Friday, September 13, 2013

Phylogenetic Tree of Caecums, Appendectomies, Microbiota Maintenance, and Anecdotal Failure of Fecal Transplants

Human Guts = Super-Organs

Human intestines are really part-carnivore, part-frugivore and part-microbe. As living entities, we are 'super organisms' or hybrids of microbes (over 100 trillion cells) + human (~10 trillion cells).  Did you do the arithmetic? (sorry -- I can't do math)

We are ~90% microbial cells. In fact all living organisms have gut flora microbes from termites, cockroaches to fish to frogs to birds to carnivores to omnivores.  Recall SFB (segmented filamentous bacteria; Firmicutes; Clostridia; Candidatus Savagella) the commensal (symbiotic) bacteria intimately residing in the ileum (small intestine) of insects, humans, chickens and rodents improving TH17 and immune system regulation and protecting against autoimmunity and T1DM.

The caecum and appendix (animals that have one -- see photo) may serve the job of storing and maintaining the microbiota that seed the gut (fore and hind). In a phylogenetic analysis of a variety of animals, evolutionary biologists have various theories that the appendix was retained for a functional purpose (Smith et al, 2010. Photo credit: PDF.)

The Human Appendix is Not Vestigial 

The appendix is not a vestigial organ. In modern healthcare, broad spectrum antibiotics are handed out carelessly and tonsils and appendices are removed without much thought -- acute symptoms or persistent infections precipate the surgery in otherwise healthy and young folks. However, a recent study shows that there is an un-ignorable and increased relative risk of unexpected sequelae (e.g. subsequent heart attack) in these people following surgery -- 44% and 33%, respectively.

Why? Tonsils and appendices are part of the hybrid microbiota-immune system and control of inflammation.  According to Smith et al, our ancient predecessors most likely had appendices for at least since 60 million years ago if not extensively longer, 80 mya.  Come on... 80 mya... that's a long time.
"The appendix has evolved independently at least twice
and has been extensively maintained, albeit not uniformly,
in at least three and perhaps four groups of
mammals; glires, primates, Diprotodont marsupials and
perhaps monotremes. The possibility that the appendix
occurred at the base of the primates suggests that the
appendix may have been preserved in that clade since
before the two primate suborders
, Strepsirrhini and
Haplorrhini, diverged an estimated 60–63 million years
ago (Gingerich, 1986; Shoshani et al., 1996; Pouydebat
et al., 2008). Similarly, the conclusion that the appendix
evolved at the base of the glires indicates that the
appendix has been maintained since before the K–T
when rodents and lagomorphs diverged
approximately 80 million years ago (Bininda-Emonds
et al., 2007)."

Caecums, Carb/Fiber Digestion, VFAs

Caecams are organs at the juncture between small and large intestines. Mammals have one, gallinaceous birds (ground-feeding) two, and fish several.  Humans and primates have a small caecum and vermiform appendix (worm-like, blind pouch). Caecums appeared to have evolved as chambers for microbial fermentation. It has made multiple appearances in evolution. Sizes vary in the animal kingdom from none to some to fully functional appendices. In species without appendices, the great majority of microbial fermentation occurs in the stomach (ruminant herbivores).  Ruminants have evolved small caecum (no appendix) since most of the fermentation occurs in the foregut. Smith et al theorize "Thus, the evolution of small ceca in some species that are foregut fermenters seems likely to have involved loss of the digestive function of a cecum with an appendix, with maintenance of the immunologic function of the cecal appendix."

Certain herbivores do a HUGE amount fermentation in the caecum -- rabbits, pika, guinea pigs.  These vegan-animals also exclusively practice coprophagia to obtain nerve/brain nutrients (vitamin B12) from caecal protein and vitamin synthesis (e.g. poo consumption).  [Curiously, porcupines have big caecums but no  observed coprophagia behavior (though dogs and tortoises have been observed to eat porcupine poo).  Yet in one study 16% of energy requirements were produced in caecal fermentation (versus 4.7%, rat).  BTW resistant starch (RS -- corn) provides different volatile acids, caecum expansion and improved insulin and blood glucose profiles in rodent studies, compared to high GI wheat/gluten starch.]

