The study, published in the Journal of Clinical Endocrinology & Metabolism, found that patients with hypothyroidism had more than double the risk of developing SIBO compared to those with normal thyroid function. The risk was even higher in patients with autoimmune thyroid disease, where the body’s immune system attacks the thyroid gland, but appeared lower in those receiving hormone treatment for the condition.

The findings offer insight into how specific changes in gut bacteria could contribute to disease beyond the gastrointestinal system.

“Studies like this remind us how interconnected the body’s systems are and the important role the microbiome plays in overall health,” said endocrinologist Ruchi Mathur, MD, director of Clinical Research and Clinical Operations for the Medically Associated Science and Technology (MAST) program and the study’s corresponding author.

Mathur sat down with the Cedars-Sinai Newsroom to share key takeaways from the investigation.

What did the study reveal about gut bacteria activity in patients with thyroid disease?

We found that patients with hypothyroidism had different patterns of bacteria in the small intestine compared with those without thyroid disease. In patients with both hypothyroidism and SIBO, we found Klebsiella bacteria dominated rather than the bacterial groups we more commonly see in SIBO. This suggests hypothyroidism may not only increase the risk of SIBO but may also influence the types of bacteria involved.

Could this mean a more severe form of SIBO?

Possibly, more research is needed to confirm this. Previous Cedars-Sinai research has shown that Klebsiella can disrupt the balance and interaction of bacteria in the small intestine more than some other bacterial groups.

How does thyroid hormone treatment affect SIBO risk?

One of the more interesting findings of our study was that patients receiving levothyroxine to treat their thyroid condition appeared to have a lower risk of developing SIBO compared with untreated patients. It is possible that thyroid hormone replacement affects gut motility, which may help reduce bacterial overgrowth in the small intestine. More research is needed, but the finding suggests thyroid treatment may influence digestive health in ways we are only beginning to understand.

Why is it important to study the small intestine directly?

Many microbiome studies rely on stool samples, but the bacteria found in stool can differ significantly from those living in the small intestine. The small intestine plays a central role in digestion, metabolism and hormone function, so studying it directly gives us a much more accurate picture of what may be happening in diseases such as hypothyroidism and SIBO. It also may help researchers identify future therapeutic targets.

What can physicians and patients learn from these new insights?

It is important to recognize the relationship between hypothyroidism and SIBO and address symptoms accordingly. If a patient with hypothyroidism is complaining of gastrointestinal symptoms such as bloating or altered bowel habits, their care team should consider evaluating them for SIBO. Likewise, if a patient presents with bloating, constipation or unexplained gastrointestinal symptoms, thyroid testing may also be appropriate.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

Concerned the developmental decline could be signs of a neurological disorder, the family’s pediatrician flagged the issue to Dylan’s parents, Michelle Tang and Ron Sonnenberg. Dylan was admitted to Cedars-Sinai Guerin Children’s, under the care of pediatric neurologist Jeffrey Swarz, MD, and pediatric endocrinologist Bahareh Schweiger, DO, MPH.

A battery of tests revealed two critical diagnoses: Dylan was severely hypoglycemic, and she was experiencing infantile spasms, a form of infantile epilepsy classified as a neurological emergency.

“The brain requires sufficient glucose to function, and hypoglycemia frequently leads to strokes in infants like Dylan,” said Swarz. “It was later determined that she had the ABCC8 mutation, causing congenital hyperinsulinism. The infantile spasms were likely related, but we can’t say for sure.”

Dylan is one of more than 350,000 children and adolescents affected by insulin-related illnesses, including diabetes, in the U.S. November marks National Insulin Awareness Month and World Diabetes Day.

The news from the doctors terrified Tang and Sonnenberg. “We were not very optimistic at that point,” Sonnenberg said. “We were devastated when we first learned her diagnosis.”

Hyperinsulinism occurs when the pancreas produces too much insulin, resulting in potentially life-threatening, low blood sugar levels. The condition can also signal health challenges that extend into adulthood, due to the risk of brain damage from recurrent hypoglycemia.

