Effects of Low Feed Intake on Gastrointestinal Function

Jennifer Dush Author

11/16/2018 Added

95 Plays

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Effects of Low Feed Intake on Gastrointestinal Function by Greg Penner.

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[00:00:00.150]So, thanks for coming to the seminar today.
[00:00:03.520]It's my pleasure to have Dr. Greg Penner on campus.
[00:00:09.310]Greg is an associate professor from
[00:00:11.840]University of Saskatchewan.
[00:00:14.640]He's a chair, I don't remember the name of the chair,
[00:00:16.420]but he's called the chair of the department.
[00:00:19.310]I first met Greg at the Florida nutrition conference,
[00:00:22.910]actually that's the first time I saw Greg,
[00:00:25.080]he won the Young Researcher Award at ASAS.
[00:00:30.715]That's been several years ago that you did that,
[00:00:33.899]and I went to his presentation and came out really impressed
[00:00:38.490]and then just through being on similar programs,
[00:00:42.410]over the years we've kind of gotten to know each other,
[00:00:44.340]went to Brazil together,
[00:00:45.960]Flavio has us both down at a conference a little over
[00:00:50.130]a year ago and really got to spend some time together,
[00:00:53.430]and it just became obvious that there's a lot
[00:00:56.140]of mutual interest and complementary expertise.
[00:01:01.860]So our program is very applied in nature,
[00:01:06.230]as is Greg's, but Greg bridges,
[00:01:10.400]I don't really want to call it a gap,
[00:01:11.960]but bridges applied questions with basic physiology,
[00:01:16.810]and I think does a very nice job of that,
[00:01:18.620]especially dealing,
[00:01:20.140]and where my interest in what he does has really peaked,
[00:01:23.930]is in dealing with integrity of the rumen epithelial tissue
[00:01:27.630]and using that as an acidosis model or to further
[00:01:31.060]our understanding of VFA absorption,
[00:01:33.150]acidosis, and then liver abscesses,
[00:01:35.520]which is something that's been heavy on our minds
[00:01:38.490]as pressure on antibiotic use has increased.
[00:01:41.620]So that was the intent, to kind of pursue that,
[00:01:45.780]Greg has spent time with several faculty,
[00:01:49.700]some of whom are in the room,
[00:01:52.040]spoke at Husker Nutrition Conference last week Friday,
[00:01:56.550]and then yesterday went to the,
[00:01:58.780]never go to a cold football game with a Canadian.
[00:02:02.465](audience laughing)
[00:02:03.640]'Cause even if you wanna leave, they're not going to.
[00:02:06.778](audience laughing)
[00:02:09.193]Yeah, it was brisk to Greg and I was freezing out there.
[00:02:13.110]But we had a really good time over the past week,
[00:02:16.915]it kinda culminates today in the departmental seminar
[00:02:19.233]and he's going to teach a class for me again this afternoon,
[00:02:23.060]and just think there's all kinds of opportunities
[00:02:25.770]for collaboration and integration,
[00:02:28.220]maybe a few more students like Lauren,
[00:02:32.090]who had Greg as an instructor as an undergrad, okay.
[00:02:35.450]So, really pleased to have you with us, Greg,
[00:02:37.490]and look forward to your presentation.
[00:02:39.300]Thank you Jim, and thank you to everyone.
[00:02:41.402](audience applauding)
[00:02:44.623]I sure enjoyed my stay so far,
[00:02:47.265]I've loved interacting with all the students
[00:02:49.717]and all the faculty and certainly seeing the facilities.
[00:02:53.330]Before I get into the meat of the presentation,
[00:02:56.450]I wanna show you where I come from,
[00:02:59.410]and actually there's four of us in this room
[00:03:01.200]that all, at some point of their program,
[00:03:04.981]were training in Saskatoon,
[00:03:07.410]through our animal science department.
[00:03:09.200]So it's good to see that there is Saskatchewan
[00:03:11.830]penetration into the Nebraska training environment.
[00:03:16.990]So if you look at Google Earth,
[00:03:19.720]boreal forest transition,
[00:03:22.250]north of that is the Canadian Shield,
[00:03:25.540]and we're about 700 kilometers south of that.
[00:03:29.460]So you don't get much further north in Canada
[00:03:33.280]than where our home institute is located in Saskatoon.
[00:03:37.610]Obviously, hopefully you guys know your US geography
[00:03:41.010]better than I do, but we're somewhere down here,
[00:03:44.496]so it's a fair ways to travel,
[00:03:46.370]but at least on a longitude standpoint
[00:03:49.170]we're not that different.
[00:03:51.330]University of Saskatchewan,
[00:03:52.163]it's a fairly small university,
[00:03:54.920]around 18,000 undergrad students,
[00:03:57.563]1,500 of 'em in agriculture,
[00:03:59.910]and this is our abbreviation for animal and poultry science,
[00:04:03.150]so about 430 undergrads within our program
[00:04:07.530]through all four years,
[00:04:08.460]so, that's not a single year, so we're fairly small.
[00:04:12.040]3,300 graduate students in our university,
[00:04:16.150]270 in agriculture and 65 of them
[00:04:19.773]in animal and poultry science.
[00:04:21.430]So we're a small department, small college.
[00:04:23.920]We occupy about 7% of the university faculty numbers,
[00:04:29.570]but we generate 25 to 50% of the research revenue,
[00:04:33.690]and research productivity.
[00:04:35.540]So we're a small but proud college.
[00:04:38.680]This is the College of Agriculture at the U of S,
[00:04:41.460]and the university was founded around agriculture,
[00:04:44.630]and it is still the most preeminent building
[00:04:47.570]within our university campus.
[00:04:49.440]Even our vet students look up to us, so.
[00:04:51.776](audience laughing)
[00:04:54.494]We have a number of resources,
[00:04:55.630]so we have a national research facility,
[00:04:58.240]Canadian Feed Research Centre,
[00:04:59.950]located about an hour outside of campus,
[00:05:02.270]full pilot scale line as well as an industrial scale line,
[00:05:06.720]we lease out the industrial scale line to Cargill
[00:05:09.210]but we have an agreement where we can take control
[00:05:12.440]over that mill and use it for production purposes,
[00:05:16.980]for our research.
[00:05:18.420]We have the Rayner Dairy Research and Teaching Facility,
[00:05:21.880]110-cow dairy, has a robotic milking system,
[00:05:25.670]it has a parlor milking system,
[00:05:27.597]and a tie-stall milking system.
[00:05:29.907]And all three of those integrate
[00:05:30.973]into the same data management.
[00:05:33.510]So we have a pretty extensive
[00:05:35.450]research capability on the dairy side,
[00:05:37.483]this is located about five minutes
[00:05:39.640]walking from our building.
[00:05:42.790]And then we just established
[00:05:43.890]the Livestock and Forage Centre of Excellence.
[00:05:46.440]It's a $38 million investment
[00:05:48.670]from an infrastructure standpoint.
[00:05:51.330]It's supposed to cover the gamut
[00:05:52.750]between soil all the way to cattle.
[00:05:56.520]We don't have a meat science department,
[00:05:58.260]that's one of our, well, we do,
[00:05:59.700]but we don't have an active meat science group,
[00:06:02.270]so that's one of our limitations.
[00:06:04.490]But if you look at the facility,
[00:06:05.860]we're looking at doubling our research capability,
[00:06:09.000]so dealing with them quite impressed
[00:06:11.910]the feedlot group by the number of pens
[00:06:13.780]and the amount of replications you can impose.
[00:06:16.510]We think this is great 'cause we're going
[00:06:17.940]to about a 1,500 head capacity.
[00:06:20.950]We also have two different cow herds,
[00:06:23.810]300 head that'll be located directly
[00:06:26.060]across the road from our intensive feeding operation,
[00:06:29.556]and then we have the veterinary research farm
[00:06:32.520]which is a bit smaller but only about
[00:06:33.810]10 minutes away from our major infrastructure.
[00:06:36.830]So pretty exciting things happening in Saskatchewan.
[00:06:41.020]This is our new facility,
[00:06:42.570]so we have large, 200-head commercial pens
[00:06:45.310]that we can divide to be four 100-head pens
[00:06:48.250]to increase replications.
[00:06:50.090]44 small pens, 15-head pens,
[00:06:54.590]and then we have a receiving yard
[00:06:56.160]and we have a brand-new metabolism barn
[00:06:58.850]within this facility,
[00:06:59.860]so hopefully the rest of my career
[00:07:01.960]is done largely with this facility.
[00:07:05.980]Doesn't show, we have micromixing capability,
[00:07:07.990]so we have a UFA micromixer
[00:07:10.313]so that we can start adding small inclusion products
[00:07:14.886]at the feed mixing side,
[00:07:17.560]and then we have commodity bays located in here.
[00:07:21.280]It's my metabolism barn.
