Last Updated on February 15, 2017 by Patricia Carter

SUMMARY:  Antibiotic resistance is invisible to most of us until you, a family member, or an acquaintance acquires such an infection.  You can check out the slides below to see state by state, US Antibiotic Resistance Risk and state Antibiotic Use.  Perhaps the most reasonable mechanism to prevent antibiotic need in the first place, is explained in the post PRESERVE & RESTORE LOSS OF MICROBIOME DIVERSITY IS AGGRESSIVE PREVENTATIVE MEDICINE.  These concepts are especially important given that the average American has lost 1/3 of their microbiome diversity, as estimated by Dr. Maria Gloria Dominguez-Bello as seen on this interview for the film “Microbirth.”   Another study estimates 1 in 4 have 40% less bacteria (see This Danish study, or read the scientific article here).  

This post teaches that the WHO, and the United States, this month took their first steps to recognize the invisible threat of antibiotic resistance, which missed the microbiome connection.  You can comment to the US Request for [Microbiome] Information and help bring this to the forefront.  Of course their goal of providing alternate antibiotics to wage the war on antibiotic resistance is wrought with difficulties due to the antibiotic pipeline:

• About 2000, numerous companies withdrew from antibiotic manufacturing, and the number of new antibiotics in development dropped from dozens to three. 
• And the cost:  The report, Review on Antimicrobial Resistance, estimates that we need 15 new antibiotics over 10 years, of which four would have to be truly new formulas (two broad-spectrum, or capable of attacking a number of bacteria, and two narrow-spectrum), while the remainder could be incremental improvements on existing formulas. It estimates the effort would require between $16 billion and $37 billion over that decade—huge amounts, but as the report points out, the global market for antibiotics now earns $40 billion every year, while resistance costs just the United States $20 billion per year in excess healthcare costs. Read more here and here, and the problem of the antibiotic pipeline, if interested.

⇒⇒Also covered last in this post, for background, is who actually lives in your gut and why it is difficult to know who truly is living in your gut. There are four dominant phyla that comprise the intestinal commensal microbiota of humans. These include Firmicutes and Bacteroidetes, which normally account for >90% of the bacterial populations in the colon, as well as Actinobacteria and Proteobacteria.  The intestinal commensal populations are altered when comparing certain disease with non-disease.  In addition, when some of these gut players are reduced, skewed, or absent there is health ramifications even beyond disease —for example, acetaminophen is toxic to the liver. 

WHO commits unanimously to tackle antibiotic resistance

The annual World Health Assembly  is the meeting of health minsters from 194 countries that serves as the decision-making body for the World Health Organization (WHO). For the first time, the global crisis of antibiotic resistance was addressed; the delegates committed unanimously to tackling the issue; WHO Director-General Dr. Margaret Chan’s welcome speech, May 2015:

“This is a unique time in history where economic progress is actually increasing threats to health instead of reducing them… As the century progressed, more and more first- and second-line antimicrobials failed. The pipeline of replacement products ran dry, raising the spectre of a post-antibiotic era in which common infections will once again kill. A draft global action plan on antimicrobial resistance is on your agenda. I urge you to adopt it.”

Five components of the WHO plan (see details here, or here for WHO pdf, or this article, World Health Organization Vows To Combat Drug Resistance):

1. “Improve awareness and understanding of antimicrobial resistance,”  Include instruction on resistance in school curricula and in professional training for healthcare, veterinary and agricultural personnel;
2. “Strengthen surveillance and research” by rapidly gathering environmental and diagnostic data on resistant organisms and support studies of costs of resistance and alternatives to antibiotics;
3. “Reduce the incidence of infection” by improving hygiene in healthcare and increase the use of vaccines to prevent infections;
4. “Optimize the use of antimicrobial medicines” by reducing over-prescription and uncontrolled over-the-counter sales, and improving rapid-result diagnostic tests that make sure the correct drugs are prescribed;
5. “Ensure sustainable investment in countering antimicrobial resistance, or put another way, develop the economic case for sustainable investment,” persuade pharmaceutical companies to return to making antibiotics and guaranteeing that low-income countries will have adequate access to drugs.