“If not managed adequately, there can be long-term challenges, including ongoing developmental delays and learning deficiencies,” Schweiger said. “With proper medical intervention, many children achieve reasonable metabolic control and normal functionality.”

Early on in Dylan’s treatment, she had to endure steroid injections, twice a day, to manage her symptoms. “She was in and out of the hospital,” said Tang. “We spent New Year’s Eve in the hospital that first year, because Dylan had to be monitored for adverse reactions to the steroids. But it was a small price to pay for us, as parents.”

Today, Dylan’s glucose levels are carefully managed via her gastrostomy tube feedings. Overnight, continuous feeds help maintain glucose stability. Schweiger said Dylan will still require lifelong multidisciplinary care, due to her medical history, but added, “Her prognosis is great, and her hyperinsulinism is showing signs of becoming less severe, with no recent spasms to report.”

Now, two years after Dylan’s diagnosis, the Tang-Sonnenberg family is celebrating new milestones.

“Dylan’s motor skills are improving—she’s walking with help and pulling herself up,” Tang said. “She’s very social with other children and is showing progress with speech and language skills.”

The family says it has Cedars-Sinai to thank for it all, including a new sense of hope for the future. “We are eternally grateful,” Sonnenberg said.

Read more in Cedars-Sinai Discoveries: Innovation and Collaboration in Pediatrics at Cedars-Sinai Guerin Children’s

The lifetime honor recognizes Melmed, the Helene A. and Philip E. Hixon Distinguished Chair in Investigative Medicine, for his decades of significant contributions to the field of endocrinology, particularly for revealing biological processes involved in pituitary tumorigenesis and control of hormone production and action.

“Over the course of decades, Dr. Melmed has been an outstanding physician-scientist and a true leader in the field of endocrine biology as evidenced by research from his laboratory that has led to fundamental and translational advances, a commitment to educating the next generation of investigators, and leadership of numerous professional societies,” said Peter L. Slavin, MD, president and CEO of Cedars-Sinai. “He is truly deserving of this honor and recognition.”

Melmed will be welcomed into the association during the annual Fellows Forum in Washington, D.C., on Saturday, June 7.

“I am both humbled by and grateful for this peer-recognized honor, which reflects the longstanding dedication of my laboratory team, including students, postdocs, fellows and colleagues, all engaged in the pursuit of new knowledge underpinning normal and disordered function of the pituitary gland and its hormones,” Melmed said. “The pituitary is indeed the master homeostatic conductor for maintaining cell communication, as well as developmental, metabolic, growth and reproductive homeostasis. I am proud of our contributions to furthering therapeutic advances for our patients with pituitary disorders.”

Melmed’s National Institutes of Health-funded laboratory and pituitary clinic have contributed to alleviating adverse impacts of pituitary failure and pituitary tumors, including prolactinomas, acromegaly, Cushing’s disease and non-secreting adenomas.

Melmed has been a leader at Cedars‑Sinai for more than 40 years and has been the health system’s chief academic officer since 1998. He has trained more than 80 physicians, scientists and graduate students who hold leading positions in academic endocrinology worldwide. He is an editor of Williams Textbook of Endocrinology, edits The Pituitary and was editor-in-chief of Endocrinology and of Pituitary.

Melmed is an elected member of the Association of American Physicians and American Society for Clinical Investigation. He served on the Endocrine Society Council, as president of the International Society of Endocrinology and as president and a founding member of the Pituitary Society. Additionally, he is a member of the California Institute for Regenerative Medicine’s Independent Citizens’ Oversight Committee.

Melmed is a master of the American College of Physicians and has been honored with the Pituitary Society’s Lifetime Achievement Award, the Transatlantic Medal and Dale Medal from the Society for Endocrinology, the Endocrine Society’s Clinical Investigator Award and Outstanding Scholarly Physician Award, and the Royal Society of Medicine’s Clinical Endocrinology Trust Medal.