[00:07:23.030]Unfortunately it looks like this today,
[00:07:24.670]they're just finishing it off,
[00:07:25.760]hopefully by the time I'm home, I can put cattle in there.
[00:07:28.680]About 24 head capability, total tract collections,
[00:07:32.980]infusion capability.
[00:07:34.580]Our goal is to move to splanchnic catheters,
[00:07:37.140]and that's kind of our interest
[00:07:40.460]in understanding animal metabolism.
[00:07:45.850]Cow-calf facility's just on the other side of the road,
[00:07:47.950]so the feedlot's kind of down over on this side,
[00:07:50.060]cow-calf facility again, we're about 300 cows,
[00:07:52.470]so the idea is to move, like you've done here,
[00:07:55.730]more towards systems types of approaches,
[00:07:59.100]but also to have a significant forage development,
[00:08:02.550]crop breeding, and cow-calf management capability.
[00:08:08.560]The other thing I want to mention is we are hiring.
[00:08:10.910]So John McKinnon is a very well-established
[00:08:13.640]research chair within our department.
[00:08:16.930]He has reached that age where he said,
[00:08:18.667]"I no longer want to come to work because I have to."
[00:08:22.590]So he is retired and we're hiring
[00:08:24.400]at the assistant professor level.
[00:08:26.450]Emphasis is the broadest we could make it.
[00:08:29.120]It's anything related to sustainable
[00:08:31.230]management of the weaned calf.
[00:08:33.240]So we don't really care what the specific expertise are,
[00:08:36.460]if you know of people or you yourself are interested,
[00:08:39.070]come talk to me, and I can let you know more information.
[00:08:44.380]So last slide before I get into the research,
[00:08:47.040]this is the benefit and the problem of my program.
[00:08:51.890]These are students that I directly mentor or advise,
[00:08:57.260]and the benefit is we have a large group,
[00:08:59.400]we have a very good funding system in Canada.
[00:09:02.740]The challenge is, at times my program is too diverse,
[00:09:05.890]and you might see that,
[00:09:06.910]but I have a plan on how we create or maintain
[00:09:10.790]the core and then expand out.
[00:09:13.000]Not going to go through all of them
[00:09:14.210]but if you look at the general core,
[00:09:15.940]gastrointestinal physiology is the core bubble,
[00:09:19.740]and then I interact with any production system
[00:09:22.690]that might have an influence back
[00:09:24.510]on gastrointestinal physiology.
[00:09:26.820]So that could be dairy management,
[00:09:28.620]it could be small ruminant management,
[00:09:30.480]it could be the cow-calf sector,
[00:09:32.160]or it could be feedlot production,
[00:09:34.540]and we work in all of those production fields
[00:09:36.760]so it's interesting, you sit with Paul
[00:09:39.250]and Paul thinks I'm a dairy researcher.
[00:09:41.520]Talk with Jim and Jim thinks I'm a beef researcher,
[00:09:44.720]and I think I'm a ruminant nutrition and physiologist.
[00:09:48.380]So I hope that I can sell most of my concepts
[00:09:52.480]to a broad ruminant production field.
[00:09:56.760]So kind of the focus of my research
[00:09:58.770]is looking at what the gastrointestinal tract does,
[00:10:02.630]and how it accomplishes those outcomes.
[00:10:05.010]I mentioned this yesterday in class,
[00:10:06.420]but these are how I classify essential
[00:10:09.350]functions of the gastrointestinal tract.
[00:10:11.690]So more from a classical standpoint
[00:10:13.820]we would say it's an absorptive organ,
[00:10:16.210]promoting feed digestion by microbes,
[00:10:19.100]regulating ruminal pH, promoting nutrient absorption,
[00:10:22.920]as well as providing a way to recycle urea,
[00:10:26.680]and so that's been well-accepted
[00:10:28.210]and I think that would be classical ruminant nutrition.
[00:10:30.950]The last two are probably more debatable
[00:10:33.630]and newer advancements.
[00:10:36.080]So barrier function of that tissue
[00:10:37.940]and how that tissue regulates what gets to cross it,
[00:10:41.470]so promoting absorption but preventing
[00:10:44.190]non-desired molecules from crossing that tissue
[00:10:47.530]is a very important factor and so because of that
[00:10:50.560]it functions as the first arm of the immune response,
[00:10:54.160]and there's a number of ways it does that
[00:10:56.370]through intrinsic, extrinsic, and immunological mechanisms.
[00:11:01.430]We're not going to go into the detail of that,
[00:11:03.480]but that is a key principle
[00:11:05.210]that you'll see in studies coming up.
[00:11:08.090]Communicative function, and so we know there is cross-talk
[00:11:11.370]between the host and the microbiota,
[00:11:14.560]and something we're really excited about
[00:11:16.640]is ruminal nutrient sensing,
[00:11:19.050]and how those sensing mechanisms
[00:11:21.720]signal broader effects on the host.
[00:11:24.340]So looking at functional nutrients
[00:11:26.140]and how you can include something
[00:11:28.210]at 0.3% of dry matter like butyrate
[00:11:31.700]that has the contribution that is far more
[00:11:34.390]than its caloric val.
[00:11:36.930]And this is an area we're actively pursuing.
[00:11:42.210]So to get back to the issue,
[00:11:43.860]I'm going to talk today about low feed intake
[00:11:45.707]and in reality I think low feed intake
[00:11:47.770]is an unrecognized challenge.
[00:11:50.535]And I'm gonna give you a couple production scenarios
[00:11:52.070]that I hope cement the concept of low feed intake
[00:11:55.170]as a model to evaluate gastrointestinal function.
[00:11:58.600]This was work we did with 14 newborn Holstein calves,
[00:12:01.660]transported them to the U of S on day one of age.
[00:12:05.950]We weaned them on day 42 after imposing
[00:12:08.940]a seven-day step-down program on milk replacer.
[00:12:12.560]So this would be a common nutritional management practice
[00:12:15.860]that we would see in the dairy industry in Saskatchewan.
[00:12:20.390]We have two groups,
[00:12:21.920]we have our group that never got weaned as our control,
[00:12:26.030]and then we have our group that was weaned.
[00:12:29.800]What you can see here is milk replacer intakes,
[00:12:31.500]so the groups were essentially equivalent
[00:12:33.500]until five weeks of age,
[00:12:34.930]at which time we started imposing
[00:12:36.610]that step-down milk replacer program,
[00:12:39.530]and so you can see milk replacer
[00:12:40.747]intake decreased for week six,
[00:12:42.540]there is no milk replacer intake
[00:12:44.150]on week seven for that group,
[00:12:45.450]because we artificially weaned them.
[00:12:49.420]If you look at starter intake,
[00:12:51.030]again this is just classical data.
[00:12:53.150]It fits well with the older literature.
[00:12:55.200]When you take away milk, starter intake goes up.
[00:12:58.590]Drops that caloric difference,
[00:13:01.340]so we saw exactly what we had expected.
[00:13:04.210]The challenge is when we did this,
[00:13:06.571]we saw the release of chromium EDTA
[00:13:10.910]in urine dramatically increased.
[00:13:13.118]And I'm going to bring this model up in a few slides.
[00:13:15.650]We're using chromium EDTA as an indicator
[00:13:18.840]of paracellular permeability,
[00:13:21.130]so the ability of molecules to cross
[00:13:23.530]the gut by moving between cells.
[00:13:26.900]So we orally dose chromium EDTA,
[00:13:30.510]and then we measure the urine,
[00:13:32.810]so we have total urine output and urinary chromium EDTA,
[00:13:36.690]and the principle is the more chromium EDTA
[00:13:38.990]that appears in the urine,
[00:13:40.380]the more permeable that gastrointestinal tract is.
[00:13:43.520]So from that we saw a couple really interesting
[00:13:45.728]outcomes in this study.
[00:13:48.020]First of all, there's a very clear age-dependent response
[00:13:52.730]where the gastrointestinal tract tightens.
[00:13:55.510]So it becomes less permeable.
[00:13:57.910]And this is probably pretty important
[00:13:59.390]if you think of the microbiota establishing
[00:14:02.440]core community as that calf ages,
[00:14:05.720]and the necessary need to restrict movement
[00:14:09.790]of molecules across that gastrointestinal tract.
[00:14:12.860]The other aspect we saw was complete disruption
[00:14:16.250]of that tightening when we weaned those calves.
[00:14:18.680]And this was not an aggressive weaning protocol,
[00:14:20.920]this was an industry-standard weaning protocol.
[00:14:23.670]But we basically reverted permeability
[00:14:26.570]back to that early stage of life.
[00:14:30.090]So it tells us a couple things.
[00:14:32.320]One is the calf is working hard to try
[00:14:35.940]to improve integrity of the gastrointestinal tract.
[00:14:39.920]And we have an influence as managers of those animals,
[00:14:43.800]where what we can perceive based on concentrate intake
[00:14:47.860]as a reasonable weaning approach
[00:14:50.250]doesn't seem to be a reasonable approach
[00:14:52.540]when we look at other indicators like permeability.
