10 replies to this topic

[Brett Black]

As many here would know, chronic systemic low-grade inflammation has been shown to play a significant role in many if not most forms of age-related disease, decline and dysfunction. That such a broad but apparently disparate range of age-associated pathologies all seem to share a common inflammatory component makes further understanding the cause(s) of such inflammation potentially very important for anti-aging purposes.

Some recent evidence suggest that lipopolysaccharides(LPS), a bacterial endotoxin, may be an important piece in this puzzle:
http://en.wikipedia....opolysaccharide

LPS is found in gram negative bacteria, and humans are constantly in contact with it, including in the gut from both the resident gut microflora and from regularly ingested bacteria and LPS in food. LPS can cause a very strong immune and inflammatory response, and humans in particular are extremely sensitive to LPS. However various mechanism(e.g. gut mucosa) normally keep acutely harmful LPS exposure(e.g. systemic circulation) to a minimum.

Inflammation is known to transiently increase in humans immediately following meals(postprandial inflammation) and there is now evidence to suggest that ingesting fats may lead to systemic and inflammation-inducing exposure to LPS. It is believed that LPS can be transported, in tandem with dietary fat, through the intestinal wall and into circulation by chylomicrons:
http://en.wikipedia....iki/Chylomicron

Rodents raised in germ-free conditions, and thus lacking gut microflora and fed sterile food, are resistant to the obesity and inflammation-inducing affects of a high fat diet compared to conventionally-raised non-germ-free rodents, further potentially implicating LPS, bacteria and dietary fat.

Experiments involving chronic low-level exposure to LPS in rodents, mimicking one aspect of a high-fat diet, also result in pro-inflammatory and pro-obesity states.

Thus, repeated systemic exposure to LPS induced by dietary fat intake might be a significant factor in the eventual development of the pathological chronic inflammatory state that is a hallmark of aging.


Following is a selection of papers exploring these issues:

Am J Clin Nutr. 2007 Nov;86(5):1286-92.

A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of
postprandial inflammation.

Erridge C, Attina T, Spickett CM, Webb DJ.

Strathclyde Institute of Pharmacy and Biomedical Science, University of
Strathclyde, Glasgow, United Kingdom. clett.erridge@strath.ac.uk

Comment in
Am J Clin Nutr. 2007 Nov;86(5):1257-8.
Am J Clin Nutr. 2008 Jul;88(1):248-9; author reply 249-50.

BACKGROUND: Bacterial endotoxin is a potently inflammatory antigen that is
abundant in the human gut. Endotoxin circulates at low concentrations in the
blood of all healthy individuals, although elevated concentrations are associated
with an increased risk of atherosclerosis.

OBJECTIVE: We sought to determine whether a high-fat meal or smoking increases
plasma endotoxin concentrations and whether such concentrations are of
physiologic relevance.

DESIGN: Plasma endotoxin and endotoxin neutralization capacity were measured for
4 h in 12 healthy men after no meal, 3 cigarettes, a high-fat meal, or a high-fat
meal with 3 cigarettes by using the limulus assay.

RESULTS: Baseline endotoxin concentrations were 8.2 pg/mL (interquartile range:
3.4-13.5 pg/mL) but increased significantly (P < 0.05) by approximately 50% after
a high-fat meal or after a high-fat meal with cigarettes but not after no meal or
cigarettes alone. These results were validated by the observations that a
high-fat meal with or without cigarettes, but not no meal or smoking, also
significantly (P < 0.05) reduced plasma endotoxin neutralization capacity, which
is an indirect measure of endotoxin exposure. Human monocytes, but not aortic
endothelial cells, were responsive to transient (30 s) or low-dose (10 pg/mL)
exposure to endotoxin. However, plasma from whole blood treated with as little as
10 pg endotoxin/mL increased the endothelial cell expression of E-selectin, at
least partly via tumor necrosis factor-alpha-induced cellular activation.

CONCLUSIONS: Low-grade endotoxemia may contribute to the postprandial
inflammatory state and could represent a novel potential contributor to
endothelial activation and the development of atherosclerosis.

PMID: 17991637 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm....pubmed/17991637

J Lipid Res. 2009 Jan;50(1):90-7. Epub 2008 Sep 24.

Chylomicrons promote intestinal absorption of lipopolysaccharides.

