Friday, March 14, 2014

Gut Microbiome Biohacking Basics; Mild Havoc? Or Unmitigated Upheaval?

Linkin Park
Roads Untraveled

Roads Untraveled?

More and more studies are pouring into our collective knowledge about the microcritters in our 'forgotten organ,' the humble gut. The latest making the rounds is a stunning article on how one of the first antibiotics created by Eli Lilly in the 1950s was used as a 'digestive aid' in livestock (like ?cocaine in COKE? or ?nicotine in tobacco once plugged by physicians or ?gliadin in modern hybridized wheat plugged by govt juggernauts) .They were used to put on fat and poundage to cattle and livestock by a 3-FOLD magnitude. In those war and post-war days, the population was skinny and desired 'fat'. In modern times, we've flipped. The majority are overweight/metabolically deranged and desire 'thin.'
Source: Big Tobacco led throat doctors to blow smoke (Stanford)

Do Antibiotics Make Us Fat?

"On the Point" with Tom Ashbrook has a new podcast that interviews the author of the new NY Times article linking agricultural use of antibiotics in animal feed decades ago with the new diabesity epidemic, Pagan Kennedy. Dr Ilseung Cho is also interviewed, gastroenterologist at NYU and gut microbiome researcher. Dr. Cho talks about the potential gut effects of antibiotics.

Dr Cho is from Marten Blaser's lab which recently concluded in their study "Infant Antibiotic Exposures and Early-Life Body Mass" that YES antibiotics are highly correlated to higher 'fatness' in babies who received antibiotics before age 6 months, and older as well but the effect was less consistent apparently after babies start to crawl around (Trasande et al 2013).

Clearly there are multiple factors that go into becoming fat. Clearly we have ignored the gut microbiome for too long. 100% of everyone that I know has had at least a single course of antibiotics if not double digits. As a child of a physician, I've had my share. For many fevers and sniffles, I got the 'pink liquid'. Partly I went into pharmacy believing that drugs were not only good, but life saving.

Can antibiotics actually be life altering and life stealing? Bringing on autoimmunity? Triggering UC, Crohn's and IBS? Ushering in the storms of autism, diabesity and allergies that are seem inescapable and epidemic? Before I had kids, I once had Shigella. It was awful and Cipro did cure it -- but did it impair my gut? Should I have taken measures to protect the commensal populations?

My oldest daughter was born ~14 years ago via emergency C-section. Despite breast feeding her, she had 2-3 months straight of inconsolable crying and colic (age ~6-9 months), endless ear infections (6-12 months), then later developing reactive asthma (1.5-10 until we started vitamin D) which required middle of the night treatments, nebulizers and urgent care visits. We have never had asthma in the 'family'. It certainly didn't appear 'genetic'. In hindsight, I suspected that her atopic hypersensitivities be related to many things not excluding the (lame gut) legacy that I handed to her, C-section birth and formula at age 6 - 18 months.
How important is the maternal microbiome bequeathed to the baby? Did my firstborn inherit a gut with major deficits secondary to the 15-20 courses of antibiotics during my life (which of course did save my life a few times, including a large third-degree burn)? In light of the new data emerging from 16S rRNA sequencing technology, all these questions are being illuminated and even answered.

ONE THE POINT PODCAST: Antibiotics and obesity. Whether it’s possible that antibiotics plump up humans the same way they do animals, livestock. American farmers commonly feed their livestock grain laced with antibiotics because it makes bigger animals. Heavier. Fatter. So what about the antibiotics we humans take – for the ear ache, the strep throat, the sinus infection. Could those make us heavier? Fatter? No one argues that diet and exercise – or lack of it – come first. But could antibiotics be a scale-tipping X-factor in American obesity?

From Tom’s Reading List
New York Times: The Fat Drug – “In the last decade, however, scrutiny of antibiotics has increased. Overuse of the drugs has led to the rise of antibiotic-resistant strains of bacteria — salmonella in factory farms and staph infections in hospitals. Researchers have also begun to suspect that it may shed light on the obesity epidemic.”
Mother Jones: Can Antibiotics Make You Fat? –”Are we being exposed to tiny levels of antibiotics through residues in the meat we eat—and are they altering our gut flora? It turns out that the Food and Drug Administration maintains tolerance limits for antibiotic residue levels, above which meat isn’t supposed to be released to the public.”
Nature: Antibiotics in early life alter the murine colonic microbiome and [INCREASE] adiposity – “Antibiotics administered in low doses have been widely used as growth promoters in the agricultural industry since the 1950s, yet the mechanisms for this effect are unclear. Because antimicrobial agents of different classes and varying activity are effective across several vertebrate species, we proposed that such subtherapeutic administration alters the population structure of the gut microbiome as well as its metabolic capabilities.”

Intro of our Gut Characters

Here is the line up. They originate from life -- mom, diet, foods, dust bunnies, soil exposures, pets, kissing, hugging, licking doorknobs, etc.