[00:14:55.570]So that calf may be faced with other challenges
[00:14:58.180]that we aren't measuring.
[00:15:02.958]So that's the dairy calf model.
[00:15:04.820]This is the model for transition dairy cattle.
[00:15:07.620]'Course I'm self-promoting here
[00:15:09.280]so I'm showing data from my master's
[00:15:11.540]where we had cattle that were going through a controlled,
[00:15:15.617]an NRC-derived control, a pre-partum program,
[00:15:19.440]or the plot at that time,
[00:15:21.640]a step-up program where we increased
[00:15:23.440]fermentability of the diet prior to parturition.
[00:15:27.343]What I want to highlight is on average
[00:15:29.130]those cows reduced dry matter intake by 30%
[00:15:33.180]relative to the day of calving,
[00:15:35.825]and if you look at the literature,
[00:15:36.990]that shouldn't be that surprising.
[00:15:39.040]Rick Grummer's group has shown that cattle
[00:15:41.260]on average decreased dry matter intake
[00:15:43.170]by about 33% and almost 90% of that occurs
[00:15:46.910]in the last week prior to parturition.
[00:15:49.130]So we effectively reproduced what we knew, which is good.
[00:15:54.210]But what I want to highlight
[00:15:55.520]is that low feed intake challenge
[00:15:57.680]has not been thought of as a challenge.
[00:15:59.940]And we all know that we want to reduce that primarily
[00:16:03.680]because we don't want to see a reduction in energy intake.
[00:16:06.290]We don't want to induce negative energy balance,
[00:16:09.970]but I'm hoping I'm going to convince you
[00:16:11.780]that there's a lot more to that low feed intake
[00:16:13.413]than just the reduction in nutrient intake.
[00:16:17.590]Receiving feedlot cattle, again, older data.
[00:16:21.300]Hutcheson and Cole show within the first week of arrival,
[00:16:24.830]cattle are eating somewhere between
[00:16:26.243]0.5 and 1.5% of their body weight in dry matter intake
[00:16:31.360]and it increases dramatically but relatively slowly
[00:16:34.560]as they advance with days on feed in a pen.
[00:16:39.700]We also know those calves went through
[00:16:41.640]probably some stage of complete feed withdrawal.
[00:16:45.870]This is some real nice data from Germany,
[00:16:48.400]where they exposed lambs to 48 hours of feed withdrawal,
[00:16:52.150]and they looked at transport
[00:16:54.190]of short-chain fatty acids across the rumen,
[00:16:57.290]and they showed even with only 48 hours of no feed,
[00:17:01.570]the ability of the rumen to absorb those acids
[00:17:03.950]was reduced by about 50%.
[00:17:07.330]So the point is the gut responds to changes
[00:17:10.130]in nutrient supply quite rapidly and quite dramatically.
[00:17:15.030]Normally we focus on the promotion effect.
[00:17:17.140]So if you feed a higher, energy-dense diet,
[00:17:20.360]you stimulate papillae proliferation,
[00:17:23.350]and very few groups actually look
[00:17:24.970]at the negative consequence of decreasing energy density
[00:17:28.640]or other nutritional challenges.
[00:17:31.750]So this is important,
[00:17:32.740]they looked at complete feed withdrawal.
[00:17:34.970]I'm not saying that's not relevant
[00:17:36.970]under transportation or marketing scenarios,
[00:17:39.950]but it certainly doesn't address this issue that we have
[00:17:43.050]early on in the feeding period,
[00:17:44.980]it doesn't address the issue we have
[00:17:47.340]when animals have metabolic or infectious disease.
[00:17:50.530]It doesn't address transition dairy cows
[00:17:52.650]and it doesn't address calves at weaned.
[00:17:56.070]So we wanted a model that we thought
[00:17:58.167]would be good at representing more broadly
[00:18:01.590]the case that we see in industry.
[00:18:04.380]So we started out here and this was
[00:18:05.915]one of the early experiments we did.
[00:18:08.700]18 cannulated heifers
[00:18:10.280]and we exposed them to three treatments.
[00:18:13.870]We're going to talk about a flaw
[00:18:14.940]in this experimental design
[00:18:16.180]but I want to show you the highlights first.
[00:18:19.300]So the three treatments we imposed were 75%, 50%, or 25%
[00:18:24.780]of their ad libitum feed intake.
[00:18:27.360]So we measured ad libitum feed intake during baseline,
[00:18:30.420]it was a five-day duration,
[00:18:32.190]and then we exposed them to five consecutive days
[00:18:35.390]of feed restriction at these values.
[00:18:38.210]After that, they were allowed to eat ad libitum.
[00:18:41.419]There was no dietary changes in this experiment,
[00:18:44.300]so they were fed a diet that was 60% forage,
[00:18:47.040]half of that grass hay, 30% barley grain,
[00:18:52.300]and the pellets high but most of that is barley grain.
[00:18:54.970]So we can say 40% barley grain.
[00:18:57.440]This is not a diet that I would assume would be risky,
[00:19:00.790]and it's very similar to what we would see
[00:19:02.810]in western Canada for receiving programs.
[00:19:07.670]Our measurements for this experiment were,
[00:19:10.800]at the end of baseline, so at the end of the five days,
[00:19:13.090]at the end of feed restriction,
[00:19:14.600]the end of the first week of recovery,
[00:19:16.400]and the end of the third week of recovery.
[00:19:17.960]So recognize it's unequal spacing,
[00:19:20.640]but what we're trying to do is look
[00:19:22.020]at the impact of feed restriction
[00:19:24.350]by comparing it to baseline,
[00:19:26.310]and then to evaluate the recovery response
[00:19:28.600]after that feed restriction event.
[00:19:30.780]So we divided the data up into two fractions
[00:19:33.910]so that we could look at the feed restriction event
[00:19:36.450]and then look at the recovery event.
[00:19:40.290]So the first thing we observed
[00:19:43.000]and again it should have been common sense.
[00:19:45.470]Once we decreased dry matter intake,
[00:19:47.580]so baseline dry matter intake
[00:19:49.210]and then our imposed feed restriction.
[00:19:52.100]We did a good job, it was very close
[00:19:53.960]to 25, 50, and 75% for their voluntary intake,
[00:19:57.910]but it's not that surprising that short-chain fatty acid
[00:20:00.940]concentration in the rumen decreased
[00:20:02.732]in a dose-dependent manner.
[00:20:05.300]We decreased fermentable substrate supply,
[00:20:08.580]microbes respond by reducing their production.
[00:20:12.310]Not that surprising.
[00:20:13.830]Mean pH also responded in a dose-dependent manner.
[00:20:19.290]So those animals that were restricted
[00:20:20.440]to a great extent had higher pH,
[00:20:24.130]and their mean pH was very close to seven.
[00:20:29.300]That's getting to be a very high mean pH.
[00:20:33.370]And if you want to avoid acidosis, you just feed restrict.
[00:20:38.230]They have almost no time below pH 5.5.
[00:20:41.950]I also use this to point out,
[00:20:43.490]and I think those of you in the lecture
[00:20:44.610]I think have this slide within that as well,
[00:20:47.750]high pH does not mean a positive response.
[00:20:51.830]I would argue high pH can be just as negative as low pH.
[00:20:54.980]Probably says those cattle aren't eating.
[00:20:57.983]So before getting to the next part,
[00:21:00.730]we use a technique quite often called
[00:21:02.280]a temporary isolated and washed reticulo-rumen model.
[00:21:05.680]And this is one of the ways that we use
[00:21:07.370]to evaluate nutrient absorption across
[00:21:10.010]the gastrointestinal tract in vivo.
[00:21:14.052]So in this model you can see our happy steer
[00:21:15.700]is fit with a rumen cannula.
[00:21:18.020]We are going to evacuate all the rumen contents.
[00:21:21.800]Once they're evacuated, we are going to put in
[00:21:24.860]a prepared buffer that's heated to 39 degrees
[00:21:28.360]and is isotonic and has short-chain fatty acids
[00:21:31.360]to make sure we're not starving the animal
[00:21:32.897]during this washing process.
[00:21:35.200]So we'll wash the rumen and the reticulum out
[00:21:37.260]five to six times.
[00:21:39.070]It is very clean after these washes.
[00:21:41.940]After that we put an occluding device
[00:21:43.940]into the omasal orifice.
[00:21:46.680]So it's basically a Foley catheter
[00:21:48.170]that we insert into the omasal orifice.
[00:21:50.840]We pass a tube through the nostril
[00:21:52.810]and it comes out the esophagus.
[00:21:55.230]We go grab that and then we attach
[00:21:57.410]an occluding device with a balloon.
[00:22:00.330]So we put the occluding device in the esophagus,
[00:22:02.710]we inflate the balloon so saliva produced
[00:22:05.830]cannot enter the rumen.