Ghoshal S, Witta J, Zhong J, de Villiers W, Eckhardt E.

Department of Internal Medicine, Division of Digestive Diseases and Nutrition,
University of Kentucky, Lexington, KY, USA.

Comment in
J Lipid Res. 2009 Jan;50(1):1-2.

Recent data suggest that dietary fat promotes intestinal absorption of
lipopolysaccharides (LPS) from the gut microflora, which might contribute to
various inflammatory disorders. The mechanism of fat-induced LPS absorption is
unclear, however. Intestinal-epithelial cells can internalize LPS from the apical
surface and transport LPS to the Golgi. The Golgi complex also contains newly
formed chylomicrons, the lipoproteins that transport dietary long-chain fat
through mesenteric lymph and blood. Because LPS has affinity for chylomicrons, we
hypothesized that chylomicron formation promotes LPS absorption. In agreement
with our hypothesis, we found that CaCo-2 cells released more cell-associated LPS
after incubation with oleic-acid (OA), a long-chain fatty acid that induces
chylomicron formation, than with butyric acid (BA), a short-chain fatty acid that
does not induce chylomicron formation. Moreover, the effect of OA was blocked by
the inhibitor of chylomicron formation, Pluronic L-81. We also observed that
intragastric triolein (TO) gavage was followed by increased plasma LPS, whereas
gavage with tributyrin (TB), or TO plus Pluronic L-81, was not. Most intestinally
absorbed LPS was present on chylomicron remnants (CM-R) in the blood. Chylomicron
formation also promoted transport of LPS through mesenteric lymph nodes (MLN) and
the production of TNFalpha mRNA in the MLN. Together, our data suggest that
intestinal epithelial cells may release LPS on chylomicrons from cell-associated
pools. Chylomicron-associated LPS may contribute to postprandial inflammatory
responses or chronic diet-induced inflammation in chylomicron target tissues.

PMID: 18815435 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm....pubmed/18815435

Diabetes. 2007 Jul;56(7):1761-72. Epub 2007 Apr 24.

Metabolic endotoxemia initiates obesity and insulin resistance.

Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F,
Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières
J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R.

Institute of Molecular Medicine, I2MR Toulouse, France.

Comment in
Diabetes. 2007 Dec;56(12):e20; author reply e21.
J Hepatol. 2008 Jun;48(6):1032-4.

Diabetes and obesity are two metabolic diseases characterized by insulin
resistance and a low-grade inflammation. Seeking an inflammatory factor causative
of the onset of insulin resistance, obesity, and diabetes, we have identified
bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal
endotoxemia increased or decreased during the fed or fasted state, respectively,
on a nutritional basis and that a 4-week high-fat diet chronically increased
plasma LPS concentration two to three times, a threshold that we have defined as
metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of
an LPS-containing microbiota in the gut. When metabolic endotoxemia was induced
for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted
glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain
were increased to a similar extent as in high-fat-fed mice. In addition, adipose
tissue F4/80-positive cells and markers of inflammation, and liver triglyceride
content, were increased. Furthermore, liver, but not whole-body, insulin
resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of
the LPS and high-fat diet-induced features of metabolic diseases. This new
finding demonstrates that metabolic endotoxemia dysregulates the inflammatory
tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14
system sets the tone of insulin sensitivity and the onset of diabetes and
obesity. Lowering plasma LPS concentration could be a potent strategy for the
control of metabolic diseases.

PMID: 17456850 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm....pubmed/17456850

PLoS One. 2010 Aug 16;5(8):e12191.

High-fat diet: bacteria interactions promote intestinal inflammation which
precedes and correlates with obesity and insulin resistance in mouse.

Ding S, Chi MM, Scull BP, Rigby R, Schwerbrock NM, Magness S, Jobin C, Lund PK.

Department of Cell & Molecular Physiology, University of North Carolina at Chapel
Hill, North Carolina, United States of America. shengli_ding@med.unc.edu

BACKGROUND: Obesity induced by high fat (HF) diet is associated with inflammation
which contributes to development of insulin resistance. Most prior studies have
focused on adipose tissue as the source of obesity-associated inflammation.
Increasing evidence links intestinal bacteria to development of diet-induced
obesity (DIO). This study tested the hypothesis that HF western diet and gut
bacteria interact to promote intestinal inflammation, which contributes to the
progression of obesity and insulin resistance.