Photo credit: talkorigins

Our caecum is microscopic (see below); herbivores, gargantuan.  The human caecum and appendix serve more of an immune function, reservoir for microbiota; the function for digestion is minor.  Both our caecums and large intestines can ferment carbs (fiber, resistant) then release the digested products into the blood circulation as volatile organic acids.  The small intestines should not... except under illness (SIBO, small intestinal bowel overgrowth).  We are not foregut fermenters.  These metabolites can be measured (propionate, acetate, butyrate, etc). GDX/Metametrix organic acids testing is available-- Nutri Eval, Organix, ION, ONE.  I favor the ONE -- requires only the first morning void urine (FMV) so non-invasive and you get the cancer/inflammatory marker 8OHdG, mineral/vitamin deficiencies are other functional metrics.

Photo credit: Smith et al, 2010
Fig. 1 The cecal appendix (a through l) or appendix-like structures (m through o) in a
variety of mammals. The cecum ⁄ appendix is oriented toward the top of each drawing,
the distal end of the small intestine toward the left and the proximal end of the largeintestine toward the bottom.
  (a) human, Homo sapiens;
  (b) Pongo pygmaeus, orangutan;
  (c) Lepilemur leucopus, sportive lemur;
  (d) Lasiorhinus latifrons, Southern hairy-nosed wombat;
  (e) Oryctolagus cuniculus, rabbit;
  (f) Phalanger gymnotis, ground cuscus;
  (g) Anomalurus derbianus, scaly-tailed flying squirrel;
  (h) Trichosurus vulpecula, common brushtail possum;
  (i) Bathyergus suillus, Cape dune mole-rat;
  (j) Atherurus africanus, brushtailed porcupine;
  (k) Castor canadensis, beaver;
  (l) Microtus pennsylvanicus, meadow vole, shown with a partially uncoiled large bowel//
  (m) Phascolarctos cinereus, koala;
  (n) Ornithorhynchus anatinus, platypus;
  (o) Tachyglossus aculeatus, echidna.

Volative organic acids include polyamines, short chain fatty acids (VFA) and others.  These can be quantified on the GDX/Metametrix GI function stool test and blood/urine organic acids testing.  This test is the best on earth. It assesses both large and small intestine function, and additionally accurately pinpoints pathogenic overgrowth, parasites, and worms which are frequent invaders despite 'clean' air, water and soil in modern continents. If pathogens exist in the small intestines, caecum and/or large intestines, putrification of undigested fats, proteins and carbs occurs.  Certain volative by-products are highly odiferous-- cadaverine, putrescene, spermidine, etc.

Treatment includes pathogen killing (charcoal, clay, herbals), healing the broken gut/brush border/GI peritalsis/acidity/pH, and replacing lost gut flora (commensal Firmicutes, Bacteroides, facultative anaerobes, SBO, good yeasts, etc).

The entire human gut has only ~17% of surfaces for fermentation compared with 50% for an animal like guinea pig. (TO ME, this is like the diff betw a select post-harvest wine versus mass produced Coors light.)

Bergman talks in-depth about VFAs. "Current estimates are that VFA contribute approximately 70% to the caloric requirements of ruminants, such as sheep and cattle, approximately 10% for humans, and approximately 20-30% for several other omnivorous or herbivorous animals. The amount of fiber in the diet undoubtedly affects the amount of VFA produced, and thus the contribution of VFA to the energy needs of the body could become considerably greater as the dietary fiber increases."  I don't think we are gorillas (57.3% energy obtained from VFAs) though some humans may exist as such (functional..? debatable?).

Role of Appendix and Failed Fecal Transplants

Our comparatively tiny human appendix is nearly non-functional yet appears to serve a purpose for maintaining maternal, birth- and early life-derived microbiota and biofilms.  This is why -- I've heard -- that fecal transplants often fail 1-3 years post-transplant (anecdotal communication,  Metametrix/GDX Tony Hoffman).  Were these cases Paleo? Consuming fermented foods frequently? Root causes for dysbiosis/permeability identified and reversed?  Toxins, mercury, pathogens addressed??

Appendectomies, Gluten Sensitivity, Gallbladders, Nutrigenomics and TMI

Not all animals have an appendix...... including members of my family; two out of 4 siblings have had surgical removal of the appendix. We also have 3/4 (diagnosed) autoimmune disorders. And 2/4 have documented gliadin sensitivity (me, positive fecal anti-gliadin sIgA in 2011 on Metametrix GI fx stool testing). Is there a connection? You tell me.

