Carl V. Crawford, MD

Carl, help me understand. You were talking about the structure, and you said it’s easy and hard. It seems as if the diversity of organisms is what trees are in our forest. The structure is what they do, and the resilience is how they do in drought periods or others. Is that a fair analogy?

Correct. It’s about how they come back. The simple part is you have this core. The more complex part is this diversity, and we don’t know what that true diversity should be from individual to individual. When we think about an organism like 

], we think about how it exploits the loss of biodiversity as well as some of the core functions. Two of the core elements are the firmicutes and the bacteroidetes. In the setting of destruction of the rainforest, for instance, if someone is exposed to an agent like antibiotics, you lose a lot of those core functions. Some of those core functions, as Dr Khanna mentioned, are immune regulation and colonization resistance. 

 will exploit that loss, and it will overgrow and begin to cause disease.

The concept is that in addition to when we talk about diversity results, the concept of richness within diversity, richness is the number of species that you have. Then we talk about diversity within richness and the fact that a lot of these species have redundant functions. It’s not that you’ve got 1 species or 1 bacterial species that has all the functions that are going to be not present with other species. There’s redundancy that we see among different bacterial species and different bacterial taxa. That redundancy is what keeps us healthier for a long period of time. It’s very difficult at times, and disrupts the microbiome in certain individuals, especially when you do have a richness along with the diversity because of the redundancy of functions out there. That makes it more complex, so you can’t attribute the entire disease mechanism to 1 bacterium because several bacteria may have similar functions with the redundancy that we see among the bacterial taxa.

What are the human conditions that result in disruption? You were talking about destroying the rainforest, which I like as an analogy. But what is it in the human condition that results in these changes? Either loss of species, which is part of it; loss of function; or loss of resilience? How does that occur? Where do we see that damage? We’ve mentioned antibiotic exposure. Is that the only 1 to worry about? Are there other things to worry about too?

There are lots of things to worry about. Antibiotic exposure is 1. How our microbiome is shaped is based on antibiotic exposure, but it starts at birth. It starts at the mode of delivery. It starts during childhood. It starts with environmental exposure during childhood and genetic conditions that we’re predisposed to. We could all probably rattle out diseases from head to toe that are impacted or associated with the gut microbiome. The big question is to distinguish between association and causation. In the prime example we understand the causation is primary and recurrent 

 infection. There are other disease entities, and I’ll name a few gastrointestinal [GI] diseases that are associated: inflammatory bowel disease, irritable bowel syndrome, nonalcoholic fatty liver disease, obesity. Then there are neuropsychiatric and other autoimmune diseases implicated.

It’s not just diseases and exposures. Even our diet plays a huge role in how we shape our microbiome. There are some superinteresting studies, primarily animal models, where animals are fed a traditional Western diet—high fat, high processed sugar—and compared with plant-based diets, which have fruits, veggies, high-end fiber. Those are completely different microbiomes. Plant-based diets tend to be anti-inflammatory, so they enrich for those health-promoting bacteria compared with Western diets, which are enriched for some of our poor-health-associated microbiota and pro-inflammatory microbes.

A superimportant question is to talk about the diet. That’s a big 1. Do you guys have any comments?

Dieting is important. If we think about 1 of the other functions that Dr Khanna had mentioned before was the metabolic functions of the microbiota. If we think about what fuels them, they’re fibers or complex carbohydrates. Depending on what kind of diet 1 consumes, you can shift the balance within days, within sight of the gastrointestinal tract. If we think about the role of fruits and vegetables, we’re always told that they have an important function in maintaining human health inside of the GI tract. When we move away from that, we start to think about all the ultra-processed foods and some of the high-protein and high-fat diets. It also shifts your floor away from the dominant species of the firmicutes as well as the bacteroidetes. Diet plays an incredible role in how we maintain our own health. It’s often overlooked because we tend to blame antibiotics all the time. Under the right antibiotic stewardship, it’s the appropriate thing to do, but there’s so much more that we can do going forward with how we manage our own health. The key is to maintain that biodiversity by fueling ourselves with the right complex carbohydrates and fibers in our diet.