METHODOLOGY/PRINCIPAL FINDINGS: Conventionally raised specific-pathogen free
(CONV) and germ-free (GF) mice were given HF or low fat (LF) diet for 2-16 weeks.
Body weight and adiposity were measured. Intestinal inflammation was assessed by
evaluation of TNF-alpha mRNA and activation of a NF-kappaB(EGFP) reporter gene.
In CONV but not GF mice, HF diet induced increases in body weight and adiposity.
HF diet induced ileal TNF-alpha mRNA in CONV but not GF mice and this increase
preceded obesity and strongly and significantly correlated with diet induced
weight gain, adiposity, plasma insulin and glucose. In CONV mice HF diet also
resulted in activation of NF-kappaB(EGFP) in epithelial cells, immune cells and
endothelial cells of small intestine. Further experiments demonstrated that fecal
slurries from CONV mice fed HF diet are sufficient to activate NF-kappaB(EGFP) in
GF NF-kappaB(EGFP) mice.

CONCLUSIONS/SIGNIFICANCE: Bacteria and HF diet interact to promote
proinflammatory changes in the small intestine, which precede weight gain and
obesity and show strong and significant associations with progression of obesity
and development of insulin resistance. To our knowledge, this is the first
evidence that intestinal inflammation is an early consequence of HF diet which
may contribute to obesity and associated insulin resistance. Interventions which
limit intestinal inflammation induced by HF diet and bacteria may protect against
obesity and insulin resistance.

PMCID: PMC2922379
PMID: 20808947 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm....pubmed/20808947

Edited by Brett Black, 17 December 2011 - 05:54 AM.

[xEva]

From wiki on Lipid A:

Lipid A is a lipid component of an endotoxin held responsible for toxicity of Gram-negative bacteria. It is the innermost of the three regions of the lipopolysaccharide (LPS, also called endotoxin) molecule, and its hydrophobic nature allows it to anchor the LPS to the outer membrane.[2] While its toxic effects can be damaging, the sensing of lipid A by the human immune system may also be critical for the onset of immune responses to Gram-negative infection, and for the subsequent successful fight against the infection.

This Lipid A is bond by lactoferrin: Lactoferrin is a lipid A-binding protein.

[niner]

Is this yet another case where having the right gut biota, in this case meaning not too many gram negative species, is important to human health? I don't know enough about the microbiome to say for sure; it seems like there are a lot of bad actors among the gram negative bacteria, but also some commonly thought of as 'friendly'. Is the type of fat in the high-fat meal important? How high is high?

[Brett Black]

Is this yet another case where having the right gut biota, in this case meaning not too many gram negative species, is important to human health? I don't know enough about the microbiome to say for sure; it seems like there are a lot of bad actors among the gram negative bacteria, but also some commonly thought of as 'friendly'.

The type and number of bacteria in the gut do appear to play a critical part in the process.
The following research suggests that altering the gut microflora using either antibiotics or prebiotics reduces the pro-obesity/inflammatory state that can be induced by a high fat diet:

2008 Jun;57(6):1470-81. Epub 2008 Feb 27.

Changes in gut microbiota control metabolic endotoxemia-induced inflammation in
high-fat diet-induced obesity and diabetes in mice.

Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R.

Unit of Pharmacokinetics, Metabolism, Nutrition and Toxicology, Université
catholique de Louvain, Brussels, Belgium.

OBJECTIVE: Diabetes and obesity are characterized by a low-grade inflammation
whose molecular origin is unknown. We previously determined, first, that
metabolic endotoxemia controls the inflammatory tone, body weight gain, and
diabetes, and second, that high-fat feeding modulates gut microbiota and the
plasma concentration of lipopolysaccharide (LPS), i.e., metabolic endotoxemia.
Therefore, it remained to demonstrate whether changes in gut microbiota control
the occurrence of metabolic diseases.

RESEARCH DESIGN AND METHODS: We changed gut microbiota by means of antibiotic
treatment to demonstrate, first, that changes in gut microbiota could be
responsible for the control of metabolic endotoxemia, the low-grade inflammation,
obesity, and type 2 diabetes and, second, to provide some mechanisms responsible
for such effect.