I'm Paleo because I'm protecting my gallbladder, appendix and other precious ~~.  Not into chopped off organs, boobies, etc.

Integrative medicine, treatment and prevention for gallbladder disease HERE (Gaby 2009).

Recently my kids and I did 23andme genotype testing. Have you done it? It revealed many gluten-sensitivity related conditions we are susceptible to based on known SNP analysis (alkylosing spondylitis, primary biliary cirrhosis, T1DM, etc).  Not a shock. I'm grateful for discovering the Paleo and gluten free diet in 2007, then functional medicine and intestinal permeability/gut dysbiosis in 2010.  We have made appropriate changes and seen improvements -- some mild, some dramatic.

This is the year of personal nutrigenomics.  We are negative for MTHFR but have the GSTT1 (glutathione, detox, heavy metals), deletion and are heterozygous for COMT (methylation -- detox of toxins, metabolism of adrenaline, dopamine, estrogens, 4OHE1, cortisol, etc).

Gallbladder stones and removal are super super super common in primary biliary cirrhosis (one of many celiac/silent-celiac conditions -- just like fatty liver, fatty pancreas, fatty heart, blah blah blah). Why? Look how anatomically close they are together to the liver, portal vein, stomach and duodenum/small intestine. When intestinal permeability allows undigested gluten through (or gluten just opens zonulin), gluten causes immunogenic havoc, scarring and immune system activation.  Same with the appendix.  When gluten and resident microbes translocate from the caecum/small/large intestines to proximal and distal organs, they hit neighbors the hardest.  Appendectomies are mega-crazy-common (my dad's a surgeon; gluten paid for my college).

Often I hear stories that the spasms and pain remain despite surgery.  Despite diligently avoiding 'high fat diets', they suffer (eating wholehealthylectins).  It's not just the 'fat, forty, fertile female' (4F's) who are afflicted (as all hazed med students are taught).  Males are affected too. Children are now affected.

It's a silent epidemic across the world in sync with vegetarianism (vegetarian males: 3-fold; vegetarian +alcohol, 7-fold) and westernized, Big Agra crop-users (like Saudi Arabia).

Gluten? Dietary removal of gluten helps a ton as Gaby above reports (two studies in celiacs 1985 and 1999).  Gluten is heat/cooking resistant. The toxic gliadin peptides can resist GI enzymatic digestion when microvilli DPP-IV  is disabled (by mercury) and when brush border enzymes are missing (SIBO, gut dysbiosis, pathogens/parasites).  At least 60 gliadin protein sequences are immunotoxic, triggering immune system reactions for susceptible individuals.  These were in relatively low concentration in ancient wheat but 50-100 years ago, transgenic hydridization and GMO techniques have bred (pun, bread) the concentration of the toxic gliadins to an estimated 500-fold amplication.

Peter at Hyperlipid cogently discusses Gluten and Gallbladders (circa 2008); good stuff, good comments.

Safe Guarding Appendices?

Smith et al talks about how the caecum is a "‘safe-house’ for biofilms containing commensal bacteria." How does antibiotics affect this? Antibiotics in food, cattle/chicken feed, eggs and their products?  How do we revive extinct commensals and healthy biofilms....? Wish I knew definitively because there are few ways to test the contents of the caecum and appendix.

If I could repeat preconception, conception, birth, postnatal, and lactation periods with my kids, I would certainly do a million things differently from the gut and gut microbe perspectives.

Further Smith et al concludes on the relationship between the caecum (which contains a region of lymphoid tissue), gut microbiota and the immune system....
 'Although microbial biofilms in the proximal large
bowel are apparently a hallmark of immune support for
the microbial flora in a wide range of mammalian species,
the biofilm distribution in the gut of an outgroup for
mammals had not been evaluated previously. Thus, the
observation that biofilms are distributed in frogs in a
manner similar to mammals, with a preference for the
proximal large bowel (Fig. 4), strongly suggests an
ancient origin for a pro-microbial immune function in
the proximal large bowel. Specifically, this observation
suggests that the adaptations supporting biofilm growth
by commensal bacteria are more ancient than blind sacs
of the gut, such as the cecum, which are involved in
fermentation. In support of this idea, microbial biofilms
are not only strengthened by secretory Immunoglobulin
A (SIgA) produced by the adaptive immune system, but
can also be supported by mucin (Orndorff et al., 2004;
Bollinger et al., 2005), a major biomolecule produced by
the more ancient innate immune system. This finding
points toward increased immune support of the gut
microbes as one of the potential driving forces for the
evolution of blind sacs in the proximal large bowel.'