[00:22:08.620]We aspirate that saliva out into a collection jug
[00:22:11.560]behind the animal or beside the animal.
[00:22:14.100]So now we have saliva production,
[00:22:17.580]we also have rates of nutrient transport,
[00:22:20.690]and we don't have to worry about passive rate
[00:22:22.650]'cause nothing comes in and nothing goes out
[00:22:24.680]unless it crosses the rumen epithelium.
[00:22:27.570]And so it's a pretty clean model
[00:22:28.900]where we don't have to avoid passive rate estimations.
[00:22:33.266]We put a sampling tube in, we put a gassing tube
[00:22:35.440]so that we're aerating the buffer with CO2
[00:22:39.530]to make sure that we're mixing that digesta.
[00:22:43.030]And then we put in a buffer that has a known
[00:22:45.210]chemical composition and a known volume,
[00:22:47.800]and we use chromium EDTA as a liquid volume marker.
[00:22:51.100]So by measuring chromium EDTA concentration,
[00:22:54.810]we can predict volume based on its dilution
[00:22:58.610]or increase in concentration,
[00:23:00.860]and by measuring the concentration
[00:23:02.800]of other compounds in the buffer,
[00:23:04.740]like short-chain fatty acids,
[00:23:06.460]we can measure their disappearance.
[00:23:08.810]So we can calculate absorption rate as a percentage per hour
[00:23:13.060]or absorption rate in millimoles per hour,
[00:23:16.380]because we know the quantity in the rumen.
[00:23:20.139]So we use this approach and when we impose feed restriction,
[00:23:23.090]it's only a tendency here,
[00:23:24.310]but we have another study where we see
[00:23:25.790]a significant response,
[00:23:26.950]so I'm going to say this is significant,
[00:23:28.900]we just didn't have power,
[00:23:30.934]and you see a reduction in short-chain fatty acid
[00:23:33.280]absorption across the rumen after being exposed
[00:23:36.560]to five days of low food intake.
[00:23:40.240]It also tended to be dose dependent.
[00:23:43.440]So the more you restrict those animals,
[00:23:46.000]the greater the reduction
[00:23:47.850]in short-chain fatty acid absorption.
[00:23:50.010]So think about this from a newly-weaned calf perspective
[00:23:52.780]that has gone through the marketing system,
[00:23:54.450]now enters the feedlot.
[00:23:56.210]They have low feed intake, low rates of fermentation,
[00:23:59.370]which means energy availability to the animal is low,
[00:24:03.170]and then there's a double whammy
[00:24:04.820]where nutrient absorption across
[00:24:06.310]the gastrointestinal tract is also reduced.
[00:24:09.200]And I want to emphasize,
[00:24:10.250]because we used the washed rumen model,
[00:24:12.530]all the buffers contained the same
[00:24:14.610]amount of short-chain fatty acids.
[00:24:16.650]So this isn't because they had a lower
[00:24:18.530]short-chain fatty acid concentration in the rumen.
[00:24:21.010]This is the capacity response of the rumen epithelium.
[00:24:24.170]So it is decreasing capacity.
[00:24:29.640]I mentioned already we use chromium EDTA
[00:24:31.550]as a marker for feed digestibility,
[00:24:35.370]but if you look at that old data,
[00:24:37.260]there's about 4 to 5% that disappears.
[00:24:39.690]So you never get 100% recovery.
[00:24:42.730]And so I looked at that as an opportunity
[00:24:44.830]and said well, if it's disappearing, where is it going?
[00:24:47.680]Did some reading on the poultry side,
[00:24:49.910]and find out they use chromium EDTA
[00:24:51.860]a lot for barrier function.
[00:24:53.250]Why don't we do it in ruminants?
[00:24:55.170]It's a non-fermentable substrate,
[00:24:57.050]it's complex, it's pretty stable.
[00:24:59.780]We know chromium EDTA crosses the gut
[00:25:02.577]via paracellular processes.
[00:25:04.890]So if we use chromium EDTA and we measure
[00:25:09.090]its recovery in urine,
[00:25:10.690]can we use that as a way to assess
[00:25:13.240]barrier function in the gastrointestinal tract?
[00:25:16.210]So we validated this model quite a few years ago now.
[00:25:19.105]Showed that within 48 hours we had 99%
[00:25:22.730]of the chromium EDTA recovered in urine
[00:25:26.230]that would be excreted.
[00:25:28.390]So we can infuse chromium EDTA,
[00:25:30.480]measure urine for the next 48 hours,
[00:25:33.560]and based on the amount of chromium EDTA excreted,
[00:25:36.480]we can provide an indication
[00:25:38.090]of whole tract barrier function.
[00:25:41.560]What happened when we imposed low feed intake?
[00:25:44.340]Those animals that were exposed to very severe
[00:25:46.950]feed intake restrictions had increased
[00:25:49.260]chromium EDTA appearance in the urine.
[00:25:52.880]So restricting to 25% of their voluntary
[00:25:55.930]dry matter intake increased permeability
[00:25:58.740]of the gastrointestinal tract.
[00:26:00.450]Probably not what we want to happen
[00:26:01.900]in these animals that are already challenged
[00:26:03.740]from a number of other ways.
[00:26:08.660]Okay, so we can see the negative impact of a challenge.
[00:26:12.500]Hopefully, if we have done our job,
[00:26:14.990]those animals survive and eat to recover.
[00:26:18.410]And if you look at the literature,
[00:26:19.243]there's a big gap in terms of understanding
[00:26:21.830]recovery of the animal after exposure to challenges.
[00:26:25.840]So we looked at the recovery for dry matter intake,
[00:26:27.793]and you can see again, we have a dose-dependent response.
[00:26:30.980]For those animals that were restricted to a greater extent
[00:26:33.620]required more time to return to ad libitum intake.
[00:26:38.220]Allowing them to consume the same diet
[00:26:41.670]but at ad libitum intakes induced ruminal acidosis.
[00:26:46.160]So even a diet that was 60% forage,
[00:26:48.920]just allowing them to increase intake
[00:26:51.160]after a period of feed restriction caused mean pH
[00:26:54.140]to drop for the 25% group all the way down to 5.9.
[00:26:59.040]That's a pretty low mean pH on a high forage-based diet.
[00:27:03.977]If you want to look at that in another way,
[00:27:05.970]we can see that the amount of time spent
[00:27:08.470]below pH 5.5 was about six hours per day,
[00:27:14.070]or, sorry, four hours per day.
[00:27:16.360]So a significant amount of time where pH is reduced.
[00:27:20.470]I don't show the data on the same slide,
[00:27:23.250]but remember this was not because of a binge-feeding event.
[00:27:26.480]These 25% heifers did not overeat.
[00:27:31.030]They still ate less than the others, but pH was lower.
[00:27:35.430]So the argument can't be made that they
[00:27:37.500]just compensated by eating more,
[00:27:39.300]no, they still ate less, but rumen pH was lower.
[00:27:44.590]And we think it's lower because they had lower rates
[00:27:46.980]of short-chain fatty acid absorption
[00:27:48.320]at point feed restriction,
[00:27:50.230]and they required more time to recover their rates
[00:27:52.420]of short-chain fatty acid absorption during recovery.
[00:27:56.260]So we've had an impact that doesn't just cause
[00:27:59.010]effects at the time of the challenge,
[00:28:01.200]but has sustained effects that they need to cope with
[00:28:04.020]as they're recovering and we're trying
[00:28:05.530]to adapt them to new situations.
[00:28:08.950]Terms of total tract barrier function,
[00:28:11.850]exactly the same response we saw before.
[00:28:14.520]Only those animals that were restricted to 25%
[00:28:17.880]still had elevated chromium EDTA excretion in urine.
[00:28:22.670]So very severe challenges are required
[00:28:25.070]to increase the permeability of the gastrointestinal tract.
[00:28:29.920]So the chromium EDTA model is a really nice model
[00:28:33.020]but the problem it has is we don't know
[00:28:35.960]where in the gastrointestinal tract
[00:28:38.240]permeability is actually affected.
[00:28:40.600]We put it in orally or we dose it in the rumen,
[00:28:44.000]we measure it in the urine and it could be anywhere
[00:28:45.670]throughout the gastrointestinal tract
[00:28:47.620]is where that chromium EDTA is crossing.
[00:28:50.266]And I think that matters if we're going to come up
[00:28:52.000]with nutritional strategies to ameliorate the response.
[00:28:55.690]Is that a rumen derived response,
[00:28:57.710]is it a small intestinal derived response,
[00:28:59.690]or is it large intestinal derived response?
[00:29:02.190]And that matters when we're designing feed products
[00:29:04.730]that might actually be able to target
[00:29:06.750]the regions of interest.
[00:29:09.720]One of the other approaches we use
[00:29:11.200]is an ex vivo tissue culture approach.