RESULTS: We found that changes of gut microbiota induced by an antibiotic
treatment reduced metabolic endotoxemia and the cecal content of LPS in both
high-fat-fed and ob/ob mice. This effect was correlated with reduced glucose
intolerance, body weight gain, fat mass development, lower inflammation,
oxidative stress, and macrophage infiltration marker mRNA expression in visceral
adipose tissue. Importantly, high-fat feeding strongly increased intestinal
permeability and reduced the expression of genes coding for proteins of the tight
junctions. Furthermore, the absence of CD14 in ob/ob CD14(-)(/)(-) mutant mice
mimicked the metabolic and inflammatory effects of antibiotics.

CONCLUSIONS: This new finding demonstrates that changes in gut microbiota
controls metabolic endotoxemia, inflammation, and associated disorders by a
mechanism that could increase intestinal permeability. It would thus be useful to
develop strategies for changing gut microbiota to control, intestinal
permeability, metabolic endotoxemia, and associated disorders.

PMID: 18305141 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm....pubmed/18305141

Diabetologia. 2007 Nov;50(11):2374-83. Epub 2007 Sep 6.

Selective increases of bifidobacteria in gut microflora improve
high-fat-diet-induced diabetes in mice through a mechanism associated with
endotoxaemia.

Cani PD, Neyrinck AM, Fava F, Knauf C, Burcelin RG, Tuohy KM, Gibson GR, Delzenne
NM.

Unit of Pharmacokinetics, Metabolism, Nutrition and Toxicology, Université
catholique de Louvain, Av. E. Mounier, 73/69, 1200 Brussels, Belgium.
patrice.cani@uclouvain.be

Comment in
J Hepatol. 2008 Jun;48(6):1032-4.

AIMS/HYPOTHESIS: Recent evidence suggests that a particular gut microbial
community may favour occurrence of the metabolic diseases. Recently, we reported
that high-fat (HF) feeding was associated with higher endotoxaemia and lower
Bifidobacterium species (spp.) caecal content in mice. We therefore tested
whether restoration of the quantity of caecal Bifidobacterium spp. could modulate
metabolic endotoxaemia, the inflammatory tone and the development of diabetes.

METHODS: Since bifidobacteria have been reported to reduce intestinal endotoxin
levels and improve mucosal barrier function, we specifically increased the gut
bifidobacterial content of HF-diet-fed mice through the use of a prebiotic
(oligofructose [OFS]).

RESULTS: Compared with normal chow-fed control mice, HF feeding significantly
reduced intestinal Gram-negative and Gram-positive bacteria including levels of
bifidobacteria, a dominant member of the intestinal microbiota, which is seen as
physiologically positive. As expected, HF-OFS-fed mice had totally restored
quantities of bifidobacteria. HF-feeding significantly increased endotoxaemia,
which was normalised to control levels in HF-OFS-treated mice.
Multiple-correlation analyses showed that endotoxaemia significantly and
negatively correlated with Bifidobacterium spp., but no relationship was seen
between endotoxaemia and any other bacterial group. Finally, in
HF-OFS-treated-mice, Bifidobacterium spp. significantly and positively correlated
with improved glucose tolerance, glucose-induced insulin secretion and normalised
inflammatory tone (decreased endotoxaemia, plasma and adipose tissue
proinflammatory cytokines).

CONCLUSIONS/INTERPRETATION: Together, these findings suggest that the gut
microbiota contribute towards the pathophysiological regulation of endotoxaemia
and set the tone of inflammation for occurrence of diabetes and/or obesity. Thus,
it would be useful to develop specific strategies for modifying gut microbiota in
favour of bifidobacteria to prevent the deleterious effect of HF-diet-induced
metabolic diseases.

PMID: 17823788 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm....pubmed/17823788

[Werner]

As many here would know, chronic systemic low-grade inflammation has been shown to play a significant role in many if not most forms of age-related disease, decline and dysfunction. That such a broad but apparently disparate range of age-associated pathologies all seem to share a common inflammatory component makes further understanding the cause(s) of such inflammation potentially very important for anti-aging purposes.