In an unrelated action, in May, 2015, the White House asked for input (by June 15) on the future of microbiome research.  Read here for details of how to summit your comment(s), but the summary of the Request For Information (RFI) is:

Advanced sequencing technologies have illuminated vast networks of microorganisms that drive essential functions in all environments on Earth. The study of these communities of microorganisms, or microbiomes, is nascent, and the potential of microbiome research has only begun to be tapped. Primary to achieving this potential is a functional understanding of microbiomes, which would be greatly advanced by addressing fundamental questions common to all fields of microbiome research; developing platform technologies useful to all fields; and identifying gaps in training or fields of research that should be addressed. The Office of Science and Technology Policy (OSTP) is interested in developing an effort to unify and focus microbiome research across sectors. The views of stakeholders—academic and industry researchers, private companies, and charitable foundations—are important to inform an understanding of current and future needs in diverse fields.

The purpose of this RFI is to solicit feedback from industry, academia, research laboratories, and other stakeholder groups on both the overarching questions that unite all microbiome research and the tools, technologies, and training that are needed to answer these questions. OSTP is specifically interested in information that corresponds to the mission statements of multiple Federal agencies, private sector interests, and current White House Policy Initiatives. In particular, respondents may wish to address the following topics:

• What are the most pressing, fundamental questions in microbiome research, common to most or all fields?

• Over the next ten years, what are the most important research gaps that must be addressed to advance this field?

• What tools, platform technologies, or technological advances would propel microbiome research from correlative to predictive?

• What crucial types of scientific and technical training will be needed to take advantage of harnessing the microbiome’s potential?

• What fields of microbiome research are currently underfunded or underrepresented?

• What specific steps could be taken by the federal government, research institutes, universities, and philanthropies to encourage multi-disciplinary microbiome research?

• Is there any additional information, not requested above, that you believe OSTP should consider in identifying crucial areas of microbiome research?

This RFI is in stark contrast to:  White House outlines plan to fight antibiotic-resistant bacteria, which totally misses PRESERVE & RESTORE LOSS OF MICROBIOME DIVERSITY IS AGGRESSIVE PREVENTATIVE MEDICINE which is likely the most reasonable mechanism to prevent antibiotic resistance in the first place:  

Antibiotic resistance is invisible but its microbiome decimating effect is here to stay.

Check out the slides below to see your states antibiotic use and risk of antibiotic resistance.  -Center for Disease Dynamics, Economics & Policy

From the White House:

More than two million Americans develop antibiotic-resistant infections each year and about 23,000 die as a result. Ineffective antibiotics have to be replaced with new drugs and antibiotic alternatives are also needed in veterinary medicine. The five-year plan released on Friday focuses on slowing the emergence and spread of resistant infections;

1. strengthening bacterial surveillance efforts;
2. developing new tests to quickly identify dangerous bacteria;
3. developing new drugs to fight the so-called “superbugs,” and
4. working more closely with international partners to achieve these goals.

President Obama’s fiscal year 2016 budget proposal would nearly double federal funding for the fight against antibiotic resistance to $1.2 billion. ‘It’s a good plan. Now we need to carry it out,” President Obama said. “We can better protect our children and grandchildren from the reemergence of diseases and infections that the world conquered decades ago, but only if we work together, for as long as it takes.”

Source: White House outlines plan to fight antibiotic-resistant bacteria, http://www.mcclatchydc.com/2015/03/27/261227/white-house-outlines-plan-to-fight.html

Source: http://www.cddep.org/sites/cddep.org/files/resistance_map_inforgraphic.jpg

Source: Antibiotic Use and Resistance in the US at a Glance: 1999-2010, http://www.cddep.org/tool/antibiotic_use_and_resistance_us_glance_1999_2010

Source: The Antibiotics Problem in Meat http://www.theatlantic.com/health/archive/2015/03/the-next-big-antibiotic-resistance-threat/388430/?utm_source=SFTwitter

Source: Who Let The Cows Out? http://sustainablog.org/2011/03/cattle-ranching-us/

Now for background for those new to Microbiome… First, define it to better understand competitive crowding out concepts

It was ~2001, when the initial sequence of the human genome shockingly and dramatically cut the number of human genes that was expected to be found which was then estimated to be about 100,000 human genes.  Instead, we incredulously learned that humans have fewer human protein-coding genes than nematode worms or even the water flea, which has 31,000 genes. Despite this, the idea that more complex organisms require more genes was not debunked since the piggyback microbiome studies, still ongoing, is unveiling the human microbiome.   

Recall the pearls of our first meeting, that the microbiota includes the organisms termed: bacteria, arachea, viruses, and eucarya. The microbiome by definition, includes the collection of ALL of the genes contained in the human microbiota; in other words, it is the cumulative genes of bacteria, arachea, viruses, and eucarya, and that is on the order of 2 to 20 million microbial genes vs only 20,000 human genes. In fact, the final number of true protein coding genes in the human genome (i.e., such genes have DNA that carries the code necessary to make a molecular chain called a polypeptide; these chains link together to form proteins and so are the bricks and mortar out of which all organism are constructed) may lie closer to 19,000 than to 20,000, see here for the study, and here for full text of the study.  