He earned his medical degree with distinction from the University of Cape Town, South Africa, and is a diplomate of the American Board of Internal Medicine, certified in endocrinology and metabolism.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

“Patients are not usually hospitalized because of diabetes, but because of another condition, so they are not admitted in one specific area of the hospital,” said Roma Gianchandani, MD, medical director of Diabetes Quality and vice chair of Quality and Innovation at Cedars-Sinai. “It’s important that specialized protocols and programs that prioritize diabetes care are available hospital-wide.”

Diabetes affects how the body turns food into energy, sometimes causing high blood sugar, also known as high blood glucose or hyperglycemia. Hospitalized patients who do not have diabetes also can develop high blood glucose—a condition called stress hyperglycemia—which can lead to poor outcomes.

Gianchandani, an endocrinologist, along with Cedars-Sinai Fellow Margaret Wei, MD, authored a paper published in Annals of Internal Medicine about hospital best practices for managing high blood glucose. Gianchandani leads the medical center’s interdisciplinary efforts to improve outcomes for hospitalized patients with diabetes or stress hyperglycemia.

The Cedars-Sinai Newsroom spoke with Gianchandani about these efforts.

What does inpatient diabetes management involve?

Hospitals should use diabetes experts to help patients reach their safest blood sugar levels, which is shown to shorten hospital stays and improve outcomes. There is no single best diabetes team format—institutions should do what works with their own processes—but the most effective teams use experts to manage a patient from admission to discharge and conduct post-discharge follow-ups.

At Cedars-Sinai, we have a heterogeneous team format that includes endocrinologists (faculty and private), endocrinology trainees, diabetes educators, pharmacists and information technologists with a focus on hospital diabetes management. We also are increasingly integrating diabetes technology into our medical ordering system to help non-diabetes practitioners better manage their patients. Our diabetes clinicians are familiar with the latest diabetes technologies and increasingly used devices like continuous glucose monitors.

What’s new about Cedars-Sinai’s approach to inpatient diabetes care?

Collectively, our teams have prioritized several key components that have been shown to improve outcomes. We have standardized care by creating nursing policies for monitoring blood sugar and administering insulin, as well as procedures for addressing low blood sugar.

We are at the forefront of technology integration. We are using a computerized tool to support nurses administering insulin through an IV—the nurse simply enters the patient’s blood sugar, and the tool calculates how much insulin to give without the nurse needing to make that complex calculation. We also have insulin pumps and glucose sensors integrated into the patient’s electronic medical record, so we can monitor patients’ blood sugar as needed after they go home. This would allow us in the future to follow up if the patient needed to adjust their insulin dosage.

I am proud to share that Cedars-Sinai also has a pharmacist surveillance program. A pharmacist reviews abnormally high and low blood sugar levels every morning and reaches out to patients’ physicians if medication orders need to be adjusted.

We also are evaluating predictive algorithms using artificial intelligence tools for managing diabetes. For example, monitoring patients over time, an algorithm could predict when their blood sugar might go too high or too low.

How does Cedars-Sinai educate diabetes patients in the hospital?

A hospital stay provides a unique opportunity for diabetes education. We have several educators in the hospital as well as outpatient educators. Our inpatient educators interact with patients during admission to address any gaps in care they may be experiencing, and they strive to ensure patients go home with the resources they need to maintain safe blood sugar levels.

Read more on the Cedars-Sinai Blog: How to Prevent Insulin Resistance and Keep Blood Sugar Levels Steady

Melmed received the inaugural Outstanding Pituitary Society Leadership Award on June 2 during the Pituitary Society Biennial Membership Forum, which took place concurrently with the Endocrine Society 2024 medical conference in Boston. A groundbreaking investigator and leader in the pituitary field for more than 40 years, Melmed has been a leader in both research and education for The Pituitary Society, and he founded its flagship journal, Pituitary.

“Dr. Melmed, through his passion and intellect, has been a leader in developing novel therapeutics, innovative research fields, and educational paradigms for endocrinologists and neurosurgeons internationally,” said Larry Katznelson, MD, vice dean of Medical Education at Cedars-Sinai and current president of The Pituitary Society. “He has mentored scores of researchers and clinicians who are leaders in neuroendocrinology internationally, and we are honored to highlight his many research and education achievements with this first-ever award.”