Some recent evidence suggest that lipopolysaccharides(LPS), a bacterial endotoxin, may be an important piece in this puzzle:

Maybe a piece in the puzzle, but not an important one. The two most important factors
are known: 1) cytokines, here especially IL-1 and TNF-alpha, 2) arachidonic acid.
Cytokines are essential for a proper working of the immune system but in the elderly
you find much more than necessary. AA is produced by eating animal food. Nowadays,
people eat too much meat, eggs, dairy. Milk products are probably the most aging
food at all.

[xEva]

Maybe a piece in the puzzle, but not an important one. The two most important factors
are known: 1) cytokines, here especially IL-1 and TNF-alpha, 2) arachidonic acid.

Apparently it evaded your attention that LPS is the known inducer of cytokines, especially IL-1 and TNF-alpha, while TNF-alpha is known to directly stimulate arachidonic acid release in neutrophils.

[Brett Black]

Is the type of fat in the high-fat meal important? How high is high?

I may make a future post on this with more data, but for now here's a little bit of info which you might find relevant:

"Four groups (12 each) of healthy normal-weight (BMI of 21.5–24.4 kg/m², aged 25–47 years) subjects ingested either 75 g (= 300 calories) of glucose (Glucola drink; Fisher Scientific, Pittsburgh, PA), 33 g (= 300 calories) of cream (gourmet heavy whipping cream; Land O'Lakes, Arden Hills, MN), an equicaloric amount of orange juice, or 300 ml of water after an overnight fast. The content of the dairy cream used includes 70% saturated fat, 28% unsaturated fat, <2% protein, and no carbohydrates."

---

"Plasma endotoxin concentrations increased significantly after the intake of cream from 0.29 ± 0.03 to 0.41 ± 0.07 endotoxin units (EU)/ml at 3 h (45 ± 17% over the baseline, P < 0.05) (Fig. 3B) but not after glucose, orange juice, or water intake."

Deopurkar R, Ghanim H, Friedman J, Abuaysheh S, Sia CL, Mohanty P, Viswanathan
P, Chaudhuri A, Dandona P. Differential effects of cream, glucose, and orange
juice on inflammation, endotoxin, and the expression of Toll-like receptor-4 and
suppressor of cytokine signaling-3. Diabetes Care. 2010 May;33(5):991-7. Epub
2010 Jan 12. PubMed PMID: 20067961; PubMed Central PMCID: PMC2858203.
http://www.ncbi.nlm....pubmed/20067961

[Hip]

This is a very interesting thread, thanks for posting it Brett.

I am always looking for ways to reduce the absorption of LPS through the gut lining. I have chronic fatigue syndrome (ME/CFS), and there is evidence that LPS in the blood is conmtributing to the severity of ME/CFS, as well as other diseases:

Gut Inflammation in Chronic Fatigue Syndrome: Endotoxemia

Shaheen E Lakhan* and Annette Kirchgessner

Global Neuroscience Initiative Foundation, Los Angeles, CA, USA

Although confidence in the link between infection and CFS pathogenesis has waned, recent studies have suggested that infection with gut pathogens could be related to CFS onset.

Raised serum concentrations of IgA and IgM to lipopolysaccharide (LPS) of gram-negative enterobacteria, such as Pseudomonas aeruginosa, Morganella morganii, Proteus mirabilis, Pseduomonas putida, Citrobacter koseri, and Klebsiella pneumoniae have been reported in CFS patients. The prevalence and median values for serum IgA against the LPS of enterobacteria were significantly greater in patients with CFS than in normal volunteers and patients with partial CFS. Moreover, serum IgA levels were significantly correlated to the severity of illness, as measured by the FibroFatigue scale. The FibroFatigue scale is an observer's rating scale with 12 items measuring pain, muscular tension, fatigue, concentration difficulties, failing memory, irritability, sadness, sleep disturbances, and autonomic disturbances and irritable bowel, headache, and subjective experience of infection. It is a reliable and valid measuring instrument that is used to monitor symptom severity and change during treatment of CFS patients.

Normally, the intestinal epithelium acts as a continuous barrier to avoid LPS translocation; however, some endogenous or exogenous events may alter this protective function. This may induce an increased bacterial translocation and thus increased serum endotoxin concentrations which, in turn may trigger an immune response. Thus, the increased serum IgA and IgM levels against LPS in CFS indicate the presence of increased gut permeability and an immune response mounted against LPS of the enterobacteria.