Source: Ch 2 The Commensal Microbiology of the GI Tract
Manson, Rauch, Gilmore 2008

Intro of Some of What Our Gut Characters Do [Caveat: If We've Got Them]

They eat and poop, and we eat their secretions (vitamins, amino acids, SCFA (short chain fatty acids)) and then poop then out. Half of our dry poop in weight is in fact them. Their DNA exceeds ours by 150-times. Basically their microbiome complements our human genome with 150-fold more genes. Our Homo sapien-derived double helixes don't alter (much, debatable here). Their's is contrastingly plastic. They can sweep up lactose digestion or antibiotic-resistant plasmids or DNA from their environment or via microbial-sex. In evolution, they appeared first and will likely appear last... "Moreover, Bacteroidetes genomes appear to be highly plastic and frequently reorganized through genetic rearrangements, gene duplications and lateral gene transfers (LGT), a feature that could have driven their adaptation to distinct ecological niches. (Thomas et al 2011)" When diet resource allocation or subpopulation neighbors shift, so do their gene expression. They shift to the diet provided. Additionally, they can control our gene expression. Bacteroidetes thetaiotamicron (one of our vital omnivorous commensal symbionts, Roberfroid et al 2010) has been shown to turn on/off over 400 genes in the host, thus altering molecular architecture and body functions (Heselmans et al 2005). Indeed, our microbes may maketh the man, woman and child (and all animals, insects, plants).

Your response to fiber, RS, g banana/plantain flour, potato starch, probiotics and food all depend on what is filling your zoo cages, the pre-existing microbiota. Do you have vipers or voles? Electric eels or earthworms? Is your apex predator for the ecosystem EXTINCT. Does excessive flatulence blow you to the moon and clear the room?
Source: Fermentation of non-digestible oligosaccharides by human colonic bacteria
Gibson et al, 1996


No one who lives in an industrialized country is exempt. Broad spectrum, potent, synthetic antimicrobials can permanently damage the gut characters originally present many new studies besides research from Cho and Blaser's work. Jansson et al discovered that for a single 7-day course of antibiotics, gut testing showed that even TWO YEARS OUT WTF, THE SYMBIOTIC GUT CHARACTERS WERE GONE. The former fingerprint and diversity were extinct. Diversity means resilience -- the ability to bounce back and be robust against inevitable changes, shifts and hurdles. Michael Pollan, author and eater of all things fibrous and fermented, stated that after a 'precautionary' course of amoxicillin antibiotics prior to oral dental surgery, his intestinal commensal populations plummeted. The healthy blooms disappeared (Prevotella), replaced by noxious Proteobacteria (NY Times, My Best Friends are Germs 2013). Antibiotics and their drug-resistant DNA are also found in feedlot poultry, pigs, cattle, dairy and eggs. It is hard to escape these chemicals even if your dental surgeon or pediatrician are not eager to whip out their blank Rx pads.

Why Do Antibiotics Do So Much Damage and Can Lead to SIBO/SIFO?

Here is our gut below -- the  intestines are long and when splayed open have a large surface area equivalent to a high-piled terry cloth towel as large as a tennis court. The small intestines are 6-8 meters and colon ~1.5m. The small intestines are significantly longer: 4-5-times longer than the colon. This is where disease can begin. The interface between the outside world and our immune system and blood supply are separated by a single layer of cells. Many microbes actually attach to the intestinal cells in the small intestines (eg SFB, segmented filamentous bacteria) and eat from our bodies directly. These are the same organisms recently shown to prevent or cure T1D model in rodents. Most of the other gut characters live in the interior of the tube (lumen) or in the slime (mucous) along the length of the whole intestines.

Functional Ecology of the Small and Large Intestines
Source: Martin F P et al., J Proteome Res 2009;8:3464–74

The Russians have studied bugs far longer and in a more integrative manner when compared to Pasteur or other micro-phobes. Some of our best probiotics (Natren), yogurt strains and gut-healing protocols (GAPS) are from Russia. Korshunov et al has been studying how gut microbes can be protected with Bifido and Lactobacillus probiotics after chemotherapeutic induced dysbacteriosis (antibiotics). His studies revealed that SIBO (small intestinal bacterial overgrowth) occurs almost instaneously. He didn't study the mycobiome but it's not unfathomable that SIFO (fungal overgrowths) occurred as well. The small intestines are vulnerable because the role of the microbes there is one of protection, immuno modulation and symbiosis. Once the ecosystem is perturbed, all health can change. Extraction of nutrients is just one single function of the small intestines. The immune system lines the entire gut from mouth to anus, and particularly in the small intestines the job is intimate and foremost. When the ecosystem is complete, our commensals + gut do the job of:
--maintaining tight junctions
--prevent permeability
--stopping breaching or bacterial/fungal translocation to other organs or blood
--allowing tolerance for other commensals (Toll receptors, toll='fantastic' in German)
--decreasing allergic reactions and hypersensitivities (asthma, eczema (Heisenbug), food intolerances (gluten/dairy -- me), sinuses (Richard N), etc)
--tagging pathogenic strains, protozoa and parasites as foreign invaders for elimination
--secreting antimicrobial peptides (AMPs) to limit the growth of unsavory characters (the commensals are the 'apex predators' of the gut ecology)
--modulating mood and behavior by facilitating neurotransmitter and hormone synthesis (HPA-thyroid-genitalia-GUT axis)
--other than the spleen and bone marrow, create immune cells necessary for host health