For fueling ourselves with this healthier diet, with more complex carbohydrates, break it down on the clinician level. I’m just a doctor, so what does that mean for my patient? How do I explain that to my patient? What’s going to be different? We mentioned inflammation. Is there anything else, or is inflammation the key to that dynamic?

Both inflammation and overall health. A common question that clinicians get asked by patients is what can I do to improve my gut microbiome on a sustained level? Not for today, not for tomorrow, but how do I improve my microbial diversity or improve my gut microbiome? A lot of the work comes from Stanford from Dr Justin Sonnenberg’s lab, where they’ve looked at the effects of diet. Other centers have looked at that too. What I talk to my patients about is the age-old advice from my grandma: you’ve got to get at least 25 to 30 g of fiber in your diet or use the fiber supplement without simple sugars. If I look at a packet of something on the grocery store, and it says 8 g of added sugars, think 4 times before you buy it. That’s simple advice that I give to my patients. That works in a lot of patients, barring some diseases where you must use a low-fiber diet. For the vast majority of patients, it works very well. That age-old advice is what we’ve learned over 10 or 15 years of microbiome research, sparing FMT [fecal microbiota transplantation] for 

 infection, is how do you change or maintain a healthy microbiome is the advice that I give my patients.

Listen to your grandmother. That’s what I just learned. That’s fantastic. Kelly, any comment?

I agree. Although it can be difficult to get patients to change their diet, it’s a simple intervention that we know can improve not only our microbiome but also our overall health. When we talk about fiber, you’ll hear the term 

. These are our substrates of the microbes that essentially act as food for the microbes, so that’s something that you can talk to your patients about because they may hear that term. We hear a lot about probiotics, but prebiotics are these dietary substrates that can help feed the microbes in the gut.

: If I’m understanding this correctly, the prebiotic is what we’re feeding our gut, almost like fertilizer for our garden.

Then the probiotics are the plants we’re putting in our gardens so you can supplement with the probiotics. Does that fit?

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Shared insight on how disruption of the gut microbiome may occur based on antibiotic exposure, environmental factors, and diet.

C Difficile Infection: What Causes Disruption of the Gut Microbiome?

 titled “The Relationship Between the Gut Microbiome and Management of 

.” I’m Dr Jamie McKinnell, from the Lundquist Institute at Harbor–UCLA Medical Center [in Los Angeles, California]. Joining me in this discussion are my colleagues Dr Carl Crawford, an assistant professor of clinical medicine at Weill Cornell Medical College in New York; Dr Sahil Khanna, a professor of medicine at the Mayo Clinic in Rochester, Minnesota; and Dr Kelly Reveles, an assistant professor at The University of Texas at Austin College of Pharmacy.In this discussion, we’re going to investigate the role between the microbiome and 

]. It starts logically by establishing the role of the gut microbiome and the impact of dysbiosis in health care.

For the first question, I’ll turn to you, Carl. What’s the gut microbiome, and what does it consist of?

That’s an easy and a complex answer at the same time. 

 refers to the collection of all the bacteria that are inside the human organism. If we think about how it pertains to 

 infections, we can focus on the microbiota of the gastrointestinal tract. 

 refers to all those bacteria and organisms as well as their genomes. We tend to use them interchangeably. We may say 

 to refer to the bacteria, and we also use the term 

, so it’s important to make a distinction between the 2. But for the most part, we’ll use 

The microbiome or the microbiota are impressive. Inside the gastrointestinal tract, there are 100 trillion kinds of organisms floating around and out of those and more than 35,000 bacterial species. These bacterial species will fit into certain kinds of phyla, with firmicutes and bacteroidetes being the 2 major phyla. There are several other phyla as well, into which almost 90% will fit into most of those bacteria. That’s just bacteria that we’re talking about, but we have to also remember all of the other kinds of organisms that live with inside of the gastrointestinal tract, such as yeast, fungi, protozoa, fungi, and so forth, as well as the viruses. It’s pretty impressive when we talk about the microbiome because we’re referring to everything that’s inside the gastrointestinal tract.

