecedented. An increased inflammatory response has been shown in ad libitum-fed steers supplemented with a DFM (Emmanuel et al., 2007) and in chickens supplemented with a Bacillus spp. (Dong et al., 2020). Regardless, understanding how different DFM and their dose interact with the gut-associated immune system warrants further investigation. Likewise, a clearer understanding of GIT hyperpermeability differences due to various stressors (e.g., pathogen challenge, heat stress, cold stress, FR) and how (and when) different DFM may ameliorate the pathology is also needed.

Notes

This project was supported, in part, by Chr. Hansen Inc. (Milwaukee, WI) and the Norman Jacobson Endowed Professorship (Iowa State University, Ames, IA). K. Bryan is an employee of Chr. Hansen.

The authors have not stated any other conflicts of interest.

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