Melmed, distinguished professor of Medicine, has led the discovery and application of novel treatments for endocrine tumors through his National Institutes of Health-funded laboratory. He has led pivotal global clinical trials and been involved in more than 400 research studies published in high-impact journals.

The Melmed Laboratory focuses on integrating basic science discovery with prospective studies of patients who have pituitary tumors. Many of the more than 90 pre- and post-doctoral scientists who trained with Melmed now hold endocrinology leadership positions in major healthcare organizations around the world.

“Dr. Melmed’s mentorship taught me that my goals were indeed possible, and that my dedication and passion for research could drive my career,” said Maria Chiara Zatelli, MD, PhD, professor of Endocrinology at the University of Ferrara in Italy, who spoke about her experience being mentored by Melmed during the awards ceremony. She trained as a research fellow in Melmed’s laboratory for two years, beginning in 1998. “After my fellowship, he continued to mentor me from a distance, helping me further advance my scientific and academic career.”

Another former mentee, Yona Greenman, MD, now chair of the Institute of Endocrinology, Diabetes, Metabolism and Hypertension at Tel Aviv Sourasky Medical Center in Israel, spent three years as a research fellow in Melmed’s laboratory during the mid-1990s. Under his guidance, Greenman says, she developed skills in basic research and in the field of pituitary disorders that helped spur her career. 

“As a mentee, I learned the importance of original and critical thinking, scientific curiosity, integrity and perseverance,” said Greenman, who is also a professor of the Faculty of Medical and Health Sciences at Tel Aviv University. “Dr. Melmed inspires through personal example. Now, as a mentor myself, I regularly reflect on his caring and the responsibility he assumes for his mentees, and I make every effort to apply this lesson to my own fellows and students.”

Melmed has been a faculty leader at Cedars-Sinai for more than 40 years and has been the health system’s chief academic leader since 1998.

He is an elected member of the Association of American Physicians, the American Society of Clinical Investigation and the Endocrine Society Council. He served as president of the International Society of Endocrinology, president and founding member of the Pituitary Society, and is a member of the California Institute for Regenerative Medicine’s Independent Citizens’ Oversight Committee.

He earned a bachelor of medicine and bachelor of surgery (MB, ChB) with distinction from the University of Cape Town, South Africa. He is a diplomate of the American Board of Internal Medicine, certified in endocrinology and metabolism.

“I was truly humbled and surprised to receive this honor from my peers worldwide and was most proud that so many of my former trainees were present at the ceremony,” Melmed said. “None of our achievements are derived in a vacuum, and I am grateful to my family, fellows, professional colleagues and Cedars-Sinai for decades of inspiring support.”

Read more on the Cedars-Sinai Blog: Growth Hormone Therapy a Potential Risk to Older Adults

A car accident and follow-up CT scan to check for related injuries pinpointed the cause of her symptoms: a rare tumor called a pheochromocytoma in one of her two adrenal glands.

Adrenal glands sit on top of each kidney and produce hormones that control various functions in the body. The pheochromocytoma, a type of adrenal tumor (also called an adrenal nodule or adrenal adenoma), was not cancerous but was producing excess hormones that were causing Paez’s symptoms. Left untreated, pheochromocytomas have the potential to become cancerous and also can produce stress hormones like adrenaline that can lead to a severe increase in blood pressure and risk of heart attack or stroke.

Paez quickly sought out experts in the treatment of adrenal tumors and found Cedars-Sinai specialists Anat Ben-Shlomo, MD, an endocrinologist and associate professor of Medicine, and Yufei Chen, MD, an endocrine surgeon and assistant professor of Surgery in the Department of Surgery. The physicians are co-directors of Cedars-Sinai’s Multidisciplinary Adrenal Program, which offers the complete spectrum of care and treatment for patients with adrenal tumors.

While most adrenal tumors are harmless, some can cause adrenal disorders and symptoms that should be addressed by a skilled team.

“We respond with appropriate treatment recommendations based on each patient’s individual needs,” Chen said. “We collaborate between endocrinology and surgery, and we involve other subspecialties, including genetics, cardiology, pediatrics, pathology, interventional radiology, radiology and oncology, as needed. The multidisciplinary aspect of our program is unique.” 