[00:29:13.860]So the downside is we do have to kill the animals
[00:29:16.700]for this experiment,
[00:29:18.150]but we're able to keep the gut tissue alive
[00:29:20.520]outside of the animal for about 14 hours.
[00:29:23.430]And we can improve viability through
[00:29:25.100]the use of secondary messengers,
[00:29:27.120]and show that we get an electrophysiological response.
[00:29:30.640]So I'm just showing rumen tissue here,
[00:29:32.210]we'll cut it into slices, we'll peel the submucosa,
[00:29:35.610]we'll mount it between two halves of the Ussing chamber,
[00:29:39.200]and then we incubate it in the lab
[00:29:41.500]and we have buffer solutions that are heated and oxygenated,
[00:29:45.290]supplying nutrients to that tissue
[00:29:47.600]and the tissue acts as a barrier
[00:29:49.450]between the blood-facing side and the rumen-facing side.
[00:29:54.200]So we can modulate the composition of the buffers
[00:29:57.330]so that represents the rumen and represents the blood
[00:30:00.940]and through the use of radio-labeled substrates
[00:30:03.370]or fluorescent markers,
[00:30:05.130]we can look at the movement
[00:30:06.530]of those molecules across the gut.
[00:30:10.640]So when we did that we thought, first of all,
[00:30:13.050]I don't want to spend my whole career
[00:30:14.730]working on the rumen with rumen acidosis
[00:30:17.070]and then find out it's a hindgut problem.
[00:30:19.800]And be real proud every time that I spent
[00:30:22.490]millions of dollars looking at the rumen
[00:30:25.040]and didn't solve the problem.
[00:30:27.190]So the first step I thought we needed to do
[00:30:29.040]is characterize the regional differences in barrier function
[00:30:32.560]across the gastrointestinal tract in ruminants.
[00:30:36.680]So we presented this data in Australia
[00:30:38.680]and we showed the movement of mannitol across that tissue.
[00:30:43.750]In this case, the greater the movement,
[00:30:45.600]the more permeable that tissue is, or that's our assumption.
[00:30:49.380]And we can see that the foregut is pretty low
[00:30:51.310]in terms of permeability.
[00:30:52.980]Small intestine, we see a bit of a spike,
[00:30:55.760]and then it decreases as we move
[00:30:58.040]throughout the large intestine.
[00:31:00.850]So this is under a non-challenged system,
[00:31:03.170]and we thought, well this is really interesting data.
[00:31:05.770]It actually might suggest that we're looking
[00:31:07.870]at the wrong region if we just focus on the rumen.
[00:31:12.406]So I had a grad student that came on board,
[00:31:14.830]and she was interested in doing this type of work
[00:31:16.900]and I said okay, let's separate the response.
[00:31:19.450]We're going to look at ruminal acidosis
[00:31:21.210]as one challenge model and look at low feed intake
[00:31:24.190]as another challenge model,
[00:31:25.990]and we're gonna compare that back to control.
[00:31:28.730]So a fairly similar diet, 50% forage, 50% concentrate.
[00:31:35.800]This was our experimental approach.
[00:31:37.720]We had an adaptation period followed by five days
[00:31:41.141]of dry matter intake, body weight measurement and pH.
[00:31:46.840]Same adaptation period for all treatments.
[00:31:50.440]We restricted feed to 25% of their voluntary intake,
[00:31:54.460]overdosed them with grain, and then one day after,
[00:31:58.410]killed the animals and collect the tissue,
[00:32:00.470]or we exposed them to low feed intakes,
[00:32:02.460]so we have the same adaption,
[00:32:04.210]five days of feed restriction
[00:32:05.490]down to 25% of their voluntary intake.
[00:32:10.230]What did we see?
[00:32:11.063]Well, in terms of body weight,
[00:32:12.429]you're going to see live body weight,
[00:32:13.350]Jim and I we arguing yesterday, I guess, about body weight.
[00:32:17.440]This is one case when I'm going to say
[00:32:18.680]live body weight does matter.
[00:32:20.750]Maybe it's all shrink, but it still matters.
[00:32:23.870]Body weight was reduced with the low feed intakes,
[00:32:26.930]significantly relative to control.
[00:32:29.380]Dry matter intake was reduced in both cases.
[00:32:32.350]So inducing ruminal acidosis caused
[00:32:34.330]those animals to go off feed,
[00:32:36.230]that was their physiological response,
[00:32:38.337]and so they dropped their feed intake.
[00:32:42.260]We looked at ruminal pH across the gastrointestinal tract,
[00:32:46.560]and we can see ruminal acidosis induced low pH in the rumen,
[00:32:50.650]so we did our job of imposing the model,
[00:32:53.430]but we also saw reductions in the cecum, the proximal colon,
[00:32:57.230]and a tendency for reduction in the distal colon.
[00:33:00.020]So again, additional evidence where we might
[00:33:03.200]not be looking at the right region
[00:33:05.350]if we're just focusing at the rumen,
[00:33:07.810]and for low feed intake,
[00:33:09.330]we can see we had an increase in pH
[00:33:12.353]in the reticulo-rumen and we also had
[00:33:14.340]an increased pH in the proximal colon.
[00:33:17.250]So this had led us to think that the colon
[00:33:19.380]is a pretty important region when we're looking
[00:33:22.060]at responses to nutritional challenges.
[00:33:26.150]We also characterized short-chain fatty acid
[00:33:28.030]concentration throughout the gastrointestinal tract,
[00:33:30.320]and we can see in response,
[00:33:32.620]probably due to reduced dry matter intake,
[00:33:35.180]we see reductions in short-chain fatty acid
[00:33:37.210]concentration in the rumen.
[00:33:39.600]We don't see much occurring in the duodenum,
[00:33:41.630]that's not surprising,
[00:33:42.730]there's not that much microbial activity
[00:33:44.720]and very little of the VFA should flow out
[00:33:47.398]of the rumen or omasum and actually reach the intestine.
[00:33:51.640]So most of this, we think is endogenous production,
[00:33:54.590]or new production by the microbes,
[00:33:56.770]but we do see very little changes
[00:33:59.240]occurring in short-chain fatty acid concentration
[00:34:01.900]once we get outside of the rumen itself.
[00:34:07.140]That said, imposing feed restriction changes
[00:34:10.660]papillae surface area.
[00:34:12.420]So this is rumen epithelial surface area
[00:34:14.890]and we can see reductions in length, width,
[00:34:17.150]perimeter, and surface area.
[00:34:19.210]Remember this is the five-day feed restriction
[00:34:21.340]and we are already have significant reductions
[00:34:23.809]in the absorptive surface area exposed.
[00:34:26.540]We also saw a reduction in width
[00:34:28.050]with rumen acidosis which again
[00:34:29.640]would be pretty consistent given previous models.
[00:34:35.550]Our real interest in this experiment was to say,
[00:34:37.880]how does permeability change across
[00:34:40.050]the gastrointestinal tract when we impose these challenges?
[00:34:45.100]Now we're looking at a different marker,
[00:34:46.720]we're using inulin, so the very large molecule.
[00:34:50.260]It's actually hard to characterize
[00:34:51.530]how large it is because it's heterogeneous,
[00:34:54.210]but we see a pretty consistent trend,
[00:34:57.010]I didn't show the data from the previous experiment
[00:34:59.350]where for large molecules,
[00:35:00.760]the rumen and the omasum seems to have
[00:35:02.650]fairly high permeability and it decreases
[00:35:05.440]throughout the gastrointestinal tract.
[00:35:07.700]The disappointing finding in this experiment
[00:35:10.200]was the outcomes were opposite to our hypothesis.
[00:35:14.340]We had speculated based on total tract permeability
[00:35:17.300]that we would see increased permeability
[00:35:20.220]of different regions of the gastrointestinal tract
[00:35:22.410]when imposed with low feed intake.
[00:35:25.140]You can see error bars are pretty large,
[00:35:26.990]that's quite common with this type of approach,
[00:35:29.490]but what we saw, if anything,
[00:35:31.330]was a reduction in permeability
[00:35:33.290]with low feed intake in the hind gut.
[00:35:36.143]So this caused us a bit of concern,
[00:35:38.920]we do have some differences in our model
[00:35:41.510]between the in vivo measurements
[00:35:43.870]and the ex vivo measurements.
[00:35:45.620]First of all, the time is different.
[00:35:47.280]We have to do the in vivo measurements first,
[00:35:50.020]and then we do the ex vivo measurements,
[00:35:51.690]'cause you can't bring 'em back to life.
[00:35:54.200]The other issue is for viable tissues
[00:35:57.290]to be incubated in Ussing chambers,
[00:35:59.180]if they have visible lesions, I cannot mount them.
[00:36:02.650]So those would be the areas where we expect
[00:36:04.780]to have the greatest permeability
[00:36:06.800]but because we can't maintain tissue viability ex vivo,
[00:36:10.740]we have to exclude those tissues
[00:36:12.290]from our tissue preparations.