It is this vast amount of microbial genes in humans (2 to 20 million) that performs functions necessary that our human genes cannot.

Big number magnitudes can be confusing; recall these slides from our early discussions:

 Who actually is in our gut microbiome; why are they there?

The majority of the intestinal bacteria belong to two phyla, the Bacteroidetes and the Firmicutes (Mariat et al. 2009).  -Intestinal microbiota in human health and disease: the impact of probiotics

Insights into what these phyla do was presented in the class, Gut Microbiome Gut Check: Exploring the Microbiome, 2014,  instructors Professor Rob Knight, Dr. Jessica L. Metcalf, Dr. Katherine R. Amato:

1. Some of the  fermicutes and bacteroids role is to digest food, produce vitamins, and metabolize drugs. The composition of the microbiome determines how drugs are metabolized and if medications are toxic or not to the liver – an example is acetaminophen and liver toxicity: you need a particular group of sulfur reducing species in the gut to not have acetaminophen toxic in the liver.   “The metabolism of drugs by both intestinal bacteria and further by enterocytes leading to their systemic absorption deserves further attention and may provide valuable insights into pre-systemic drug metabolism, delivery, and toxicity… sulfation of acetaminophen in the liver competes with sulfation of p-cresol, a metabolite exclusively generated by gut bacteria… A number of other drugs that are mainly metabolized through phase II sulfation pathways and could potentially be presenting with similar issues are minoxidil, tamoxifen, and apomorphine, among others.” -The Gut Microbiome and Pre-systemic Metabolism: Current State and Evolving Research.
2. The microbiome can steal genes from our food to help us digest it better.  One example is the Japanese gut… it has genes that were transferred from consumption of food, namely fermented live probiotic seaweed.  Incidentally, the US coverage is misleading; this is not about sushi, it’s about the seaweed called “nori” which is fermented and teeming with live bacteria. -Bacteria of the human gut microbiome catabolize red seaweed glycans with carbohydrate-active enzyme updates from extrinsic microbes.  

It was Jeffery Gordon’s lab in St Louis that found no genes for degrading seaweed in the microbiome of healthy Americans:

Marine algae – seaweeds – contain special sulphur-rich carbohydrates that aren’t found on land. Fortunately, bacteria  aren’t just limited to the genes that they inherit from their ancestors. They can swap genes between individuals as easily as we humans trade money or gifts. This ‘horizontal gene transfer’ means that bacteria have an entire kingdom of genes, ripe for the borrowing. All they need to do is sidle up to the right donor. And in the world’s oceans, one such donor exists – a seagoing bacterium called Zobellia galactanivorans…is a seaweed-eater.

When hungry diners wolfed down morsels of these algae, some of them also swallowed marine bacteria. Suddenly, this exotic species was thrust among our own gut residents. As the unlikely partners mingled, they traded genes, including those that allow them to break down the carbohydrates of their marine meals. The gut bacteria suddenly gained the ability to exploit an extra source of energy and those that retained their genetic loans prospered…People might only gain the genes after eating lots and lots of sushi but Hehemann has some evidence that they could be passed down from parent to child. One of the people he studied was an unweaned baby girl, who had clearly never eaten a mouthful of sushi in her life. And yet, her gut bacteria had a porphyranase gene, just as her mother’s did… This result reinforces the need to conduct a broad and culturally diverse survey of who harbours what microbes.” -Eating seaweed: Japanese gut microbiome bacteria are not like mine. I do want to note that one prominent microbiome researcher, Jonathon Eisen, UC Davis, still is not yet convinced of this whole gene stealing concept.  I’ll add this reference once I find it in my resource links.

In short, we are only now discovering the breath and capability of the microbiome: “You can not disregard the microbiome; that is like throwing away the brain and saying it is useless.” –Professor Rob Knight, week 1 class, Gut Microbiome Gut Check: Exploring the Microbiome, 2014

Phylum bacteria is further broken down into classes

Intestinal microbiota in human health and disease: the impact of probiotics further explains: The phylum Bacteroidetes consists of three classes, of which the class Bacteroidetes, containing the well-known genera Bacteroides and Prevotella, is probably the most well studied.