Ben-Shlomo called the program a “one-stop shop” that benefits both patients and physicians.

“A powerful benefit of our program is that the patient doesn’t need to go all over the place visiting doctors—we have everything required to address an adrenal tumor, and all physicians on the patient’s care team are in constant communication,” she said. “Some patients with adrenal tumors will need treatment and monitoring for the rest of their lives, and we’re here for them for the duration.”

Ben-Shlomo reviewed Paez’s CT scan, ordered bloodwork and a urine test, and referred Paez to Chen to discuss surgery to remove the tumor and alleviate her symptoms.

Paez’s experience—having a noncancerous adrenal tumor discovered incidentally through unrelated imaging—is the norm. And while pheochromocytomas are not common, adrenal tumors overall are being discovered more commonly as people undergo imaging scans more frequently.

“About 4% of all imaging scans reveal an adrenal tumor,” Ben-Shlomo said. “And, because we human beings tend to grow nodules as we get older, that percentage can increase to 10% as we age. That’s a significant amount.”

Most adrenal tumors are “nonfunctioning,” meaning they do not produce excess hormones or cause symptoms. Although nonfunctioning tumors don’t require long-term monitoring, Ben-Shlomo and Chen encourage all patients with an adrenal tumor to be evaluated by a specialist.

“An imaging report will often note a ‘benign-appearing adrenal adenoma,’ and the word ‘benign’ can lead to the tumor being overlooked,” Ben-Shlomo said. “Instead, there is a real need for a functional evaluation by an endocrinologist and perhaps a surgeon. Every tumor should be evaluated for size, shape and functionality because they can lead to serious and sometimes life-threatening diseases. Not all of them need to be removed, but they may need to be monitored in case they grow or symptoms arise.”

By the time Diana Wan found Cedars-Sinai’s Multidisciplinary Adrenal Program, she had been facing infertility, “off-the-charts” high cholesterol, high blood pressure, uncharacteristic weight gain and prediabetes for more than a year. Despite exercising consistently and eating well, her health was not improving. One day she experienced sudden, excruciating, abdominal pain, which led to a CT scan. The scan revealed a benign-appearing adrenal tumor.

Ben-Shlomo diagnosed Wan with adrenal Cushing’s syndrome—a rare disease caused by an adrenal tumor’s production of too much cortisol, a steroid hormone that regulates metabolism, blood pressure, blood sugar, stress and more. Cushing’s syndrome causes many of the symptoms Wan was experiencing, including weight gain, high blood pressure and infertility. 

“You’re so lucky that we found this when we did,” Ben-Shlomo told Wan. “It’s very bad for your body, and it will worsen over time.”

Chen removed Wan’s adrenal gland and today, nearly a year later, she no longer has Cushing’s syndrome. Her experience reinforces the benefits of having every adrenal tumor expertly evaluated.

“A lot of patients have their lives dramatically changed post-surgery,” Chen said. “Just a bit of cortisol over-secretion, for example, can lead to weight gain and metabolic syndrome, which increases the risk of heart disease, diabetes, stroke, bone loss, anxiety and depression. If this is an issue for years, symptoms worsen, leading to early mortality. Aldosterone over-secretion, another adrenal hormone, can lead to hypertension and low potassium and is associated with arrhythmias, sleep apnea and fatigue. When we’re able to remove certain hormone-producing tumors, some patients can be completely cured of related conditions.”

Wan, who continues to see Ben-Shlomo for follow-up monitoring, said, “I had complete trust in my team at Cedars-Sinai throughout the process, and it is comforting to know that I was—and continue to be—in good hands there.”

Paez’s symptoms also improved after surgery. Chen removed her adrenal gland laparoscopically, through tiny incisions in the abdomen, during a minimally invasive procedure known as an adrenalectomy. Her tumor was 6 centimeters—adrenal tumors over 4 centimeters are considered large and have an increased risk of being cancerous. Other removal options include robotic surgery, retroperitoneoscopic “through-the-back” surgery, and subtotal or partial adrenalectomy, which only removes the tumor. Most are done on an outpatient basis.