[00:36:14.080]So we may be artificially affecting permeability
[00:36:18.150]by excluding tissues that were visibly damaged.
[00:36:23.247]Mannitol flux followed the same response,
[00:36:26.050]tended to be lower for low feed intake,
[00:36:28.610]or was lower for low feed intake
[00:36:30.270]in the distal part of the colon.
[00:36:33.240]So this still bugged us,
[00:36:34.410]why are the ex vivo results
[00:36:35.860]and the in vivo results different?
[00:36:37.950]We looked at gene expression for genes
[00:36:41.580]that are related to tight cell junctions
[00:36:44.010]as well as pro-inflammatory responses,
[00:36:46.550]so LTA and LPS receptors, so lumenal receptors,
[00:36:51.780]and we found that those low feed-intake-exposed animals
[00:36:55.867]had increased expression of these
[00:36:57.640]tight cell junction proteins
[00:36:59.380]and increased expression of TLR-2.
[00:37:04.313]So what do we think this means?
[00:37:05.430]We think again, because the gut is such
[00:37:07.820]a rapidly-turning-over tissue,
[00:37:10.130]timing of sampling really matters,
[00:37:12.650]and what we're dealing with here
[00:37:14.000]is probably a recovery response
[00:37:16.360]rather than the induction response.
[00:37:18.770]So we think the tissue is actually trying to compromise
[00:37:22.250]and react to the increased permeability
[00:37:25.210]by stimulating production of tight cell junctions.
[00:37:32.850]Sorry, that was ruminal gene expression,
[00:37:35.190]this this duodenal gene expression,
[00:37:37.570]so FCAR is related to LPS reception,
[00:37:42.327]and we see again changes throughout
[00:37:45.040]the gastrointestinal tract.
[00:37:46.750]Generally, low feed intake increased the response
[00:37:50.440]and then again when we look at the colon,
[00:37:52.420]we see a very similar response.
[00:37:54.440]So three regions throughout the gastrointestinal tract,
[00:37:57.410]all suggesting increased tight cell junction expression
[00:38:01.210]from a transcript level, which to me,
[00:38:03.701]our conclusion was the tissue is already
[00:38:06.190]trying to adapt or cope with that low feed intake challenge
[00:38:10.040]while preventing unintended molecule passage.
[00:38:16.710]So that's nice, and the beef producers love it when I say,
[00:38:19.260]you know what, these are your challenges,
[00:38:21.400]and they say great,
[00:38:22.233]we don't pay you to tell us our problems,
[00:38:23.890]we pay you to help us find solutions.
[00:38:27.060]And so we started looking at what solutions
[00:38:29.080]could we actually use, or what tools could we use,
[00:38:32.390]to try to stabilize or accelerate
[00:38:34.560]the recovery of the gastrointestinal tract.
[00:38:36.880]There's a lot of work done looking at butyrate,
[00:38:39.279]and butyrate's role to stimulate
[00:38:40.640]gastrointestinal development,
[00:38:42.530]so we thought butyrate needs to be in that cocktail.
[00:38:45.510]Betaine isn't really looked at a lot
[00:38:47.300]from a gut physiology standpoint.
[00:38:49.170]It's a methyl donor, it helps regulate osmotic balance.
[00:38:52.710]In poultry models, it's been shown to help
[00:38:55.400]be protective against Coccidia infection challenges
[00:38:59.640]and then antioxidants, more from the feed supply,
[00:39:03.060]probably not crossing the gastrointestinal tract,
[00:39:06.000]but there is some suggestions that antioxidants in the diet
[00:39:09.710]could have beneficial effects on the gastrointestinal tract.
[00:39:13.160]So this was kind of a proof of concept study.
[00:39:16.220]We said, these are the things we think might help.
[00:39:18.910]Let's put 'em in at doses based on previous studies
[00:39:22.070]in isolation and let's throw it in and see what happens.
[00:39:27.190]So we used 32 lambs in this experiment.
[00:39:29.450]We decided to use a finishing model,
[00:39:31.890]so we fed them what we would call a standard finishing diet.
[00:39:35.350]Again, this seems high,
[00:39:36.810]but it's just a mechanism of how our feeding management was.
[00:39:39.830]Most of this is barley grain.
[00:39:41.930]So we have a diet that's essentially
[00:39:43.360]9% barley silage on a dry matter basis.
[00:39:46.640]Our producers use storm rations,
[00:39:48.530]so if they expect cattle to go off intake,
[00:39:51.570]they will decrease the amount of concentrate in the diet,
[00:39:55.000]so we wanted to see is the storm practice beneficial,
[00:39:58.950]and can we enhance the storm practice by including
[00:40:02.640]our functional ingredients within this approach.
[00:40:08.100]Similar experimental design I showed you before,
[00:40:11.420]little bit different.
[00:40:12.253]We restricted dry matter intake,
[00:40:13.810]in this case probably three days.
[00:40:15.210]I was worried about killing the lambs,
[00:40:16.610]so the five-day feed restriction coupled with refeeding
[00:40:19.760]at a diet that was only 9% barley silage.
[00:40:22.590]So we shortened the duration and we reduced
[00:40:24.480]the severity down to 50%.
[00:40:27.750]Dry matter intake, we have one outlier here,
[00:40:29.760]we just can't seem to figure out why that's there,
[00:40:32.600]but the point is,
[00:40:33.520]when you look at the treatment by time interactions,
[00:40:36.240]it was actually the storm diets
[00:40:38.270]and the storm plus cocktail diets
[00:40:40.550]that recovered most rapidly after the challenge.
[00:40:44.640]If we look at the flux rate,
[00:40:46.900]in this case this is butyrate flux rate,
[00:40:50.303]and this is acetate flux rate,
[00:40:52.580]we can see tendencies for improvement
[00:40:54.530]when we fed the cocktail post-challenge
[00:40:57.500]and we see a significant improvement
[00:40:59.530]when we fed the cocktail post-challenge
[00:41:01.417]for butyrate absorption.
[00:41:02.750]So some initial pilot data suggesting
[00:41:05.600]that we can modulate recovery responses
[00:41:08.210]using functional ingredients.
[00:41:11.007]Mannitol flux followed very similar
[00:41:13.190]to what I showed you in the past,
[00:41:14.410]where actually imposing the model
[00:41:16.490]reduced movement of mannitol across.
[00:41:19.240]Again, different to what we see
[00:41:22.307]when we measure this in vivo,
[00:41:23.700]but we have a time delay again
[00:41:25.992]and we have no effect for other regions,
[00:41:28.670]so we're just looking at this in this case within the rumen.
[00:41:34.510]We also went and measured same gene expression,
[00:41:37.950]and showed that in all cases,
[00:41:39.930]the storm diet and the storm plus diet
[00:41:42.710]stimulated increased claudin and occludin,
[00:41:46.150]two pretty important proteins involved
[00:41:48.340]in tight cell junction formation,
[00:41:50.410]and that occurred in the rumen,
[00:41:53.120]and we also see tendencies but they're not significant
[00:41:56.090]that occurred in the jejunum.
[00:41:57.560]So again, evidence suggesting
[00:41:59.500]that there could be opportunity,
[00:42:01.680]it's not a real clean model,
[00:42:03.040]but the goal was to run a pilot experiment
[00:42:06.230]and see whether or not we can manipulate the response.
[00:42:10.050]So this is kind of our model to integrate the outcome
[00:42:13.010]when we look at ruminal acidosis at low feed intake.
[00:42:16.360]This was recently published in the Journal of Dairy Science
[00:42:19.530]in a peer-review article,
[00:42:21.220]but in response to our low feed intake challenge,
[00:42:24.230]we have a period of high-feed intake
[00:42:25.970]prior to the challenge,
[00:42:27.440]followed by a pretty rapid decline in feed intake,
[00:42:30.110]but again it's not zero,
[00:42:31.900]and then dependent on the challenge there,
[00:42:34.170]we see a delayed recovery response.
[00:42:36.810]And interestingly, this looks very similar
[00:42:38.940]to what we would see for newly-received feedlot cattle.
[00:42:42.270]Absorptive capacity follows,
[00:42:44.650]and so initially we have high absorptive capacity
[00:42:47.120]in response to low feed intake,
[00:42:49.200]absorptive capacity declines,
[00:42:52.220]and the recovery response lags behind dry matter intake,
[00:42:56.260]and permeability goes the other way,
[00:42:58.580]where we think initially permeability is low
[00:43:00.710]and that's good.
[00:43:01.740]In response and as an acute response to low feed intake,
[00:43:04.970]permeability increases but even before
[00:43:07.780]the low feed intake challenge ceases,
[00:43:10.260]the gastrointestinal tract start to adapt
[00:43:13.110]and mitigate the negative impact and so permeability
[00:43:15.760]decreases and then gradually increases again.