Our Gut Anatomy and Physiology:  Part Carnivore + Part Frugivore

The curious thing is that advanced hominids are not exclusive frugivores. Though it makes sense that we lost the capacity to synthesize Vitamin C and must find and outsource this to dietary Vitamin C, our digestive tract length, volume and capacity to produce low pH and secretions are akin to carnivores.  Additionally, our shrunken small intestines possess really exceptional digestive capacities and efficient absorptive surfaces synonymous with carnivores, not herbivores (3-5X our height, not 10X as in herbivores).

 Photo credit: Biocyclopedia.

Nearly ALL digestive work and absorption are concentrated in the small intestines, which varies in length by individuality, 15 -30 feet. This is why illness in the small intestines (SIBO/gut dysbiosis) disrupts all health, including even distant, peripheral tissues (brain, breasts, fat/belly, bones, joints, vasculature, gonads-b**ners), not only proximal (liver, pancreas, gallbladder). Energy dense food provide long acting fuel (fats, complex carbs). Our small intestines, gallbladder bile acids for fats and carbs, pancreatic enzymes (lipases, proteases, carb-ases) compensated.   Our carnivorous small intestines are the super gift we acquired through evolution.

Our immune system is 70-80% based in the gut. Despite, our immunity being outsourced to microbes (caecal, appendix, intestines), only a fraction of our nutrition is (~10% from VFAs) because we obtain the energy from broken down, digested high-energy bonded food (e.g. fatty acids, complex carbs) in the small intestines.  Our sophisticated and elite human small intestines suck all this energy up taking what first-pass at the liver misses. Human nutrition is super nutrient dense and fat based (my diet is 30-40% fat) allowing us to forgo chewing and grazing but only every 3-5 hours.

The remaining marginal allotment of our nutrition is brewed by symbiotic bacteria and yeasts... It's arguable that butyrate is both a nutrient for the intestinal cells as well as an extension of the ancient immune system for the entire body. Our hindgut (large intestines) continues methodical fermentation and microbial metabolite harvesting (organic acids, volatile fatty acids, B12, butyrate, other bacterial Firmicutes/Bacteroides end-products).  It's absolutely not necessary to produce heaps and heaps of dung like our four-legged herbivore friends all day post-digestion without anal control.


Anonymous said...

Geat information, too much to digest in one post, would benefit from beaking down into several segments and more detailed review of the literature. Good if you already know the background, though.

Dr. B G said...

Thx for the comments. Confused? More questions than answers? Would you like more opinions or just more explanations? I don't spoon feed. The links are provided for background.

Anonymous said...

"...I would certainly do a million things differently from the gut and gut microbe perspectives..."

Short list of 10 things you'd do differently??

Dr. B G said...

Pre-reproduction I would've

1. Tested all toxins (GDX/Metametrix CORE -- pesticides, solvents, PCBs, prophyrins (mercury) and hair Toxic Elements (heavy metals)
2. Rid all the toxins over 1-2 yrs safely and gradually
3. Test minerals, vitamins
4. Replete them all
5. Test markers of dysbiosis (organic acids -- GDX ION or Nutri Eval)
6. Test status of digestion, gut function, parasites, pathogenic overgrowth, worms (GDX/Metametrix GI fx stool)
7. Fix the gut (which requires #8, 9, 10)
8. Hormone panel -- fix any defects
9. Adrenal and thyroid panel -- support and optimize. New data shows low thyroid increases autism by 4-FOLD
10. Barefoot yoga, cardio (improves GI promotility and supports the gut), Vegas and lots of good SEXXX (because there's not much after babies)

Help? Thoughts? Dissent?

Dr. B G said...

#10-- add Organic Asian/rice-based Paleo (~70% plant based) + homemade ferments

Dr. B G said...