“The tumor is gone, my bloodwork is normal, and everything is under control,” Paez said. “I’m grateful for Dr. Chen and Dr. Ben-Shlomo, who worked together as a team from my very first appointment and who will continue to monitor me in the coming years.”

Read more on the Cedars-Sinai Blog: Debunking Adrenal Fatigue

The study, published in the peer-reviewed journal Diabetes, found people with higher levels of a bacterium called Coprococcus tended to have higher insulin sensitivity, while those whose microbiomes had higher levels of the bacterium Flavonifractor tended to have lower insulin sensitivity. 

For years, investigators have sought to understand why people develop diabetes by studying the composition of the microbiome, which is a collection of microorganisms that include fungi, bacteria and viruses that live in the digestive tract. The microbiome is thought to be affected by medications and diet. Studies have also found that people who don’t process insulin properly have lower levels of a certain type of bacteria that produce a type of fatty acid called butyrate.

Mark Goodarzi, MD, PhD, the director of the Endocrine Genetics Laboratory at Cedars-Sinai, is leading an ongoing study that is following and observing people at risk for diabetes to learn whether those with lower levels of these bacteria develop the disease. 

 “The big question we're hoping to address is: Did the microbiome differences cause the diabetes, or did the diabetes cause the microbiome differences?” said Goodarzi, who is the senior author of the study and principal investigator of the multicenter study called Microbiome and Insulin Longitudinal Evaluation Study (MILES). 

Investigators involved in MILES have been collecting information from participating Black and non-Hispanic white adults between 40 and 80 years of age since 2018. An earlier cohort study from the MILES trial found that birth by cesarean section is associated with a higher risk for developing prediabetes and diabetes.

For the most recent study to come out of this ongoing trial, investigators analyzed data from 352 people without known diabetes who were recruited from the Wake Forest Baptist Health System in Winston-Salem, North Carolina.

Study participants were asked to attend three clinic visits and collect stool samples prior to the visits. Investigators analyzed data collected at the first visit. They conducted genetic sequencing on the stool samples, for example, to study the participants’ microbiomes, and specifically look for bacteria that earlier studies have found to be associated with insulin resistance. Each participant also filled out a diet questionnaire and took an oral glucose tolerance test, which was used to determine ability to process glucose.

Investigators found 28 people had oral glucose tolerance results that met the criteria for diabetes. They also found that 135 people had prediabetes, a condition in which a person’s blood-sugar levels are higher than normal but not high enough to meet the definition of diabetes. 

The research team analyzed associations between 36 butyrate-producing bacteria found in the stool samples and a person’s ability to maintain normal levels of insulin. They controlled for factors that could also contribute to a person’s diabetes risk, such as age, sex, body mass index and race. Coprococcus and related bacteria formed a network of bacteria with beneficial effects on insulin sensitivity. Despite being a producer of butyrate, Flavonifractor was associated with insulin resistance; prior work by others have found higher levels of Flavonifractor in the stool of people with diabetes. 

Investigators are continuing to study samples from patients who participated in this study to learn how insulin production and the composition of the microbiome change over time. They also plan to study how diet may affect the bacterial balance of the microbiome. 

Goodarzi emphasized, however, that it is too early to know how people can change their microbiome to reduce their diabetes risk.

“As far as the idea of taking probiotics, that would really be somewhat experimental,” said Goodarzi, who is also the Eris M. Field Chair in Diabetes Research at Cedars-Sinai. “We need more research to identify the specific bacteria that we need to be modulating to prevent or treat diabetes, but it's coming, probably in the next five to 10 years.”

Jinrui Cui, a biostatistician in the Goodarzi Laboratory at Cedars-Sinai, was the first author of the study.   

Funding: The study was funded by the National Institutes of Health (R01-DK109588), the National Institute of Diabetes and Digestive and Kidney Disease (P30-DK063491), the National Center for Advancing Translational Sciences (grants UL1TR001420, UL1TR001881). 

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