[00:43:19.130]So this our running hypothesis model,
[00:43:22.140]wanna be sure it's not concluded
[00:43:25.530]but this is what we think is happening
[00:43:27.810]and how we explain the differences
[00:43:29.500]in results between studies that have
[00:43:32.150]different timelines for data collection.
[00:43:36.060]So my conclusions, and I hope what I've convinced you
[00:43:38.600]that low feed intake in a under-appreciated challenge.
[00:43:42.120]The gastrointestinal tract responds
[00:43:44.070]to this challenge by altering morphology,
[00:43:47.400]reducing nutrient absorption,
[00:43:49.680]and decreasing barrier function
[00:43:50.960]in the gastrointestinal tract.
[00:43:52.570]And I have that question mark
[00:43:53.870]because I think that's really time dependent.
[00:43:57.520]We think these are evolutionary adaptations,
[00:44:00.280]why maintain a large gastrointestinal tract
[00:44:02.800]if nutrient supply is low?
[00:44:05.832]The gastrointestinal tract would use too much,
[00:44:08.500]or a disproportionate amount of energy
[00:44:10.450]relative to the energy consumed.
[00:44:13.920]What I think we still don't know
[00:44:15.680]is a lot of the regulatory factors
[00:44:17.730]that promote recovery and really what we can do
[00:44:20.560]to accelerate that recovery or minimize the impact
[00:44:24.710]if you can predict the low feed intake
[00:44:26.511]challenge from happening.
[00:44:29.500]With that, this is my crew.
[00:44:32.150]Not today obviously, there's snow on the ground now,
[00:44:35.080]but I'd also like to find funders, ALMA's no more,
[00:44:38.340]Beef Cattle Research Council's been a great supporter
[00:44:40.550]and our federal dollars equivalent to USDA,
[00:44:43.830]National Sciences and Engineering
[00:44:45.250]Research Council of Canada.
[00:44:47.470]So with that, I hope I taught you something
[00:44:49.260]or I hope you received a little bit of insight
[00:44:52.310]and if you have any questions or comments,
[00:44:54.210]I'd love to address them.
[00:44:59.020](audience applauding)
[00:45:04.223]Question, 'kay.
[00:45:09.170]No problem.
[00:45:11.120]Greg, you said that you used
[00:45:12.640]the chromium EDTA for the marker
[00:45:17.350]for when you put it in the rumen,
[00:45:19.881]and you talk about chromium EDTA being absorbed,
[00:45:22.120]so is that time frame,
[00:45:24.500]I'm intrigued by that rumen methodology that you're using
[00:45:26.923]when you put in that solution--
[00:45:29.570]Measure it later, yeah.
[00:45:30.920]How many hours is that,
[00:45:31.867]and are you worried about leakage during that procedure,
[00:45:36.020]or it just not long enough?
[00:45:37.910]We think it's not long enough,
[00:45:39.790]probably have some leakage, I wouldn't deny that,
[00:45:42.710]but those incubations are 45 minutes to an hour and a half.
[00:45:47.430]So the time frame is pretty short to have much loss.
[00:45:51.720]We've done recovery responses,
[00:45:54.260]and we can recover about 97%,
[00:45:56.620]which I think when you're vacuuming a rumen,
[00:46:00.540]97% is pretty close.
[00:46:03.080]Well, I was going to comment that,
[00:46:04.093]we talked about student exchanges,
[00:46:05.640]I think we have to wait til we have
[00:46:06.520]a whole new crop of students 'cause they're not going
[00:46:07.940]to want to come on that day.
[00:46:09.960]They love it.
[00:46:11.263]It's a lot of work.
[00:46:12.250]It's a lot of work, but we typically run
[00:46:14.260]four animals simultaneously,
[00:46:15.770]so we'll have a group of seven students in the barn.
[00:46:19.480]You spend probably four hours together in rumen fluid.
[00:46:24.360]It's a lot of fun, it really is.
[00:46:27.600]It seems crazy but you see some neat things.
[00:46:30.630]I don't know how many students get to palpate the esophagus,
[00:46:33.810]how many students are really palpating the omasal orifice,
[00:46:36.280]maybe if you're omasal sampling, and I think you guys--
[00:46:39.102]That's the ones who don't want to come,
[00:46:40.590]that's why I was feeling pretty--
[00:46:41.471]No, it's, but it's a lot of fun.
[00:46:43.610]So I have two other questions,
[00:46:44.780]if I may.
[00:46:48.040]You can quantify saliva production now
[00:46:49.940]based on what you're doing there.
[00:46:50.860]I assume you've been doing that.
[00:46:52.250]Yep, I'll show that in class.
[00:46:54.020]And then, second question is,
[00:46:56.690]why couldn't you just dose chromium EDTA
[00:47:00.560]in different parts if you had ruminally,
[00:47:05.188]duodenally, and cecal cannulate cavity,
[00:47:07.990]now that wouldn't get to the tissues
[00:47:09.540]within those part of the tract,
[00:47:11.450]but at least it'd tell you rumen, intestinal,
[00:47:13.676]or large intestine.
[00:47:14.509]To be honest, my goal,
[00:47:16.150]and I was trying to convince a company to do it,
[00:47:18.580]they didn't take the bait,
[00:47:20.260]but I thought, what if we have different
[00:47:23.540]heavy metal complexes and we rumen-protect some.
[00:47:27.780]So if we have rumen-protected cobalt EDTA,
[00:47:32.340]and hopefully it would bypass the rumen
[00:47:34.067]but would be released in the abomasum,
[00:47:36.370]then we could look at ratios between chromium EDTA
[00:47:38.830]and cobalt EDTA and we could say
[00:47:41.460]it's mostly foregut or mostly hindgut
[00:47:44.420]that respond the same.
[00:47:45.760]We just haven't been able to develop that,
[00:47:47.330]nobody's wanted to fund that,
[00:47:49.746]I think Jim said yesterday that's one of those things
[00:47:51.640]that feeds the beast, right?
[00:47:54.160]Yeah, you would use the tool to answer important questions,
[00:47:56.700]but you gotta develop the tool first,
[00:47:59.130]and so how much effort do you put into the tools?
[00:48:01.540]Terms of regional secretion, yeah,
[00:48:03.560]you could do that but if we have a timeline response,
[00:48:07.660]then you have to probably have three animals
[00:48:09.400]as an experimental unit,
[00:48:11.230]one gets a ruminal infusion,
[00:48:12.738]one gets a duodenal infusion,
[00:48:14.516]the other one gets a cecal infusion.
[00:48:16.140]Well, that's true.
[00:48:16.973]And animal-to-animal variability,
[00:48:19.650]it's a great concept,
[00:48:20.970]we've thought a lot about omasal,
[00:48:23.780]we're getting back to doing some duodenal cannulas,
[00:48:26.840]but we've been just doing omasal dosing for quite a while,
[00:48:30.440]and omasal sampling for a while.
[00:48:32.360]I don't like it, and so we're going back.
[00:48:37.920]But it's just challenging to do that when we're dosing.
[00:48:42.420]May I ask one more about it?
[00:48:45.020]No, you're done, to be honest with you.
[00:48:47.359]So the evolutionary adaptation
[00:48:49.238]makes sense to me, right.
[00:48:50.942]You starve animals, you nutrient-restrict them,
[00:48:53.590]obviously it makes sense that the gut
[00:48:55.017]would become more permeable,
[00:48:58.210]just because there's greater opportunity
[00:49:00.240]to capture any nutrients that might be coming,
[00:49:02.863]or flowing through the gut, right?
[00:49:04.360]Question is, just naturally, we talk a lot about
[00:49:09.680]and we measure SGLT-1 and sodium-dependent
[00:49:13.180]and independent processes for amino acid transport.
[00:49:16.530]How much of those and how much do we know,
[00:49:19.940]i.e. how much glucose and how much of those amino acids,
[00:49:24.850]essential or non, leak across the gut,
[00:49:29.340]which calls into question again,
[00:49:33.300]not the active transporters per se
[00:49:35.410]but some of the net flux approaches that we've used
[00:49:37.827]and how those nutrients actually
[00:49:40.590]get into portal circulation.
[00:49:43.219]It's a good question.
[00:49:44.471]I'm going to try to answer it first,
[00:49:45.503]and then I'm going to ask you another question
[00:49:47.150]that poses challenges with net flux type approaches.
[00:49:51.640]So first of all, there's a concentration gradient,
[00:49:54.130]and if the concentration gradient favors absorption,
[00:49:57.370]passive leakage will drive absorption,
[00:49:59.630]and we can measure that response ex vivo as well.
[00:50:02.560]So that's where a lot of the debate has come on,
[00:50:04.700]are amino acids transported across the rumen?
[00:50:07.400]If I put radiolabeled amino acids on the lumenal side
[00:50:10.590]and I have tissues ex vivo,
[00:50:12.610]I can measure appearance of that label on the other side.
[00:50:15.320]There is passive permeation.