There are a ton of factors for dysbiosis and unbalanced microbiota -- but antibiotics seem to be at the core, like here and here. Without commensal symbionts guarding the gut due to potent pharmaceutical antibiotics, the minor population of pests and vermin strains are left alone and un-mitigated. When there is plenty of food around, they will bloom or double overnight (or sooner). Korshunov et all called this 'contamination of the small intestines,' in other words SIBO/SIFO. It is indeed a common clinical feature in modern medicine as new human gut microbiome studies are revealing, yet largely undiagnosed with no modern medical solutions. The 7 steps for the ultimate gut health restores the commensal populations to a level that allows the gut to recover stability, diversity and optimal health.
[Characteristics of experimental antibiotic-induced dysbacteriosis]. [Article in Russian]
Martynov AI, Grinevich AS, Korshunov VM, Pinegin BV. Zh Mikrobiol Epidemiol Immunobiol. 1982 Jan;(1):48-54. 
Changes in the microflora of the large and small intestines in mice and guinea pigs after the oral administration of canamycin (a hardly absorbable antibiotic) and ampiox (an easily absorbable antibiotic) in different doses. The administration of these antibiotics in different doses (therapeutic, subtherapeutic and over therapeutic) led to an increase in the number of opportunistic microorganisms and the contamination of the small intestine by these organisms. These changes were also well pronounced in guinea pigs, normally having no enterobacteria. After the administration of the antibiotics was stopped, opportunistic microorganisms were gradually eliminated from the small intestine. The rate of decontamination depended on the administered dose of the antibiotic: the higher the dose was the longer the process of the decontamination of the small intestine lasted. An increase in the amount of opportunistic microbes in the large intestine and the decontamination of the small intestine occurred simultaneously with the decrease in the amount of lactobacilli and bifidobacteria in both the small and large intestines.  

OTHER MICROBIOME KILLERS = Atkin's, VLC, Ketotic, Low-Fiber Diets

There are many ways to kill your gut besides antibiotics. Dietary changes make profound changes to the gut. Diet is in fact one of the primary drivers of diversity and populations in the gut. As we know with Darwin and his finches, diet drives evolution of morphology and anatomy. The main gut characters that produce the anti-inflammatory BUTYRIC ACID and other SCFAs are also the same ones often associated with longevity in centanarians, better health and less fraility (Roseburia, F prausnitzii, Ruminococci, Bifidobacteria). The preferred diet of these butyrate-producers is fiber + RS. These 2 groups: (1) Ruminococci (Clostridium cluster IV) and (2) Roseburia (Clostridium cluster XIVa) munch on mostly RS, not inulin, other fibers or meat (eg other a bacteria eats bacteria world LOL). They do not appear too diversified in their culinary palate, yet they comprise the great majority of gut characters in healthy, disease-free, cancer-free individuals. Ruminococcus bromii assists all of the other gut inhabitants by being an enthusiastic and primary degrader of resistant starches, making carb by-products that can be utilized by others lower in the ecosystem. When these 2 groups 'bloom' in the colon, gut pathogen populations go down, gut inflammation is reduced and even horrific diseases completely and 100% reverse in new research trials (C diff antibiotic-induced colitis, UC, IBS, autism, etc).

Butyrate drops precipitously with a low-carbohydrate, low fiber/RS diet in a study by Duncan et al 2007. The anti-inflammatory gut species took nosedives (see below) -- Roseburia, F prausnitzii, Ruminococci, and Bifidobacteria. Subsequently, butyrate in the stools became only 1/5 to 1/4 of the maintenance diet amount. Butyrate trended with Roseburia (Clostridium cluster XIVa) populations. The prime fuel (70-80%) for colonocytes is butyrate from microbial fermentation (the next best is glutamine from skeletal muscle, then glucose). An energy crisis occurs when they are not supplied well.

Human gut characters prefer and need indigestible carbohydrates. Indigestible to Homo sapien but digestible to microbial amylases and a consortium of enzymes that break down all configurations of fiber and RS starches down. These butyrate-producers are not as carnivorous as other species (Bacteroidetes). This is likely from millions or perhaps I suspect billions of years of co-evolution where our gut species took advantage of the environmental bounty and abundance of plant fibers. The biomass of earth is 75% plant carbohydrates;  microbes blanket the earth, air and water.


Source: Karen Scott PhD ROWETT SLIDES
Duncan et al (2007) AEM 73; 1073-1078