The Firmicutes is currently the largest bacterial phylum, which contains more than 200 genera. The majority of the Firmicutes detected in the GI tract fall primarily into two main groups,

• the Clostridium coccoides group (also known as Clostridium cluster XIVa) and the
• Clostridium leptum group (also referred to as Clostridium cluster IV) ( Collins et al. 1994; Mariat et al.  2009).
• Both groups contain members of the genera Clostridium, Eubacterium and Ruminococcus that are taxonomically polyphyletic.

In addition to the two phyla Bacteroidetes and Firmicutes, other phyla such as Proteobacteria, Actinobacteria, Fusobacteria, Spirochaetes, Verrucomicrobia and Lentisphaerae, have been detected (Rajilić-Stojanović et al. 2007; Zoetendal et al. 2008).-Intestinal microbiota in human health and disease: the impact of probiotics

The Microbiome: What it Means for Medicine, British Journal of Medical Practice, Dr. Emma Allen-Vercoe, et.al, Editorial:

“It is impossible not to notice the enormous surge in human microbiome research currently underway around the world. For the past decade, new molecular methods have started to unlock the secrets of this unseen universe, and suddenly it is dawning on us that human individuals are not the dominant life-form in the symbiosis of our existence. It is often quoted that humans are 10% human and 90% microbial when a comparative count of cell numbers is taken into consideration,[1] but perhaps more astonishingly, it is now clear that our human microbiome, the collection of genes encoded by our microbial passengers, is at least one hundred-fold greater than our own genome. The diversity of the human ‘microbiota’ is enormous, with approximately 500–1000 species existing in our gastrointestinal tracts alone. We are the vessels for this community of microbes (including bacteria, viruses, and yeasts) living on us and in us, and as we start to unravel the multitude of roles that this microbiota fulfills, it is becoming clear that our microbes play a far more relevant and important role in the maintenance of our health than we have ever stopped to consider before.[2] Therefore, it stands to reason that we are at a pivotal point in our attitude towards microbes in a medical context.”

Relevancy of the ‘omics’ technology:

2008 marks about the time researchers began to stop examining the genome of an individual bacterial strain that had been grown in a laboratory; technological advances such as the metagenomic approach enabled examination of the collection of genomes derived from microbial communities sampled from natural environments and relevance of community function was appreciated.   The term ‘functional redundancy’, takes on a new definition as omics shows the capacity for multiple microbes within the same ecosystem to carry out the same tasks:

“These microbes have recently been revealed to have functions beyond their clear role as niche dwellers that competitively exclude pathogens. These functions vary widely across body sites and between resident microbes. The microbiota is known to ‘educate’ the immune system, steering it away from needless attacks on commensal microbes such that its efforts can be concentrated on real threats. The gut microbiota also plays a role in breakdown of complex dietary compounds, provision of key molecules and micronutrients essential to health (such as B vitamins), and even makes (as yet poorly understood) contributions to mood, behaviour and sleep patterns.”-The microbiome: what it means for medicine, British Journal of Medical Practice, Dr. Emma Allen-Vercoe, et.al, Editorial.  

“The microecology of the healthy human microbiota is highly diverse and carries ‘functional redundancy’, the capacity for multiple microbes within the same ecosystem to carry out the same tasks. Consequently, it has a moderate ability to withstand antibiotic-inflicted stress and to recover from it. However, because we all have a microbiota that is uniquely shaped by our environment and by other factors that are less well understood, this exclusivity means that it is not yet possible to predict individual responses to antimicrobial exposure. Furthermore, evidence indicates that disturbance of our microbial ecosystems at critical points… may result in long-lasting damage that is not easily reversible and may lead to later susceptibility to chronic diseases such as inflammatory bowel disease, asthma, atopy, diabetes, obesity, and even autism.–The microbiome: what it means for medicine, British Journal of Medical Practice, Dr. Emma Allen-Vercoe, et.al, Editorial.  

There are numerous proposed mechanisms through which diet could influence the incidence of disease including direct dietary antigens, altering the gut microbiome, and affecting gastrointestinal permeability. Role of diet in the development of inflammatory bowel disease. It is very challenging to identify the components of the luminal content that drive the underlying inflammation.  Luminal content is a complex mixture of bacteria, other microorganisms, digested food content, and the metabolic products of digestion of food components by the host and microbiota. Furthermore, these components are not independent of each other. –Diet and Inflammatory Bowel Disease, Review of Patient-Targeted Recommendations, Clinical Gastroenterology and Hepatology, 2014.html pdf  Realize with a permeable gut, the above contents leak stimulating the immune system and this mechanism is behind many chronic diseases.