It’s almost like a forest of different organisms. There are lots of different components in there. Is there a function of this stuff? Is there a purpose to having this?

There are a lot of functions. Back in the day, we were thinking that these microbes might just be pathogens. They’re causing human disease. But over the last decade or 2, we’ve understood that these microbes have a 2-way symbiotic relationship with the human body. There’s a lot of function out there, not only from digestion but from production of lots of vitamins and short-chain fatty acids the body needs, harnessing energy from different components of food that we can digest ourselves. From that to immune regulation, we understand that these microbes are not just sitting inert in our bodies but constantly interacting with the lining of the colon, leading to systemic and local immune regulation and prevention of autoimmune diseases. More important, colonization resistance, is a big function of the gut microbiome. If you have a healthy, diverse microbiome, you have a property called colonization resistance, meaning this gut garden or Amazon rain forest that lives inside your large and your small intestine does not allow colonization and infection from other pathogenic organisms, notably 

 infection. We see this as a big problem as this colonization resistance goes down.

Let me make sure I’m understanding this correctly. This Amazon or garden that we’re talking about will help you with digestion? So the organisms will help break down the food we eat. Is that making sense?

 Not only that, but the healthy garden helps your immune system regulate what’s happening in the gut, keeps things stabilized like a healthy garden would. Explain to me more about this invasion of other bacteria like this. For lack of a simple term, 

 is the bad bug that you chose to talk about. How does that work? How does that impact things? What’s the protection mechanism?

In simple terms, when you have a complex gut microbiome or a diverse gut microbiome, they have functions, what we call complex metabolism. They interact with one another, produce lots of mediators, and help convert some of the primary bile acids in our body to secondary bile acids. When you disrupt this balance of gut microbiome with risk factors like antibiotics and hospitalizations; uncontrollable risk factors, like age over 65; or other comorbid conditions, which we’ll go into later in our discussion, then the complex metabolism goes into what we call simple metabolism. The diversity goes down, the metabolism goes down, and the number of metabolites that they produce goes down. There is less conversion from primary to secondary bile acids. In simple terms, 

 finds an empty home where it can germinate from the spore form to the vegetative form and cause disease.

 Kelly, I’ll turn to you on this 1. When we’re looking at the structure of this garden in the intestines, is there a way to describe that or explain how that would help protect you from these sorts of things? Is there a structure that can help us understand that concept?

Yes, absolutely. We’ve had several very large-scale projects that have attempted to identify what constitutes a healthy microbiome, and it’s not that simple. Some projects, like the human microbiome project, took samples from healthy volunteers to describe what diversity and what community structure is associated with health. What they found is very interesting. We have variability in our microbiome across individuals, and no 2 microbiomes are the same. It’s like a fingerprint. We see the core microbiome mostly maintained across humans, but there’s significant variability, especially at the lower taxonomic levels.

What constitutes a healthy microbiome is a hard question to answer. Scientists have proposed several factors that would make a healthy microbiome. One is having a core structure that’s going to provide all the housekeeping genes and the production of compounds that are necessary to support human life. The next is having high microbial diversity. That typically refers to the total number of bacterial taxa within the ecosystem. With increased diversity, you have increased functional capacity and functional redundancy. If you lose some beneficial microbes, you still maintain that core function. The last marker of health is stability and resilience of the microbiome, which refers to the ability of the microbiome to recover once it’s been disrupted. Those are our core components of what constitutes a healthy microbiome.

Opening their discussion on Clostridioides difficile, experts provide an overview on the gut microbiome and colonization resistance.

Carl V. Crawford, MD

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