[00:50:17.030]That's different than driven absorption.
[00:50:21.450]The issue that I think you're getting at,
[00:50:23.970]there's two challenges,
[00:50:25.620]is if we have increased permeability,
[00:50:29.430]we still need to make sure
[00:50:30.370]that that permeability is regulated,
[00:50:32.610]because it's not just amino acids or glucose that can cross.
[00:50:37.020]There could be histamine, or LTA, or other biogenic amines,
[00:50:42.110]and we don't necessarily want them
[00:50:43.690]to reach portal circulation.
[00:50:46.570]The other challenge with just interpreting what we have
[00:50:49.020]from splanchnic catheters is,
[00:50:51.650]I think we underestimate arterial supply.
[00:50:55.380]We're looking at net flux,
[00:50:57.080]so it's a relative balance between
[00:50:59.640]what came in and what came out,
[00:51:01.680]and Clint, if I remember back,
[00:51:03.440]you did some work looking at butyrate infusion
[00:51:06.190]and when you infuse butyrate into the rumen,
[00:51:09.590]the net portal flux of glucose became less negative.
[00:51:14.710]It's not because more glucose was being absorbed.
[00:51:17.040]If anything, it's because less glucose utilization
[00:51:20.090]occurred from arterial circulation,
[00:51:23.260]and I think too often we forget about the arterial
[00:51:25.630]nutrient supply and we're just thinking
[00:51:28.120]about the gut as a nutrient exporting tissue.
[00:51:31.890]It's also a nutrient importing tissue.
[00:51:36.130]Yeah, so, harm-an-neals, and acetate's
[00:51:38.361]a good example of that
[00:51:39.680]that's one molecule we have a few measures of.
[00:51:42.640]The bias in that portal flux relative
[00:51:45.693]to what's been contributed from there.
[00:51:47.341]110% release. Yeah.
[00:51:49.525]Relative to what's absorbed.
[00:51:50.860]Yeah. Yeah.
[00:51:52.360]Jim, could I get a little question?
[00:51:53.740]No, wait.
[00:51:55.200]Tyler has been trying to ask
[00:51:56.798]a question Oh, sorry, sorry.
[00:51:58.247]Wait, something's come up.
[00:51:59.562](audience members laughing)
[00:52:01.045]Sorry, so I understand your model,
[00:52:03.563]what gives an acidosis,
[00:52:04.880]monitor your parameters as far as low feed intake goes,
[00:52:08.480]but how do you separate the differences
[00:52:09.810]in low feed intake experimentally induced
[00:52:11.800]by withholding feed and low feed intake caused by sickness,
[00:52:15.880]like you're talking about cattle newly-weaned,
[00:52:18.220]getting off a truck,
[00:52:19.053]going through marketing stress and things like that.
[00:52:20.470]They have reduced feed intake a lot of times
[00:52:22.300]because they're sick, too.
[00:52:23.400]Yep.
[00:52:24.233]So as far as some of this gut barrier function,
[00:52:26.240]things like that goes,
[00:52:27.480]is there any way you could induce a challenge model,
[00:52:30.490]see if those things still happen if you challenge
[00:52:32.500]them with some sort of sickness,
[00:52:34.750]do you have gut barrier function changing
[00:52:36.860]versus low feed intake and what the interactions
[00:52:38.730]actually might be between those two things.
[00:52:40.500]Excellent question, and it's the next place to go.
[00:52:43.802]One of the things I don't mention is when you impose
[00:52:47.290]feed restriction to cattle in the metabolism barn,
[00:52:50.610]they're not happy about it.
[00:52:52.212](audience laughing)
[00:52:53.045]They're standing there,
[00:52:54.030]I would say there's some emotional stress--
[00:52:56.110]Absolutely.
[00:52:56.943]On top of just the nutrient stress,
[00:53:00.380]and transportation and illness cause different signals.
[00:53:07.959]Catecholamine responses.
[00:53:08.792]We know there's beta-adrenergic receptors
[00:53:11.130]along the gastrointestinal tract.
[00:53:13.830]So I would say this is a stepping stone
[00:53:16.380]in having a clean model to understand,
[00:53:19.020]should we look at low feed intake?
[00:53:21.990]I think we have enough data to say
[00:53:23.170]low feed intake is a problem.
[00:53:25.890]To apply it to commercial situations
[00:53:28.350]and prove commercial (sneezing drowns out speaker),
[00:53:30.689]I think that's the next step.
[00:53:34.680]How much time passed between the end
[00:53:37.710]of the feed restriction and the tissue sampling
[00:53:40.106]for your gene expression?
[00:53:41.750]So they were not fed that,
[00:53:44.310]well, they received their low feed allocation that morning,
[00:53:48.160]and we typically kill three to four hours,
[00:53:50.910]depending on the study,
[00:53:51.750]but it's usually three or four hours post-feeding time.
[00:53:56.100]So they ate their small quantity of feed,
[00:54:00.180]but they're still within feed restriction.
[00:54:03.730]I was thinking that the time,
[00:54:06.515]the differences in epithelial restitution
[00:54:08.747]between rumen and the duodenum, right,
[00:54:14.132]the cow cleared them.
[00:54:15.460]Yeah, there is a lag time that we can't account for.
[00:54:19.600]The other thing we often don't think about enough,
[00:54:22.850]I think, is are the time points appropriate?
[00:54:25.750]So we've selected a ruminal time point
[00:54:27.700]that we would think represents near-maximal
[00:54:30.660]or approaching maximal fermentation.
[00:54:33.240]Maybe if we're looking for the outcomes,
[00:54:34.850]we should have gone prior to feeding, right?
[00:54:37.540]When the responses could be most dramatic,
[00:54:41.600]and if you look at gene expression,
[00:54:43.870]people take a single sample.
[00:54:45.470]I'm not sure gene expression
[00:54:46.650]is a chronic indicator of status.
[00:54:49.470]Time in flux would tell us they're not.
[00:54:54.296]Yep.
[00:54:55.129]So it looks like you've got
[00:54:57.260]an inflammatory response.
[00:54:58.680]That's right
[00:55:00.180]So why aren't you using any sort
[00:55:02.110]of anti-inflammatory factors like in the back.
[00:55:06.850]I mean antioxidants may induce somewhat,
[00:55:09.390]but actually an anti-inflammatory.
[00:55:11.809]Might mitigate some of the damage?
[00:55:13.149]Molecule might actually be better.
[00:55:15.290]Yeah, we haven't tried any NSAIDS or,
[00:55:18.470]and maybe we can now with oral meloxicam,
[00:55:21.270]that might be a way to go.
[00:55:23.167]But the question is, I think that would be useful
[00:55:27.410]from a fundamental science standpoint,
[00:55:29.690]the question is how to we deliver that in industry?
[00:55:32.980]Especially when they have low feed intake.
[00:55:35.730]So I think it's probably something we need to look at,
[00:55:37.890]to understand is inflammation driving the negative response,
[00:55:42.480]but we have a second challenge of,
[00:55:44.740]how do we deliver that under commercial situations?
[00:55:49.740]Does that makes sense?
[00:55:50.980]Yeah, but I would say
[00:55:51.813]there are a lot of diseases and disorders
[00:55:54.610]that start with inflammation and result
[00:55:57.360]in some sort of liver damage,
[00:55:59.310]and so giving it sooner than later
[00:56:05.160]might actually enhance your result.
[00:56:08.470]So pre-shipping meloxicam?
[00:56:11.730]That's a nice concept.
[00:56:13.048]Well, from here.
[00:56:13.881]It's something we'll have to think about, yeah.
[00:56:16.049]Thank you.
[00:56:17.823]It's been tried.
[00:56:21.946]I don't know about the pre, post.
[00:56:23.310]Pre and post. Pre.
[00:56:26.447]All right, well, excellent discussion.
[00:56:29.919]If you didn't get a chance to interact with Greg,
[00:56:31.490]he'll be around some.
[00:56:33.250]Probably best time to do that would be after 3:00 today.
[00:56:36.600]He's getting on a plane like 6:00 in the morning,
[00:56:41.220]so he's going home tomorrow,
[00:56:43.694]but we hope that there'll be a lot of interaction
[00:56:46.280]in the future, like I said,
[00:56:48.380]I think there's a lot of opportunity for collaboration.
[00:56:51.700]Right now, I promised Greg a runza,
[00:56:56.770]to have the entire time that he's here.
[00:56:58.380]So we're gonna go find one of those
[00:56:59.970]and we'll see if that affects his gut barrier at all.
[00:57:04.550]I'm sure I'm low already.
[00:57:06.235]Before we get back to class.
[00:57:07.920]So let's thank him for coming.
[00:57:09.349](audience applauding)

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effects of low feed intake on gastrointestinal function
gastrointestinal function
greg penner
low feed intake effects
unl animal science
unl animal science department seminars

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Effects of Low Feed Intake on Gastrointestinal Function

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