LPS is problematic in ME/CFS not only because of its pro-inflammatory effects, but also because it redirects the immune response away from the desired Th1 mode (the intracellular mode of the immune system, which fights viruses and bacteria inside cells), and into the Th2 mode (the extracellular mode of the immune system which fights pathogens located outside of cells, usually bacteria).

People with ME/CFS are already shifted far too much into the Th2 mode, and need to move back towards Th1, so that the body can fight of the intracellular viral and bacterial infections associated with ME/CFS. But LPS pushes the immune system to Th2, making it harder for the body to fight off these intracellular pathogens.

Having a leaky gut (intestinal permeability) is one reason that LPS from gut bacteria enters the blood; leaky gut can be tested for, and can be treated with various supplements. Fixing a leaky gut should reduce LPS blood levels.

However, as this thread details, dietary fat is another way that LPS in the gut can hitchhike a ride into the blood stream. This is fascinating; I was not aware of this before.

I'd be very interested to know if there are types of dietary fat that LPS cannot adhere to. If so, it may be possible to create a diet that contains only fats that LPS cannot stick to, in order to prevent LPS from hitchhiking into the blood stream. Such a diet may be a good way to treat ME/CFS. Failing that, just a low fat, high protein diet may help reduce LPS translocation from gut to blood.

Also the fact that lactoferrin binds to the lipid A component of LPS, as I read above, means that lactoferrin supplements may also reduce the inflammatory effects of LPS.

Edited by Hip, 07 January 2012 - 03:43 PM.

[Werner]

Maybe a piece in the puzzle, but not an important one. The two most important factors
are known: 1) cytokines, here especially IL-1 and TNF-alpha, 2) arachidonic acid.

Apparently it evaded your attention that LPS is the known inducer of cytokines, especially IL-1 and TNF-alpha, while TNF-alpha is known to directly stimulate arachidonic acid release in neutrophils.

No.
Original posting: "However various mechanism(e.g. gut mucosa)
normally keep acutely harmful LPS exposure(e.g. systemic circulation)
to a minimum."
LPS is not the decisive producer of cytokines. They are produced by
the immune system via disease => reaction of immune system =>
cytokines => inflammation. A very good model in the normal way.
In the elderly, instead, you have certain low grade diseases at bones,
joints, osteoporosis, vascular ecc. The immune system therefore
produces a higher level of cytokines than normal. One of its
consequences is geriatric cachexia.

[niner]

LPS is not the decisive producer of cytokines. They are produced by
the immune system via disease => reaction of immune system =>
cytokines => inflammation. A very good model in the normal way.
In the elderly, instead, you have certain low grade diseases at bones,
joints, osteoporosis, vascular ecc. The immune system therefore
produces a higher level of cytokines than normal. One of its
consequences is geriatric cachexia.

What exactly do you mean by 'not the decisive producer'? LPS is a hell of a good way to produce cytokines. In the pharmaceutical industry, a great deal of effort goes into the development of anti-inflammatory compounds. LPS challenge is the standard way to set off a very aggressive inflammation in an animal model. LPS is a seriously bad actor if it's present in the body. Are you saying that normal LPS levels are insignificant as cytokine producers compared to other processes?

[Werner]

LPS is not the decisive producer of cytokines. They are produced by
the immune system via disease => reaction of immune system =>
cytokines => inflammation. A very good model in the normal way.
In the elderly, instead, you have certain low grade diseases at bones,
joints, osteoporosis, vascular ecc. The immune system therefore
produces a higher level of cytokines than normal. One of its
consequences is geriatric cachexia.

What exactly do you mean by 'not the decisive producer'? LPS is a hell of a good way to produce cytokines. In the pharmaceutical industry, a great deal of effort goes into the development of anti-inflammatory compounds. LPS challenge is the standard way to set off a very aggressive inflammation in an animal model. LPS is a seriously bad actor if it's present in the body. Are you saying that normal LPS levels are insignificant as cytokine producers compared to other processes?

Normally insignificant, as stated in the OP. Otherwise all people would
have serious inflammative problems. Instead, NF-kB is a "treasure trove"
for the development of anti-inflammatory drugs:
http://www.nature.co...bs/nrd1279.html