--never introduce gluten (barley baby food, goldfish crackers, cereal) or GMO corn
--not excised so hard (I lost 20lbs quickly I believe induced my first to wean at 8months-- toxins are excreted from fat during weight loss apparently and go to breastmilk or re-distribute unless good fiber/chlorophyll/detox)
--held the baby more
--introduced ferments early (or SBO probiotics) and continuously as they grew up
--let the kids play in dirt more (they did! Certainly not enuf though) in the sunlight (vitamin D)
--avoided all antibiotics, vaccines until older and no mercury/aluminum containing ones
--avoided all amalgams
--avoided sugar and gluten grains
--avoided all toxic suncream, Vaseline and body lotions (carrot seed and raspberry seed oils have SPF of 20-30)
--fed the kids organic pastured lard and pork, butter oil and CLO for cavity protection (my kids stopped having all cavities 12-18 months after Paleo but before annually or more)

tess said...

very interesting indeed -- both article AND contents! thanks, BG.

Dr. B G said...

So glad you enjoyed it, Tess. I've heard it's called edu-tainment.

I love your comments and paleo blog for a while

Galina L. said...

I live my life without tonsils, appendix and gallbladder. I guess nothing could be done about it. My issues are mostly autoimmune ones except a tendency to have migraines. I am LCarbing for last 6 years, exercising and cooking all my food and holding on so far...

Dr. B G said...


I hear ya.

I almost eradicated my thyroid and brain into vestigial organs... LOL ahaaaa (Hashimoto's autoimmune thyroiditis during college years). I was lucky that it healed gradually with exercise, sunlight, and eating less processed foods (wheat).

Toxins in our environment trigger most autoimmunity I believe. YES -- wheat and gluten certainly are gut immunogenetic factors, however the toxome has reached a limit. For many with more 'ancestral' type genomes and SNPs, the threshold is far lower than the average human. My kids and I have these genes but so do many; the incidence is 40-60% for some of these SNPs.

Where is your home country? This is for the USA -- EVERYONE TESTED has an extremely HIGH level of toxins.

I feel that in healthcare we don't bridge the immune system well or adequately. Too many unknowns, no drugs, no quick fixes... Broadspectrum antibiotics, NSAIDs and halogenated high potency corticosteroids are all handed out like candy. All potently disrupt the gut, even after a single course.

So many things hyperstimulate or severely depress the vast, elaborate immune system.

Definitely eliminating immunogenic foods works -- SCD, GAPS, Feingold, anti-FODMAP, Paleo diets all work for many. These are all essentially hypoallergenic diets because the body has developed an intolerance via immuno-triggering to undigested food parts and the gut inhabitants (yeasts, enteric commensals, pathogens, anything including good stuff).

Sometimes the thyroid, gonad and adrenals perk back up to normal. Sometimes they don't because continued immuno-dammage is ongoing. Heavy metals, pthalates, PCBs, plastics, and pesticides are the worse immuno-triggering factors. Even low doses synergistically will damage for many....

Dr. B G said...

Until health is totally reclaimed, I suspect people need to totally outsource many organ functions for digestion and immunity...

Stomach -- betaine HCl, acidity, digestive enzymes, coating herbs (marshmellow, slippery elm, mastic gum, etc)

Duodenum, pancreas/GB, brush border, commensal bacteria -- SBO, probiotics, raw live 'kraut and fermented drinks/food, pancreatic digestive enzymes (lipases, proteases, carb-ases), 'elemental diet (e.g. predigested liquid diet/babyfood)', ox bile, coating herbs (marshmellow, slippery elm, mastic gum, etc)

Vagal innervation -- yoga, calm, qi gong, laughter, cholinergic and dopaminergic herbs, rest/repose/REM/sexxx

Peristalsis -- extended mild-mod exercise

Large colon -- probiotics, SBO, butyrate supplements, coating herbs (marshmellow, slippery elm, mastic gum, etc), extra (sublingual) B12, methylated B vitamins, fat soluble vitamin ADEK2 (the gut microbiota conjugates a lot of these to make them bioavailable), calcium d glucurate, etc

When the gut is still damaged, cortisol is typically dysregulated. If so, then tissue damaging auto-antibodies and immune complexes continue being produced and circulated. Immune support means adrenal herbs, lifestyle, qi gong, yoga, acupuncture, massage, and etc to bring cortisol back into controlled, normal regulation. This is a big problem for a lot of people, especially when the toxin burden/toxome is high because toxins are endocrine-disruptors and cause redox mitochondrial problems/death.

This is an integrative physician on immune recovery. Thoughts? Would love to hear your insights....


Galina L. said...

I am from Moscow, Russia. Of course, there are a lot of pollutants in a big city. I also blame some health issues on me having negative rhesus factor while my mom is positive.When I was born at 1960, no one was screen for that. Well, Hashimodo is one of my autoimmune conditions as well.
My cooking is very old-fashioned, I always have at least a gallon of a self-made sauerkraut in my fridge all the time. Fermented foods and soups are staples in my family.

Dr. B G said...


I'm sorry to hear about the potential link for Rh compatability. Yes -- I don't how the pollution is in Moscow but it seems major cities tend to share more because of the density of people, living away from life-sustaining farms, high energy demands, etc.

China and USA produce most of the world's mercury and arsenic emissions from coal-burning. USA still has coal plants and 30-50% of the energy still comes from coal.

Unfortunately the downstream effects can no longer be ignored. It has been recently observed that wetland birds have changed sex, no longer mate with song and mother birds fail to care for eggs and hatchlings properly due to environmental poisoning.


Dr. B G said...

Also I think that is fantastic how you cook 'old fashioned'! There's a Chinese saying 'if you live by the shore, eat from the shore; if you live on a mountain, eat from the mountain.'

The problem nowadays is that many of us are urbanized living in concrete towers... We cannot eat from concrete jungles or dirt. I have to admit I soak my organic vegetables in vinegar water to kill any possible pests, remove pesticide residues and parasites... probably not a good idea! I struggle with how to incorporate good dirt. I'm considering making the next 'kraut batch with adding SBO probiotics. Some people make yogurt using a probiotic as a starter...

Many bacterial/fungal symbionts live near the roots and shoots of plants, providing them with protection, hormones, stimulus, nutrients, amino acids and other benefits. Guess what? Soil based organisms are among them including Bacillus subtilis and others which are found in traditionally fermented vegetables and sourdough.
"A huge range of bacterial symbionts colonize plants. Many of these are pathogenic, but others known as plant-growth promoting bacteria (PGPB) provide the host with essential services such as nitrogen fixation, solubilization of minerals such as phosphorus, synthesis of plant hormones, direct enhancement of mineral uptake, and protection from pathogens.[24][25] PGPBs may protect plants from pathogens by competing with the pathogen for an ecological niche or a substrate, producing inhibitory allelochemicals, or inducing systemic resistance in host plants to the pathogen[26]"

Galina L. said...

Well,yes, we can't rely on a dirt in concrete jungles. I use some herbs that grow around my house and I also try to chew some eatable plant parts when outdoor, as we did as children when went in a country-side. Young new growth is eatable, also , if you pull off the top part of a grass with seeds, the site which is opposite to the seed part is eatable. I hope it gives me a little bit of natural microbes.

Dr. B G said...

Yes microbes appear to colonize the whole plant! That's so FUNNY. I do exactly the same thing!!! I pull (organic) plants and nibble on them... It is like sampling our 'ecological niche' in more intimate ways -- plant DNA, microbes and all... haa

Galina L. said...

It is what I used to do while collecting mushrooms or berries with a group of children several decades ago. It was normal for my grandma to sent me to find and harvest wild sorrel or mushrooms if she wanted to use it for cooking. We(a group of children) also liked to stick a grass stem into a ant mound and lick the traces of acid resulted from ants bites, we chew pine sap, knew which flower parts had tiny drops of a nectar, and basically put one thing or another into mouths all the time while being outdoor.
I wish I wouldn't be made to eat everything with bread since early age, because over-wise my environment was very healthy, except my grandma, who was rising me till I turned 10 yo, being a neat-freak.
Now I managed to convince my mother to stop eating bread and drop a good portion of carbs from her diet, which dramatically improved her heath.

Dr. B G said...

You were deeply tied to the earth as a child. Mushroom foraging is quite a skill! That sounds so wonderful. I received a lot of antibiotics growing up -- and no fermented foods/probiotics. Obviously children now have gut-damaging factors that we never grew up (besides hyper-hygeine, whole grain madness).
--GMO crop products with DNA transfer to human gut microflora to produce gut-toxic Bt lectins
--antibacterial (triclosan, etc) in the water supply
--ubiquitious environmental heavy metals, pesticides, chemicals